转录调节因子ATF4对破骨细胞分化的调节
|
摘要
骨骼是一个不断更新的具有多种功能的器官,包括调节钙平衡,支撑软组织提供造血场所等。这些功能是通过骨组织的不管更新,即重塑而完成的。破骨细胞是唯一具有骨吸收能力的多核细胞。破骨细胞来源于定向的髓系前体细胞。多种细胞及其分泌的因子可以调节破骨细胞的分化及功能,尤其是骨髓基质细胞及其分泌的M-CSF和RANKL。过度的骨溶解是多种病理性损伤中的一个重要的临床问题,如癌症骨转移,类风湿关节炎,骨质疏松以及Paget's骨病等。因此临床上需要有效的能抑制骨过度溶解或促进骨生成的治疗方法,以预防或减轻骨质疏松的发生,提高病人的生活质量。过去的十年里,在解析破骨细胞生成方面有许多重要的突破,破骨细胞的分化过程及功能越来越清晰。许多因子在这过程中发挥重要的作用,如M-CSF, RANKL, OPG, PU.1以及MITF等。激活转录因子4(ATF4)是一种重要的转录因子,通过定点突变的方法,ATF4最早被发现对于eye lens纤维的形成至关重要。随后越来越多的研究证明其在成骨细胞的分化及骨形成的过程中发挥着重要的作用。有研究证明ATF4可以通过影响成骨细胞产生RANKL的量来间接调节破骨细胞的分化和骨吸收。但是目前尚未见有关ATF4可以直接调节破骨细胞的分化的研究报道。我们认为ATF4可以直接影响破骨细胞的分化。
首先,我们通过蛋白印迹的方法以及免疫组织化学染色的方法确立了ATF4在破骨细胞系中的表达,并且通过磷酸酶处理的方法,发现了其磷酸化形式的存在。然后我们利用了功能丧失和获得的方法确立了此因子在破骨细胞形成中的直接作用。在Atf4-/-小鼠的骨中,Trap阳性区域所占的比例明显减小,信号强度也减弱；在体外的分化实验中,由Atf4-/-BMM细胞所形成的多核破骨细胞MNCs(大于等于三个核)的数量也显著减少。而且通过骨片溶解吸收实验(Pitassay)可知,在体外由Atf4-/-BMM所形成破骨细胞的骨吸收凹陷数量也明显减少,但是骨吸收凹陷数目与MNCs数目的比值没有明显的变化,说明ATF4敲除后,破骨细胞的骨吸收能力没有明显改变。在由破骨细胞特异的Trap启动子驱动下,使ATF4在破骨细胞中转基因过表达时,转基因小鼠呈现出明显的骨减少症；血清CTX的水平大幅度升高；破骨细胞的形成在体内和体外都有显著增加,并且与破骨细胞分化相关的基因的表达水平,不论是蛋白水平还是mRNA水平都显著上调。
进一步研究发现,由Atf4-/-小鼠的骨髓细胞所形成的GM-CFU的集落数量也明显少于野生型对照组,GM-CFU是具有向破骨细胞分化能力的最原始的造血前体细胞。
将Atf4-/-BMM细胞与野生型的成骨细胞共培养或用高浓度的RANKL来刺激其分化,都不能弥补其向破骨细胞分化的缺陷。RANKL的信号是由其受体RANK来传递的。我们通过免疫组织化学染色的方法以及免疫印迹方法发现,在Atf4-/-BMM细胞中,RANK的表达显著降低,并且其mRNA水平也不能被M-CSF所上调。此外RANKL对多条MAPK信号通路的诱导激活也受ATF4的调节。在缺乏ATF4的状态下,RANKL对于三条MAPK的通路的激活能力明显下降,而NF-kB途径、PI3K/Akt途径却不受影响。但是,ATF4对于M-CSF的信号却没有明显的调节作用。
到目前为止,NFATcl是破骨细胞分化的最关键基因。无论是在体内还是在体外,ATF4的缺乏都导致NFATcl的表达水平明显下降。用逆转录病毒为载体,使NFATcl在ATF4WT和KO BMM中过表达,可以以剂量依赖性的方式使Trap阳性的MNCs增多。我们利用腺病毒作为载体,在BMM细胞中过表达ATF4,发现ATF4可以以剂量依赖性的方式上调NFATcl蛋白的表达水平。在体外,ATF4可以与NFATcl的启动子结合并能剂量依赖性的激活NFATcl (?)勺启动子,另外,通过ChIP assay的方法可以发现ATF4可以与NFATcl近启动子端的片段相作用并且该作用可以在RANKL的诱导下增强。在BMM细胞中,ATF4的蛋白水平受M-CSF以及PI3K/AKT途径的调节。在缺乏M-CSF的情况下,ATF4的蛋白水平以时间依赖性的方式明显减少,M-CSF可以阻断这一进程。M-CSF的这一作用可以被PI3K/Akt途径的抑制剂LY294002阻断,并且随着LY2094002的浓度的增高,BMM细胞向破骨细胞的分化也相应的受抑制。ATF4的缺乏可以使BMM的分化由破骨细胞系向巨噬细胞系迁移,导致巨噬细胞数量的增多。我们的研究结果证明ATF4在调节破骨细胞分化方面有着重要的内在作用,这也许可以作为治疗与破骨细胞相关的骨疾病的治疗靶点。
Bone is a dynamic organ that exhibits multiple functions that include the regulation of calcium levels, providing mechanical support to soft tissues, housing the central nervous system, and supporting hematopoiesis. These functions are accomplished by continuous tissue renewal, called bone remodeling. The osteoclast is a unique bone-resorbing cell which contains multiple nuclei, derived from committed myeloid progenitors. Their differentiation and function are regulated by a number of other cells and their products, especially by RANKL and M-CSF, which are secreted by bone marrow stromal cells and osteoblasts. Excessive osteolysis is an important clinical problem in many common lesions, including cancer metastases in bone, rheumatoid arthritis, and implanted joint prosthesis failure, as well as metabolic diseases such as Paget's disease of bone and osteoporosis. Therefore, new therapeutic strategies are urgently needed to efficiently inhibit excessive osteolysis or promote bone formation, furthermore to prevent or alleviate osteoporosis formation and to improve the quality of patients' life. During the past decade, many major breakthroughs have been made in understanding osteoclast differentiation; the process of osteoclast differentiation and its function have become clearer. Many factors have important roles during this process including M-CSF, RANKL, OPG and MITF etc. Activating transcription factor4(ATF4) is an important transcription factor, which is firstly found to be crucial in eye lens fiber formation through site-specific mutagenesis. Later on, more and more evidence showed that it is critical for osteoblast differentiation and bone formation. It has been reported that ATF4regulates osteoclast differentiation and ultimately bone resorption through its expression in osteoblasts and regulation of the production of RANKL. But no one shows that ATF4can directly affect osteoclast differentiation.
Our hypothesis is that ATF4can directly regulate osteoclast differentiation.
First, we confirmed that ATF4protein was expressed and phosphorylated in primary mouse bone marrow monocytes (BMMs). Then loss-and gain-of-function approaches were used to establish a direct role of this factor in osteoclast differentiation. In the bone of Atf4-/-mice, the percentage of TRAP positive area is drastically decreased and the signal is weaker. When cultured in vitro differentiation system, the number of TRAP positive multiple nucleated cells (MNCs)(>3nuclei) in Atf4-/-group is dramatically decreased than in WT group. Furthermore, we found the bone resorption ability is not impaired in At/4-/-osteoclast in vitro. Conversely, transgenic over-expression of ATF4driven by an OCL-specific Trap promoter dramatically increased osteoclastogenesis in vitro and in vivo, transgenic mice had a severe osteopenic phenotype, serum level of CTX, an indicator of in vivo osteoclast activity, was dramatically elevated and the expression of most of genes related to osteoclast differentiation are up-regulated both at mRNA level and protein level.
What's more, the formation of the granulocyte-macrophage colony forming units (GM-CFUs) colony is also severely compromised in At/4-/-bone marrow cell cultures. GM-CFU is the earliest identifiable hematopoietic precursor able to form osteoclasts. Coculture with wt osteoblasts or high concentration of RANKL failed to restore the OCL differentiation defect in Atf4-/-BMM cultures. As the cellular effects of RANKL are mediated by its receptor RANK, we then determined the level of RANK in ATF4WT and KO BMM by IHC and Western blot, and we found the RANK expression is dramatically reduced in the absence of ATF4, and its mRNA level couldn't be upregulated by M-CSF. ATF4is critical for RANKL to activate multiple MAPK pathways in OCL progenitors. Lack of ATF4compromised RANKL-induced activation of MAPK pathways. In contrast, no difference was seen in RANKL activation of NF-kB and PI3K/Akt pathways. ATF4deficiency did not markedly affect M-CSF signaling in BMMs.
Till now, NFATcl is the most important master regulator of osteoclast differentiation. The expression of NFATcl is dramatically reduced in the deficiency of ATF4both in vitro and in vivo. Over expression of NFATcl by retrovirus vector in wt and Atf4-/-BMMs can dose-dependently increase the number of TRAP-positive MNCs in Atf4-/-BMM cultures. Over expression of ATF4by adenovirus vector in BMMs can increase the expression of NFATcl dose-dependently. And we then found that ATF4activate the Nfatcl promoter in a dose-dependent manner in vitro; also, ATF4can interact with a chromatin fragment of the proximal Nfatcl promoter in RAW264.7osteoclast-like cells by chromatin immunoprecipitation (ChIP) assays and this interaction was greatly stimulated by RANKL.
ATF4is regulated by M-CSF and PI3K/Akt pathway in BMMs. The level of ATF4protein was dramatically edueed-in the absence of M-CSF in a time-dependent manner. However, this reduction was completely blocked by M-CSF. LY294002, a specific inhibitor of the PI3K/AKT pathway, dramatically reduced total and phospho-ATF4in the presence of M-CSF. Importantly, exposure to LY294002for only24h prior to the addition of differentiation media inhibited in vitro OCL differentiation in a dose-dependent manner.
The lack of ATF4causes a lineage shift between OCLs and macrophages, resulting in an increase in macrophages.
Our results demonstrate that ATF4plays an intrinsic role in regulating osteoclast differentiation and may provide therapeutic target for treating osteoclast-based or involved bone diseases.
首先,我们通过蛋白印迹的方法以及免疫组织化学染色的方法确立了ATF4在破骨细胞系中的表达,并且通过磷酸酶处理的方法,发现了其磷酸化形式的存在。然后我们利用了功能丧失和获得的方法确立了此因子在破骨细胞形成中的直接作用。在Atf4-/-小鼠的骨中,Trap阳性区域所占的比例明显减小,信号强度也减弱；在体外的分化实验中,由Atf4-/-BMM细胞所形成的多核破骨细胞MNCs(大于等于三个核)的数量也显著减少。而且通过骨片溶解吸收实验(Pitassay)可知,在体外由Atf4-/-BMM所形成破骨细胞的骨吸收凹陷数量也明显减少,但是骨吸收凹陷数目与MNCs数目的比值没有明显的变化,说明ATF4敲除后,破骨细胞的骨吸收能力没有明显改变。在由破骨细胞特异的Trap启动子驱动下,使ATF4在破骨细胞中转基因过表达时,转基因小鼠呈现出明显的骨减少症；血清CTX的水平大幅度升高；破骨细胞的形成在体内和体外都有显著增加,并且与破骨细胞分化相关的基因的表达水平,不论是蛋白水平还是mRNA水平都显著上调。
进一步研究发现,由Atf4-/-小鼠的骨髓细胞所形成的GM-CFU的集落数量也明显少于野生型对照组,GM-CFU是具有向破骨细胞分化能力的最原始的造血前体细胞。
将Atf4-/-BMM细胞与野生型的成骨细胞共培养或用高浓度的RANKL来刺激其分化,都不能弥补其向破骨细胞分化的缺陷。RANKL的信号是由其受体RANK来传递的。我们通过免疫组织化学染色的方法以及免疫印迹方法发现,在Atf4-/-BMM细胞中,RANK的表达显著降低,并且其mRNA水平也不能被M-CSF所上调。此外RANKL对多条MAPK信号通路的诱导激活也受ATF4的调节。在缺乏ATF4的状态下,RANKL对于三条MAPK的通路的激活能力明显下降,而NF-kB途径、PI3K/Akt途径却不受影响。但是,ATF4对于M-CSF的信号却没有明显的调节作用。
到目前为止,NFATcl是破骨细胞分化的最关键基因。无论是在体内还是在体外,ATF4的缺乏都导致NFATcl的表达水平明显下降。用逆转录病毒为载体,使NFATcl在ATF4WT和KO BMM中过表达,可以以剂量依赖性的方式使Trap阳性的MNCs增多。我们利用腺病毒作为载体,在BMM细胞中过表达ATF4,发现ATF4可以以剂量依赖性的方式上调NFATcl蛋白的表达水平。在体外,ATF4可以与NFATcl的启动子结合并能剂量依赖性的激活NFATcl (?)勺启动子,另外,通过ChIP assay的方法可以发现ATF4可以与NFATcl近启动子端的片段相作用并且该作用可以在RANKL的诱导下增强。在BMM细胞中,ATF4的蛋白水平受M-CSF以及PI3K/AKT途径的调节。在缺乏M-CSF的情况下,ATF4的蛋白水平以时间依赖性的方式明显减少,M-CSF可以阻断这一进程。M-CSF的这一作用可以被PI3K/Akt途径的抑制剂LY294002阻断,并且随着LY2094002的浓度的增高,BMM细胞向破骨细胞的分化也相应的受抑制。ATF4的缺乏可以使BMM的分化由破骨细胞系向巨噬细胞系迁移,导致巨噬细胞数量的增多。我们的研究结果证明ATF4在调节破骨细胞分化方面有着重要的内在作用,这也许可以作为治疗与破骨细胞相关的骨疾病的治疗靶点。
Bone is a dynamic organ that exhibits multiple functions that include the regulation of calcium levels, providing mechanical support to soft tissues, housing the central nervous system, and supporting hematopoiesis. These functions are accomplished by continuous tissue renewal, called bone remodeling. The osteoclast is a unique bone-resorbing cell which contains multiple nuclei, derived from committed myeloid progenitors. Their differentiation and function are regulated by a number of other cells and their products, especially by RANKL and M-CSF, which are secreted by bone marrow stromal cells and osteoblasts. Excessive osteolysis is an important clinical problem in many common lesions, including cancer metastases in bone, rheumatoid arthritis, and implanted joint prosthesis failure, as well as metabolic diseases such as Paget's disease of bone and osteoporosis. Therefore, new therapeutic strategies are urgently needed to efficiently inhibit excessive osteolysis or promote bone formation, furthermore to prevent or alleviate osteoporosis formation and to improve the quality of patients' life. During the past decade, many major breakthroughs have been made in understanding osteoclast differentiation; the process of osteoclast differentiation and its function have become clearer. Many factors have important roles during this process including M-CSF, RANKL, OPG and MITF etc. Activating transcription factor4(ATF4) is an important transcription factor, which is firstly found to be crucial in eye lens fiber formation through site-specific mutagenesis. Later on, more and more evidence showed that it is critical for osteoblast differentiation and bone formation. It has been reported that ATF4regulates osteoclast differentiation and ultimately bone resorption through its expression in osteoblasts and regulation of the production of RANKL. But no one shows that ATF4can directly affect osteoclast differentiation.
Our hypothesis is that ATF4can directly regulate osteoclast differentiation.
First, we confirmed that ATF4protein was expressed and phosphorylated in primary mouse bone marrow monocytes (BMMs). Then loss-and gain-of-function approaches were used to establish a direct role of this factor in osteoclast differentiation. In the bone of Atf4-/-mice, the percentage of TRAP positive area is drastically decreased and the signal is weaker. When cultured in vitro differentiation system, the number of TRAP positive multiple nucleated cells (MNCs)(>3nuclei) in Atf4-/-group is dramatically decreased than in WT group. Furthermore, we found the bone resorption ability is not impaired in At/4-/-osteoclast in vitro. Conversely, transgenic over-expression of ATF4driven by an OCL-specific Trap promoter dramatically increased osteoclastogenesis in vitro and in vivo, transgenic mice had a severe osteopenic phenotype, serum level of CTX, an indicator of in vivo osteoclast activity, was dramatically elevated and the expression of most of genes related to osteoclast differentiation are up-regulated both at mRNA level and protein level.
What's more, the formation of the granulocyte-macrophage colony forming units (GM-CFUs) colony is also severely compromised in At/4-/-bone marrow cell cultures. GM-CFU is the earliest identifiable hematopoietic precursor able to form osteoclasts. Coculture with wt osteoblasts or high concentration of RANKL failed to restore the OCL differentiation defect in Atf4-/-BMM cultures. As the cellular effects of RANKL are mediated by its receptor RANK, we then determined the level of RANK in ATF4WT and KO BMM by IHC and Western blot, and we found the RANK expression is dramatically reduced in the absence of ATF4, and its mRNA level couldn't be upregulated by M-CSF. ATF4is critical for RANKL to activate multiple MAPK pathways in OCL progenitors. Lack of ATF4compromised RANKL-induced activation of MAPK pathways. In contrast, no difference was seen in RANKL activation of NF-kB and PI3K/Akt pathways. ATF4deficiency did not markedly affect M-CSF signaling in BMMs.
Till now, NFATcl is the most important master regulator of osteoclast differentiation. The expression of NFATcl is dramatically reduced in the deficiency of ATF4both in vitro and in vivo. Over expression of NFATcl by retrovirus vector in wt and Atf4-/-BMMs can dose-dependently increase the number of TRAP-positive MNCs in Atf4-/-BMM cultures. Over expression of ATF4by adenovirus vector in BMMs can increase the expression of NFATcl dose-dependently. And we then found that ATF4activate the Nfatcl promoter in a dose-dependent manner in vitro; also, ATF4can interact with a chromatin fragment of the proximal Nfatcl promoter in RAW264.7osteoclast-like cells by chromatin immunoprecipitation (ChIP) assays and this interaction was greatly stimulated by RANKL.
ATF4is regulated by M-CSF and PI3K/Akt pathway in BMMs. The level of ATF4protein was dramatically edueed-in the absence of M-CSF in a time-dependent manner. However, this reduction was completely blocked by M-CSF. LY294002, a specific inhibitor of the PI3K/AKT pathway, dramatically reduced total and phospho-ATF4in the presence of M-CSF. Importantly, exposure to LY294002for only24h prior to the addition of differentiation media inhibited in vitro OCL differentiation in a dose-dependent manner.
The lack of ATF4causes a lineage shift between OCLs and macrophages, resulting in an increase in macrophages.
Our results demonstrate that ATF4plays an intrinsic role in regulating osteoclast differentiation and may provide therapeutic target for treating osteoclast-based or involved bone diseases.
引文
[1]Yeo, H., et al., NFATcl:a novel anabolic therapeutic target for osteoporosis. Ann N Y Acad Sci,2006.1068:p.564-7.
[2]Peppone, L.J., et al., The efficacy of calcitriol therapy in the management of bone loss and fractures:a qualitative review. Osteoporos Int,2009.
[3]Virk, M.S. et al., Tumor metastasis to bone. Arthritis Res Ther,2007.9 Suppl l:p. S5.
[4]Roodman, G.D., Regulation of osteoclast differentiation. Ann N Y Acad Sci, 2006.1068:p.100-9.
[5]Boyle, W.J., et al., Osteoclast differentiation and activation. Nature,2003. 423(6937):p.337-42.
[6]Hong, J.W., et al., Oral bisphosphonate-related osteonecrosis of the jaw:the first report in Asia. Osteoporos Int,2009.
[7]Ash, P., et al., Osteoclasts derived from haematopoietic stem cells. Nature, 1980.283(5748):p.669-70.
[8]Tondravi, M.M., et al., Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature,1997.386(6620):p.81-4.
[9]Felix, R., et al., Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology,1990.127(5):p. 2592-4.
[10]Grigoriadis, A.E., et al., c-Fos:a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science,1994.266(5184):p. 443-8.
[11]Lacey, D.L., et al., Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell,1998.93(2):p.165-76.
[12]Li,J., et al.,RANK is the-intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A,2000.97(4):p.1566-71.
[13]Lomaga, M.A., et al., TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev,1999.13(8):p.1015-24.
[14]Wei, S., et al., Receptor activator of nuclear factor-kappa b ligand activates nuclear factor-kappa b in osteoclast precursors. Endocrinology,2001.142(3): p.1290-5.
[15]Soriano, P., et al., Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell,1991.64(4):p.693-702.
[16]Gelb, B.D., et al., Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science,1996.273(5279):p.1236-8.
[17]Hollberg, K., et al., Osteoclasts from mice deficient in tartrate-resistant acid phosphatase have altered ruffled borders and disturbed intracellular vesicular transport. Exp Cell Res,2002.279(2):p.227-38.
[18]Lee, S.H., et al., v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat Med,2006.12(12):p. 1403-9.
[19]Takayanagi, H., The role of NFAT in osteoclast formation. Ann N Y Acad Sci, 2007.1116:p.227-37.
[20]Iotsova, V., et al., Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med,1997.3(11):p.1285-9.
[21]Yamashita, T., et al., NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATcl. J Biol Chem,2007. 282(25):p.18245-53.
[22]Matsuo, K., et al., Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem,2004.279(25):p. 26475-80.
[23]Takayanagi, H., et al., Induction and activation of the transcription factor NFATcl (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell,2002.3(6):p.889-901.
[24]Schoch, S., et al., Modular structure of cAMP response element binding protein 2 (CREB2). Neurochem Int,2001.38(7):p.601-8.
[25]Xiao, G., et al., Cooperative interactions between activating transcription factor 4 and Runx2/Cbfal stimulate osteoblast-specific osteocalcin gene expression. J Biol Chem,2005.280(35):p.30689-96.
[26]Tanaka, T., et al., Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres. Genes Cells,1998.3(12):p.801-10.
[27]Masuoka, H.C., et al., Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood,2002.99(3):p.736-45.
[28]Song, H., et al., Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. J Biol Chem,2008.283(52):p.36687-97.
[29]Yang, X., et al., ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell,2004. 117(3):p.387-98.
[30]Elefteriou, F., et al., Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature,2005.434(7032):p.514-20.
[31]Yu, S., et. al., Parathyroid hormone increases activating transcription factor 4 expression and activity in osteoblasts:requirement for osteocalcin gene expression. Endocrinology,2008.149(4):p.1960-8.
[32]Yu, S., et al., Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone. PLoS One,2009.4(10):p. e7583.
[33]Seo, J., et al., Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes,2009.58(11):p.2565-73.
[34]Hinoi, E., et al., An Osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion. Ann N Y Acad Sci,2009.1173 Suppl 1:p. E20-30.
[35]Elefteriou, F., et al., ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab,2006.4(6):p. 441-51.
[36]Zhang, X., et al., Activating transcription factor 4 is critical for proliferation and survival in primary bone marrow stromal cells and calvarial osteoblasts. J Cell Biochem,2008.105(3):p.885-95.
[37]Yang, X., et al., ATF4, the osteoblast accumulation of which is determined post-translationally, can induce osteoblast-specific gene expression in non-osteoblastic cells. J Biol Chem,2004.279(45):p.47109-14.
[38]Begg, S.K., et al., Delayed hematopoietic development in osteopetrotic (op/op) mice. J Exp Med,1993.177(1):p.237-42.
[39]Yavropoulou, M.P., et al., Osteoclastogenesis--current knowledge and future perspectives. J Musculoskelet Neuronal Interact,2008.8(3):p.204-16.
[40]Anderson, T.R., et al., Effect of Fe2+ and ascorbic acid on acid phosphatases from rat bone. Calcif Tissue Int,1982.34(1):p.54-8.
[41]Marks, S.C., Jr., et al., Tartrate-resistant acid phosphatase in mononuclear and multinuclear cells during the bone resorption of tooth eruption. J Histochem Cytochem,1987.35(11):p.1227-30.
[42]Hamilton, J.A., CSF-1 signal transduction. J Leukoc Biol,1997.62(2):p. 145-55.
[43]Felix, R., et al., Impairment of macrophage colony-stimulating factor production and lack of resident bone marrow macrophages in the osteopetrotic op/op mouse. J Bone Miner Res,1990.5(7):p.781-9.
[44]Wiktor-Jedrzejczak, W., et al., Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A,1990.87(12):p.4828-32.
[45]McKercher, S.R., et al., Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J,1996.15(20):p.5647-58.
[46]Jack, G.D., et al., M-CSF elevates c-Fos and phospho-C/EBPalpha(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification. Blood,2009.114(10):p. 2172-80.
[47]Yasuda, H., et al., Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A,1998.95(7):p.3597-602.
[48]Sundaram, K., et al., RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Exp Cell Res,2007.313(1):p.168-78.
[49]Troen, B.R., The regulation of cathepsin K gene expression. Ann N Y Acad Sci,2006.1068:p.165-72.
[50]Crotti, T.N., et al., NFATcl directly induces the human beta3 integrin gene in osteoclast differentiation. J Musculoskelet Neuronal Interact,2005.5(4):p. 335-7.
[51]So, H., et al., Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. J Biol Chem,2003.278(26):p.24209-16.
[52]Kim, K., et al., MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood,2007.109(8):p.3253-9.
[53]Yu, M., et al., Complex regulation of tartrate-resistant acid phosphatase (TRAP) expression by interleukin 4 (IL-4):IL-4 indirectly suppresses receptor activator of NF-kappaB ligand (RANKL)-mediated TRAP expression but modestly induces its expression directly. J Biol Chem,2009.284(47):p. 32968-79.
[54]Kim, K., et al., NFATcl induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol Endocrinol,2008.22(1):p.176-85.
[55]Ishida, N., et al., Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J Biol Chem,2002.277(43): p.41147-56.
[56]Sun, L., et al., Evidence that calcineurin is required for the genesis of bone-resorbing osteoclasts. Am J Physiol Renal Physiol,2007.292(1):p. F285-91.
[57]Macian, F., et al., Partners in transcription:NFAT and AP-1. Oncogene,2001. 20(19):p.2476-89.
[58]Asagiri, M., et al., Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med,2005.202(9):p.1261-9.
[59]Hai, T., et al., Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci U S A,1991. 88(9):p.3720-4.
[60]Kato, Y., et al., Presence of activating transcription factor 4 (ATF4) in the porcine anterior pituitary. Mol Cell Endocrinol,1999.154(1-2):p.151-9.
[61]Matsumoto, M., et al., Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATcl and PU.1. J Biol Chem,2004.279(44):p.45969-79.
[62]Yavropoulou, M.P., et al., Osteoclastogenesis-Current knowledge and future perspectives. J Musculoskelet Neuronal Interact,2008.8(3):p.204-16.
[63]Ikeda, F., et al., Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest,2004.114(4): p.475-84.
[64]Chinenov, Y., et al., Close encounters of many kinds:Fos-Jun interactions that mediate transcription regulatory specificity. Oncogene,2001.20(19):p. 2438-52.
[65]Fuller, K., et al., Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts. J Exp Med,1993.178(5):p. 1733-44.
[66]Otero, K., et al., Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP 12 and beta-catenin. Nat Immunol,2009.10(7):p.734-43.
[67]Arai, F., et al., Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med,1999.190(12):p.1741-54.
[68]Curry, J.M., et al., M-CSF signals through the MAPK/ERK pathway via Spl to induce VEGF production and induces angiogenesis in vivo. PLoS One, 2008.3(10):p. e3405.
[69]Chang, M., et al., Phosphatidylinostitol-3 kinase and phospholipase C enhance CSF-1-dependent macrophage survival by controlling glucose uptake. Cell Signal,2009.21(9):p.1361-9.
[70]Sugatani, T., et al., Aktl/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem,2005.280(5):p.3583-9.
[71]Kawamura, N., et al., Regulation of bone mass by PI3 kinase/Akt signaling. Nippon Rinsho,2007.65 Suppl 9:p.67-70.
[72]Yang, F.C., et al., Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. J Clin Invest,2006.116(11):p.2880-91.
[73]Kuorilehto, T., et al., Decreased bone mineral density and content in neurofibromatosis type 1:lowest local values are located in the load-carrying parts of the body. Osteoporos Int,2005.16(8):p.928-36.
[74]Lammert, M., et al., Decreased bone mineral density in patients with neurofibromatosis 1. Osteoporos Int,2005.16(9):p.1161-6.
[75]Illes, T., et al., Decreased bone mineral density in neurofibromatosis-1 patients with spinal deformities. Osteoporos Int,2001.12(10):p.823-7.
[76]Halmai, V., et al., [Decreased bone mineral density as a risk factor in the development of spinal deformities in neurofibromatosis]. Orv Hetil,2001. 142(52):p.2893-7.
[77]Yan, J., et al., Racl mediates the osteoclast gains-in-function induced by haploinsufficiency of Nfl. Hum Mol Genet,2008.17(7):p.936-48.
[78]Krysinska, H., et al., A two-step, PU.1-dependent mechanism for developmentally regulated chromatin remodeling and transcription of the c-fins gene. Mol Cell Biol,2007.27(3):p.878-87.
[1]Roodman, G.D., Cell biology of the osteoclast. Exp Hematol,1999.27(8):p. 1229-41.
[2]Vaananen, H.K., et al., Osteoclast lineage and function. Arch Biochem Biophys,2008.473(2):p.132-8.
[3]Quinn, J.M., et al., Modulation of osteoclast formation. Biochem Biophys Res Commun,2005.328(3):p.739-45.
[4]Klemsz, M.J., et al., The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell,1990.61(1):p.113-24.
[5]Krysinska, H., et al., A two-step, PU.1-dependent mechanism for developmentally regulated chromatin remodeling and transcription of the c-fms gene. Mol Cell Biol,2007.27(3):p.878-87.
[6]DeKoter, R.P., et al.,, PU.1 regulates both cytokine-dependent proliferation and differentiation of granulocyte/macrophage progenitors. EMBO J,1998. 17(15):p.4456-68.
[7]Tondravi, M.M., et al., Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature,1997.386(6620):p.81-4.
[8]Kwon, O.H., et al., The hematopoietic transcription factor PU.1 regulates RANK gene expression in myeloid progenitors. Biochem Biophys Res Commun,2005.335(2):p.437-46.
[9]Ishii, J., et al., Lipopolysaccharide suppresses RANK gene expression in macrophages by down-regulating PU.l and MITF. J Cell Biochem,2008. 105(3):p.896-904.
[10]Crotti, T.N., et al., PU.1 and NFATcl mediate osteoclastic induction of the mouse beta3 integrin promoter. J Cell Physiol,2008.215(3):p.636-44.
[11]So, H., et al., Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. J Biol Chem,2003.278(26):p.24209-16.
[12]Mansky, K.C., et al., The microphthalmia transcription factor (MITF) contains two N-terminal domains required for transactivation of osteoclast target promoters and rescue of mi mutant osteoclasts. J Leukoc Biol,2002.71(2):p. 295-303.
[13]Hu, R., et al., Eos, MITF, and PU.1 recruit corepressors to osteoclast-specific genes in committed myeloid progenitors. Mol Cell Biol,2007.27(11):p. 4018-27.
[14]Sharma, S.M., et al., MITF and PU.1 recruit p38 MAPK and NFATcl to target genes during osteoclast differentiation. J Biol Chem,2007.282(21):p. 15921-9.
[15]Otero, K., et al., Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP 12 and beta-catenin. Nat Immunol,2009.10(7):p.734-43.
[16]Curry, J.M., et al., M-CSF signals through the MAPK/ERK pathway via Spl to induce VEGF production and induces angiogenesis in vivo. PLoS One, 2008.3(10):p. e3405.
[17]Jack, G.D., et al.,, M-CSF elevates c-Fos and phospho-C/EBPalpha(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification. Blood,2009.114(10):p. 2172-80.
[18]Chang, M., et al., Phosphatidylinostitol-3 kinase and phospholipase C enhance CSF-1-dependent macrophage survival by controlling glucose uptake. Cell Signal,2009.21(9):p.1361-9.
[19]Felix, R., et al., Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology,1990.127(5):p. 2592-4.
[20]Wiktor-Jedrzejczak, W., et al., Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A,1990.87(12):p.4828-32.
[21]Fuller, K., et al., Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts. J Exp Med,1993.178(5):p. 1733-44.
[22]Arai, F., et al., Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med,1999.190(12):p.1741-54.
[23]Begg, S.K., et al., Delayed hematopoietic development in osteopetrotic (op/op) mice. J Exp Med,1993.177(1):p.237-42.
[24]Faccio, R., et al., Localization and possible role of two different alpha v beta 3 integrin conformations in resting and resorbing osteoclasts. J Cell Sci,2002. 115(Pt 14):p.2919-29.
[25]Faccio, R., et al., c-Fms and the alphavbeta3 integrin collaborate during osteoclast differentiation. J Clin Invest,2003.111(5):p.749-58.
[26]Elsegood, C.L., et al., M-CSF induces the stable interaction of cFms with alphaVbeta3 integrin in osteoclasts. Int J Biochem Cell Biol,2006.38(9):p. 1518-29.
[27]Dai, X.M., et al., Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood,2002.99(1):p.111-20.
[28]Nakamura, I., et al., Involvement of alpha(v)beta3 integrins in osteoclast function. J Bone Miner Metab,2007.25(6):p.337-44.
[29]Schoch, S., et al., Modular structure of cAMP response element binding protein 2 (CREB2). Neurochem Int,2001.38(7):p.601-8.
[30]Xiao, G., et al., Cooperative interactions between activating transcription factor 4 and Runx2/Cbfal stimulate osteoblast-specific osteocalcin gene expression. J Biol Chem,2005.280(35):p.30689-96.
[31]Tanaka, T., et al., Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres. Genes Cells,1998.3(12):p.801-10.
[32]Masuoka, H.C., et al.,, Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood,2002.99(3):p. 736-45.
[33]Song, H., et al., Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. J Biol Chem,2008.283(52):p.36687-97.
[34]Yang, X., et al., ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell,2004. 117(3):p.387-98.
[35]Elefteriou, F., et al., Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature,2005.434(7032):p.514-20.
[36]Yu, S., et al., Parathyroid hormone increases activating transcription factor 4 expression and activity in osteoblasts:requirement for osteocalcin gene expression. Endocrinology,2008.149(4):p.1960-8.
[37]Yu, S., et al., Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone. PLoS One,2009.4(10):p. e7583.
[38]Seo, J., et al., Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes,2009.58(11):p.2565-73.
[39]Hinoi, E., et al., An Osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion. Ann N Y Acad Sci,2009.1173 Suppl 1:p. E20-30.
[40]Elefteriou, F., et al., ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab,2006.4(6):p. 441-51.
[41]Matsumoto, M., et al., Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATcl and PU.1. J Biol Chem,2004.279(44):p.45969-79.
[42]Yavropoulou, M.P., et al., Osteoclastogenesis-Current knowledge and future perspectives. J Musculoskelet Neuronal Interact,2008.8(3):p.204-16.
[43]Ikeda, F., et al., Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest,2004.114(4): p.475-84.
[44]Yang, X., et al., ATF4, the osteoblast accumulation of which is determined post-translationally, can induce osteoblast-specific gene expression in non-osteoblastic cells. J Biol Chem,2004.279(45):p.47109-14.
[45]Sugatani, T., et al., Aktl/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem,2005.280(5):p.3583-9.
[46]Kawamura, N., et al., Regulation of bone mass by PI3 kinase/Akt signalin. Nippon Rinsho,2007.65 Suppl 9:p.67-70.
[47]Yang, F.C., et al., Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. J Clin Invest,2006.116(11):p.2880-91.
[48]Yasuda, H., et al., Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A,1998.95(7):p.3597-602.
[49]Kong, Y.Y., et al., OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature,1999.397(6717):p. 315-23.
[50]Rho, J., et al., Osteoimmunology:interactions of the immune and skeletal systems. Mol Cells,2004.17(1):p.1-9.
[51]Sankar, U., et al., RANKL coordinates cell cycle withdrawal and differentiation in osteoclasts through the cyclin-dependent kinase inhibitors p27KIP1 and p21CIP1.J Bone Miner Res,2004.19(8):p.1339-48.
[52]Sundaram, K., et al., FGF-2 stimulation of RANK ligand expression in Paget's disease of bone. Mol Endocrinol,2009.23(9):p.1445-54.
[53]Li, P., et al., RANK signaling is not required for TNFalpha-mediated increase in CD 11 (hi) osteoclast precursors but is essential for mature osteoclast formation in TNFalpha-mediated inflammatory arthritis. J Bone Miner Res, 2004.19(2):p.207-13.
[54]Kanazawa, K., et al., Self-assembled RANK induces osteoclastogenesis ligand-independently. J Bone Miner Res,2005.20(11):p.2053-60.
[55]Taguchi, Y, et al., A unique domain in RANK is required for Gab2 and PLCgamma2 binding to establish osteoclastogenic signals. Genes Cells,2009. 14(11):p.1331-45.
[56]Shinohara, M., et al., Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell,2008.132(5):p. 794-806.
[57]Islam, S., et al., Receptor activator of nuclear factor-kappa B ligand induces osteoclast formation in RAW 264.7 macrophage cells via augmented production of macrophage-colony-stimulating factor. Microbiol Immunol, 2008.52(12):p.585-90.
[58]Horowitz, M.C., et al., Control of osteoclastogenesis and bone resorption by members of the TNF family of receptors and ligands. Cytokine Growth Factor Rev,2001.12(1):p.9-18.
[59]Simonet, W.S., et al., Osteoprotegerin:a novel secreted protein involved in the regulation of bone density. Cell,1997.89(2):p.309-19.
[60]Boyce, B.F., et al., TNF-alpha and pathologic bone resorption. Keio J Med, 2005.54(3):p.127-31.
[61]Kobayashi, K., et al., Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med,2000.191(2):p.275-86.
[62]Azuma, Y., et al., Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem,2000.275(7):p.4858-64.
[63]Mormann, M., et al., Lipopolysaccharides (LPS) induce the differentiation of human monocytes to osteoclasts in a tumour necrosis factor (TNF) alpha-dependent manner:a link between infection and pathological bone resorption. Mol Immunol,2008.45(12):p.3330-7.
[64]Arai, S., et al., Osteoclastogenesis-related antigen, a novel molecule on mouse stromal cells, regulates osteoclastogenesis. J Bone Miner Res,2003.18(4):p. 686-95.
[65]Kim, N., et al., A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med,2002.195(2):p.201-9.
[66]Herman, S., et al., Induction of osteoclast-associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis. Arthritis Rheum,2008.58(10): p.3041-50.
[67]Yamada, T., et al., Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells. Blood,2003. 101(6):p.2227-34.
[68]Bai, S., et al., NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem,2008. 283(10):p.6509-18.
[69]Fukushima, H., et al., The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Mol Cell Biol,2008.28(20):p.6402-12.
[70]Naito, A., et al., Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells,1999.4(6): p.353-62.
[71]Lomaga, M.A., et al., TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev,1999.13(8):p.1015-24.
[72]Kaji, K., et al., Tumor necrosis factor alpha-induced osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6. J Bone Miner Res, 2001.16(9):p.1593-9.
[73]Asagiri, M., et al., The molecular understanding of osteoclast differentiation. Bone,2007.40(2):p.251-64.
[74]Kobayashi, N., et al., Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J,2001.20(6):p.1271-80.
[75]Wu, H., et al., TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays,2003.25(11):p.1096-105.
[76]Bai, S., et al., Tumor necrosis factor receptor-associated factor 6 is an intranuclear transcriptional coactivator in osteoclasts. J Biol Chem,2008. 283(45):p.30861-7.
[77]Bai, S., et al., FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner. J Clin Invest,2005.115(10):p.2742-51.
[78]Kanazawa, K., et al., TRAF5 functions in both RANKL-and TNFalpha-induced osteoclastogenesis. J Bone Miner Res,2003.18(3):p. 443-50.
[79]Kanazawa, K., et al., TRAF2 is essential for TNF-alpha-induced osteoclastogenesis. J Bone Miner Res,2005.20(5):p.840-7.
[80]Xing, L., et al., NF-kappaB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK-and cytokine-mediated osteoclastogenesis. J Bone Miner Res,2002.17(7):p. 1200-10.
[81]Yamashita, T., et al., NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATcl. J Biol Chem,2007. 282(25):p.18245-53.
[82]Takatsuna, H., et al., Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATcl. J Bone Miner Res,2005.20(4):p.653-62.
[83]Asagiri, M., et al., Autoamplification of NFATcl expression determines its essential role in bone homeostasis. J Exp Med,2005.202(9):p.1261-9.
[84]Battaglino, R., et al., c-myc is required for osteoclast differentiation. J Bone Miner Res,2002.17(5):p.763-73.
[85]Chinenov, Y., et al., Close encounters of many kinds:Fos-Jun interactions that mediate transcription regulatory specificity. Oncogene,2001.20(19):p. 2438-52.
[86]Wang, Z.Q., et al., Bone and haernatopoietic defects in mice lacking c-fos. Nature,1992.360(6406):p.741-5.
[87]Grigoriadis, A.E., et al., c-Fos:a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science,1994.266(5184):p. 443-8.
[88]Matsuo, K., et al., Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem,2004.279(25):p. 26475-80.
[89]Takayanagi, H., The role of NFAT in osteoclast formation. Ann N Y Acad Sci, 2007.1116:p.227-37.
[90]Liu, Q., et al., Interaction between TAK1-TAB1-TAB2 and RCANl-calcineurin defines a signalling nodal control point. Nat Cell Biol, 2009.11(2):p.154-61.
[91]Macian, F., et al., Partners in transcription:NFAT and AP-1. Oncogene,2001. 20(19):p.2476-89.
[92]Ranger, A.M., et al., The transcription factor NF-ATc is essential for cardiac valve formation. Nature,1998.392(6672):p.186-90.
[93]Takayanagi, H., et al., Induction and activation of the transcription, factor NFATcl (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell,2002.3(6):p.889-901.
[94]Winslow, M.M., et al., Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell,2006.10(6):p.771-82.
[95]Aliprantis, A.O., et al., NFATcl in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest,2008.
[96]Crotti, T.N., et al., NFATcl directly induces the human beta3 integrin gene in osteoclast differentiation. J Musculoskelet Neuronal Interact,2005.5(4):p. 335-7.
[97]Kim, K., et al., NFATcl induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol Endocrinol,2008.22(1):p.176-85.
[98]Mundy, G.R., et al., Boning up on ephrin signaling. Cell,2006.126(3):p. 441-3.
[99]Zhao, C., et al., Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab,2006.4(2):p.111-21.
[100]Ma, T., et al., Human interleukin-1-induced murine osteoclastogenesis is dependent on RANKL, but independent of TNF-alpha. Cytokine,2004.26(3): p.138-44.
[101]Onoe, Y., et al., IL-13 and IL-4 inhibit bone resorption by suppressing cyclooxygenase-2-dependent prostaglandin synthesis in osteoblasts. J Immunol,1996.156(2):p.758-64.
[102]Barton, B.E., et al., IL-3 induces differentiation of bone marrow precursor cells to osteoclast-like cells. J Immunol,1989.143(10):p.3211-6.
[103]Axmann, R., et al., Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum,2009.60(9):p. 2747-56.
[104]Ogata, Y., et al., A novel role of IL-15 in the development of osteoclasts: inability to replace its activity with IL-2. J Immunol,1999.162(5):p. 2754-60.
[105]Huang, H., et al., IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells:implications for bone remodeling. Cell Death Differ,2009.16(10):p.1332-43.
[106]Li, X., et al., IL-23 induces receptor activator of NF-kappaB ligand expression in fibroblast-like synoviocytes via STAT3 and NF-kappaB signal pathways. Immunol Lett,2009.
[107]Kamel Mohamed, S.G., et al., Interleukin-4 inhibits RANKL-induced expression of NFATcl and c-Fos:a possible mechanism for downregulation of osteoclastogenesis. Biochem Biophys Res Commun,2005.329(3):p.839-45.
[108]Mohamed, S.G., et al., Interleukin-10 inhibits RANKL-mediated expression of NFATcl in part via suppression of c-Fos and c-Jun in RAW264.7 cells and mouse bone marrow cells. Bone,2007.41(4):p.592-602.
[109]Okahashi, N., et al., Osteoclast differentiation is associated with transient upregulation of cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1). J Cell Biochem,2001.80(3):p.339-45.
[110]Ogasawara, T., et al., Osteoclast differentiation by RANKL requires NF-kappaB-mediated downregulation of cyclin-dependent kinase 6 (Cdk6). J Bone Miner Res,2004.19(7):p.1128-36.
[111]Yagi, M., et al., Role of DC-STAMP in cellular fusion of osteoclasts and macrophage giant cells. J Bone Miner Metab,2006.24(5):p.355-8.
[112]Yagi, M., et al., Induction of DC-STAMP by alternative activation and downstream signaling mechanisms. J Bone Miner Res,2007.22(7):p. 992-1001.
[113]Ainola, M., et al., Involvement of ADAM8 in osteoclastogenesis and pathological bone destruction. Ann Rheum Dis,2008.
[114]Abe, E., et al., Meltrin-alpha, a fusion protein involved in multinucleated giant cell and osteoclast formation. Calcif Tissue Int,1999.64(6):p.508-15.
[115]Lum, L., et al., Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem,1999.274(19):p.13613-8.
[116]Choi, S.J., et al., ADAM8:a novel osteoclast stimulating factor. J Bone Miner Res,2001.16(5):p.814-22.
[117]Ma, G, et al., Increased expression and processing of ADAM 12 (meltrin-alpha) in osteolysis associated with aseptic loosening of total hip replacement implants. J Rheumatol,2005.32(10):p.1943-50.
[118]Mbalaviele, G., et al., The role of cadherin in the generation of multinucleated osteoclasts from mononuclear precursors in murine marrow. J Clin Invest, 1995.95(6):p.2757-65.
[119]Ilvesaro, J.M., et al., Inhibition of bone resorption in vitro by a peptide containing the cadherin cell adhesion recognition sequence HAV is due to prevention of sealing zone formation. Exp Cell Res,1998.242(1):p.75-83.
[120]Monaghan, H., et al., Adenomatous polyposis coli (APC), beta-catenin, and cadherin are expressed in human bone and cartilage. Histopathology,2001. 39(6):p.611-9.
[121]Mbalaviele, G., et al., Cadherin-6 mediates the heterotypic interactions between the hemopoietic osteoclast cell lineage and stromal cells in a murine model of osteoclast differentiation. J Cell Biol,1998.141(6):p.1467-76.
[122]Castro, C.H., et al., Targeted expression of a dominant-negative N-cadherin in vivo delays peak bone mass and increases adipogenesis. J Cell Sci,2004. 117(Pt 13):p.2853-64.
[123]Stains, J.P., et al., Cell-cell interactions in regulating osteogenesis and osteoblast function. Birth Defects Res C Embryo Today,2005.75(1):p. 72-80.
[124]Shin, C.S., et al., Dominant negative N-cadherin inhibits osteoclast differentiation by interfering with beta-catenin regulation of RANKL, independent of cell-cell adhesion. J Bone Miner Res,2005.20(12):p. 2200-12.
[125]Lai, C.F., et al., Accentuated ovariectomy-induced bone loss and altered osteogenesis in heterozygous N-cadherin null mice. J Bone Miner Res,2006. 21(12):p.1897-906.
[126]Chabadel, A., et al., CD44 and beta3 integrin organize two functionally distinct actin-based domains in osteoclasts. Mol Biol Cell,2007.18(12):p. 4899-910.
[127]Sterling, H., et al., CD44 occupancy prevents macrophage multinucleation. J Cell Biol,1998.143(3):p.837-47.
[128]Kania, J.R., et al., CD44 antibodies inhibit osteoclast formation. J Bone Miner Res,1997.12(8):p.1155-64.
[129]de Vries, T.J., et al., Effect of CD44 deficiency on in vitro and in vivo osteoclast formation. J Cell Biochem,2005.94(5):p.954-66.
[130]Hayer, S., et al., CD44 is a determinant of inflammatory bone loss. J Exp Med, 2005.201(6):p.903-14.
[131]Spessotto, P., et al., Hyaluronan-CD44 interaction hampers migration of osteoclast-like cells by down-regulating MMP-9. J Cell Biol,2002.158(6):p. 1133-44.
[132]Ariyoshi, W., et al., Mechanisms involved in enhancement of osteoclast formation and function by low molecular weight hyaluronic acid. J Biol Chem, 2005.280(19):p.18967-72.
[133]Cao, J.J., et al., Hyaluronan increases RANKL expression in bone marrow stromal cells through CD44. J Bone Miner Res,2005.20(1):p.30-40.
[134]Duong, L.T., et al., Integrins and signaling in osteoclast function. Matrix Biol, 2000.19(2):p.97-105.
[135]Nakamura, I., et al., Osteoclast integrin alphaVbeta3 is present in the clear zone and contributes to cellular polarization. Cell Tissue Res,1996.286(3):p. 507-15.
[136]Crippes, B.A., et al., Antibody to beta3 integrin inhibits osteoclast-mediated bone resorption in the thyroparathyroidectomized rat. Endocrinology,1996. 137(3):p.918-24.
[137]Schaffner, P., et al., Structure and function of RGD peptides involved in bone biology. Cell Mol Life Sci,2003.60(1):p.119-32.
[138]Zou, W., et al., Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J Cell Biol, 2007.176(6):p.877-88.
[139]Chellaiah, M.A., et al., The integrin alpha(v)beta(3) and CD44 regulate the actions of osteopontin on osteoclast motility. Calcif Tissue Int,2003.72(3):p. 197-205.
[140]Wiwanitkit, V., Effect of interleukin-2 and tumor necrosis factor-alpha on osteopontin:molecular function and biological process. Pediatr Int,2008. 50(2):p.213-5.
[141]Chellaiah, M.A., et al., Rho-dependent Rho kinase activation increases CD44 surface expression and bone resorption in osteoclasts. J Biol Chem,2003. 278(31):p.29086-97.
[142]Hayashi, H., et al., The role of Mac-1 (CDllb/CD18) in osteoclast differentiation induced by receptor activator of nuclear factor-kappaB ligand. FEBS Lett,2008.582(21-22):p.3243-8.
[143]Cipriano, D.J., et al., Structure and regulation of the vacuolar ATPases. Biochim Biophys Acta,2008.1777(7-8):p.599-604.
[144]Zaidi, M., et al., Osteoclastogenesis, bone resorption, and osteoclast-based therapeutics. J Bone Miner Res,2003.18(4):p.599-609.
[145]Kornak, U., et al., Loss of the C1C-7 chloride channel leads to osteopetrosis in mice and man. Cell,2001.104(2):p.205-15.
[146]Feng, S., et al., Atp6vlc1 is an essential component of the osteoclast proton pump and in F-actin ring formation in osteoclasts. Biochem J,2009.417(1):p. 195-203.
[147]Smith, A.N., et al., The d subunit plays a central role in human vacuolar H(+)-ATPases. J Bioenerg Biomembr,2008.40(4):p.371-80.
[148]Feng, H., et al., Myocyte enhancer factor 2 and microphthalmia-associated transcription factor cooperate with NFATcl to transactivate the V-ATPase d2 promoter during RANKL-induced osteoclastogenesis. J Biol Chem,2009. 284(21):p.14667-76.
[149]Dew, G., et al., Localisation of matrix metalloproteinases and TIMP-2 in resorbing mouse bone. Cell Tissue Res,2000.299(3):p.385-94.
[150]Ortega, N., et al., How proteases regulate bone morphogenesis. Ann N Y Acad Sci,2003.995:p.109-16.
[151]Engsig, M.T., et al., Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones. J Cell Biol,2000.151(4):p.879-89.
[152]Sundaram, K., et al., RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Exp Cell Res,2007.313(1):p.168-78.
[153]Everts, V., et al., Functional heterogeneity of osteoclasts:matrix metalloproteinases participate in osteoclastic resorption of calvarial bone but not in resorption of long bone. FASEB J,1999.13(10):p.1219-30.
[154]Li, Y.P., et al., Characterization of mouse cathepsin K gene, the gene promoter, and the gene expression. J Bone Miner Res,1999.14(4):p.487-99.
[155]Soderstrom, M., et al., Cathepsin expression during skeletal development. Biochim Biophys Acta,1999.1446(1-2):p.35-46.
[156]Gelb, B.D., et al., Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science,1996.273(5279):p.1236-8.
[157]Johnson, M.R., et al., A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. Genome Res,1996.6(11):p.1050-5.
[158]Saftig, P., et al., Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci U S A,1998.95(23):p. 13453-8.
[159]Pennypacker, B., et al., Bone density, strength, and formation in adult cathepsin K (-/-) mice. Bone,2008.
[160]Fujisaki, K., et al., Receptor activator of NF-kappaB ligand induces the expression of carbonic anhydrase Ⅱ, cathepsin K, and matrix metalloproteinase-9 in osteoclast precursor RAW264.7 cells. Life Sci,2007. 80(14):p.1311-8.
[161]Pang, M., et al., AP-1 stimulates the cathepsin K promoter in RAW 264.7 cells. Gene,2007.403(1-2):p.151-8.
[162]Wilson, S.R., et al., Cathepsin K activity dependent regulation of osteoclast actin ring formation and bone resorption. J Biol Chem,2008.
[163]Stoch, S.A., et al., Cathepsin K inhibitors:a novel target for osteoporosis therapy. Clin Pharmacol Ther,2008.83(1):p.172-6.
[164]Kim, S.H., et al., Effect of novel N-cyano-tetrahydro-pyridazine compounds, a class of cathepsin K inhibitors, on the bone resorptive activity of mature osteoclasts. Bioorg Med Chem Lett,2008.18(14):p.3988-91.
[2]Peppone, L.J., et al., The efficacy of calcitriol therapy in the management of bone loss and fractures:a qualitative review. Osteoporos Int,2009.
[3]Virk, M.S. et al., Tumor metastasis to bone. Arthritis Res Ther,2007.9 Suppl l:p. S5.
[4]Roodman, G.D., Regulation of osteoclast differentiation. Ann N Y Acad Sci, 2006.1068:p.100-9.
[5]Boyle, W.J., et al., Osteoclast differentiation and activation. Nature,2003. 423(6937):p.337-42.
[6]Hong, J.W., et al., Oral bisphosphonate-related osteonecrosis of the jaw:the first report in Asia. Osteoporos Int,2009.
[7]Ash, P., et al., Osteoclasts derived from haematopoietic stem cells. Nature, 1980.283(5748):p.669-70.
[8]Tondravi, M.M., et al., Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature,1997.386(6620):p.81-4.
[9]Felix, R., et al., Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology,1990.127(5):p. 2592-4.
[10]Grigoriadis, A.E., et al., c-Fos:a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science,1994.266(5184):p. 443-8.
[11]Lacey, D.L., et al., Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell,1998.93(2):p.165-76.
[12]Li,J., et al.,RANK is the-intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A,2000.97(4):p.1566-71.
[13]Lomaga, M.A., et al., TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev,1999.13(8):p.1015-24.
[14]Wei, S., et al., Receptor activator of nuclear factor-kappa b ligand activates nuclear factor-kappa b in osteoclast precursors. Endocrinology,2001.142(3): p.1290-5.
[15]Soriano, P., et al., Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell,1991.64(4):p.693-702.
[16]Gelb, B.D., et al., Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science,1996.273(5279):p.1236-8.
[17]Hollberg, K., et al., Osteoclasts from mice deficient in tartrate-resistant acid phosphatase have altered ruffled borders and disturbed intracellular vesicular transport. Exp Cell Res,2002.279(2):p.227-38.
[18]Lee, S.H., et al., v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat Med,2006.12(12):p. 1403-9.
[19]Takayanagi, H., The role of NFAT in osteoclast formation. Ann N Y Acad Sci, 2007.1116:p.227-37.
[20]Iotsova, V., et al., Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med,1997.3(11):p.1285-9.
[21]Yamashita, T., et al., NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATcl. J Biol Chem,2007. 282(25):p.18245-53.
[22]Matsuo, K., et al., Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem,2004.279(25):p. 26475-80.
[23]Takayanagi, H., et al., Induction and activation of the transcription factor NFATcl (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell,2002.3(6):p.889-901.
[24]Schoch, S., et al., Modular structure of cAMP response element binding protein 2 (CREB2). Neurochem Int,2001.38(7):p.601-8.
[25]Xiao, G., et al., Cooperative interactions between activating transcription factor 4 and Runx2/Cbfal stimulate osteoblast-specific osteocalcin gene expression. J Biol Chem,2005.280(35):p.30689-96.
[26]Tanaka, T., et al., Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres. Genes Cells,1998.3(12):p.801-10.
[27]Masuoka, H.C., et al., Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood,2002.99(3):p.736-45.
[28]Song, H., et al., Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. J Biol Chem,2008.283(52):p.36687-97.
[29]Yang, X., et al., ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell,2004. 117(3):p.387-98.
[30]Elefteriou, F., et al., Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature,2005.434(7032):p.514-20.
[31]Yu, S., et. al., Parathyroid hormone increases activating transcription factor 4 expression and activity in osteoblasts:requirement for osteocalcin gene expression. Endocrinology,2008.149(4):p.1960-8.
[32]Yu, S., et al., Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone. PLoS One,2009.4(10):p. e7583.
[33]Seo, J., et al., Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes,2009.58(11):p.2565-73.
[34]Hinoi, E., et al., An Osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion. Ann N Y Acad Sci,2009.1173 Suppl 1:p. E20-30.
[35]Elefteriou, F., et al., ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab,2006.4(6):p. 441-51.
[36]Zhang, X., et al., Activating transcription factor 4 is critical for proliferation and survival in primary bone marrow stromal cells and calvarial osteoblasts. J Cell Biochem,2008.105(3):p.885-95.
[37]Yang, X., et al., ATF4, the osteoblast accumulation of which is determined post-translationally, can induce osteoblast-specific gene expression in non-osteoblastic cells. J Biol Chem,2004.279(45):p.47109-14.
[38]Begg, S.K., et al., Delayed hematopoietic development in osteopetrotic (op/op) mice. J Exp Med,1993.177(1):p.237-42.
[39]Yavropoulou, M.P., et al., Osteoclastogenesis--current knowledge and future perspectives. J Musculoskelet Neuronal Interact,2008.8(3):p.204-16.
[40]Anderson, T.R., et al., Effect of Fe2+ and ascorbic acid on acid phosphatases from rat bone. Calcif Tissue Int,1982.34(1):p.54-8.
[41]Marks, S.C., Jr., et al., Tartrate-resistant acid phosphatase in mononuclear and multinuclear cells during the bone resorption of tooth eruption. J Histochem Cytochem,1987.35(11):p.1227-30.
[42]Hamilton, J.A., CSF-1 signal transduction. J Leukoc Biol,1997.62(2):p. 145-55.
[43]Felix, R., et al., Impairment of macrophage colony-stimulating factor production and lack of resident bone marrow macrophages in the osteopetrotic op/op mouse. J Bone Miner Res,1990.5(7):p.781-9.
[44]Wiktor-Jedrzejczak, W., et al., Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A,1990.87(12):p.4828-32.
[45]McKercher, S.R., et al., Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J,1996.15(20):p.5647-58.
[46]Jack, G.D., et al., M-CSF elevates c-Fos and phospho-C/EBPalpha(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification. Blood,2009.114(10):p. 2172-80.
[47]Yasuda, H., et al., Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A,1998.95(7):p.3597-602.
[48]Sundaram, K., et al., RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Exp Cell Res,2007.313(1):p.168-78.
[49]Troen, B.R., The regulation of cathepsin K gene expression. Ann N Y Acad Sci,2006.1068:p.165-72.
[50]Crotti, T.N., et al., NFATcl directly induces the human beta3 integrin gene in osteoclast differentiation. J Musculoskelet Neuronal Interact,2005.5(4):p. 335-7.
[51]So, H., et al., Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. J Biol Chem,2003.278(26):p.24209-16.
[52]Kim, K., et al., MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood,2007.109(8):p.3253-9.
[53]Yu, M., et al., Complex regulation of tartrate-resistant acid phosphatase (TRAP) expression by interleukin 4 (IL-4):IL-4 indirectly suppresses receptor activator of NF-kappaB ligand (RANKL)-mediated TRAP expression but modestly induces its expression directly. J Biol Chem,2009.284(47):p. 32968-79.
[54]Kim, K., et al., NFATcl induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol Endocrinol,2008.22(1):p.176-85.
[55]Ishida, N., et al., Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J Biol Chem,2002.277(43): p.41147-56.
[56]Sun, L., et al., Evidence that calcineurin is required for the genesis of bone-resorbing osteoclasts. Am J Physiol Renal Physiol,2007.292(1):p. F285-91.
[57]Macian, F., et al., Partners in transcription:NFAT and AP-1. Oncogene,2001. 20(19):p.2476-89.
[58]Asagiri, M., et al., Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med,2005.202(9):p.1261-9.
[59]Hai, T., et al., Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci U S A,1991. 88(9):p.3720-4.
[60]Kato, Y., et al., Presence of activating transcription factor 4 (ATF4) in the porcine anterior pituitary. Mol Cell Endocrinol,1999.154(1-2):p.151-9.
[61]Matsumoto, M., et al., Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATcl and PU.1. J Biol Chem,2004.279(44):p.45969-79.
[62]Yavropoulou, M.P., et al., Osteoclastogenesis-Current knowledge and future perspectives. J Musculoskelet Neuronal Interact,2008.8(3):p.204-16.
[63]Ikeda, F., et al., Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest,2004.114(4): p.475-84.
[64]Chinenov, Y., et al., Close encounters of many kinds:Fos-Jun interactions that mediate transcription regulatory specificity. Oncogene,2001.20(19):p. 2438-52.
[65]Fuller, K., et al., Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts. J Exp Med,1993.178(5):p. 1733-44.
[66]Otero, K., et al., Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP 12 and beta-catenin. Nat Immunol,2009.10(7):p.734-43.
[67]Arai, F., et al., Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med,1999.190(12):p.1741-54.
[68]Curry, J.M., et al., M-CSF signals through the MAPK/ERK pathway via Spl to induce VEGF production and induces angiogenesis in vivo. PLoS One, 2008.3(10):p. e3405.
[69]Chang, M., et al., Phosphatidylinostitol-3 kinase and phospholipase C enhance CSF-1-dependent macrophage survival by controlling glucose uptake. Cell Signal,2009.21(9):p.1361-9.
[70]Sugatani, T., et al., Aktl/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem,2005.280(5):p.3583-9.
[71]Kawamura, N., et al., Regulation of bone mass by PI3 kinase/Akt signaling. Nippon Rinsho,2007.65 Suppl 9:p.67-70.
[72]Yang, F.C., et al., Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. J Clin Invest,2006.116(11):p.2880-91.
[73]Kuorilehto, T., et al., Decreased bone mineral density and content in neurofibromatosis type 1:lowest local values are located in the load-carrying parts of the body. Osteoporos Int,2005.16(8):p.928-36.
[74]Lammert, M., et al., Decreased bone mineral density in patients with neurofibromatosis 1. Osteoporos Int,2005.16(9):p.1161-6.
[75]Illes, T., et al., Decreased bone mineral density in neurofibromatosis-1 patients with spinal deformities. Osteoporos Int,2001.12(10):p.823-7.
[76]Halmai, V., et al., [Decreased bone mineral density as a risk factor in the development of spinal deformities in neurofibromatosis]. Orv Hetil,2001. 142(52):p.2893-7.
[77]Yan, J., et al., Racl mediates the osteoclast gains-in-function induced by haploinsufficiency of Nfl. Hum Mol Genet,2008.17(7):p.936-48.
[78]Krysinska, H., et al., A two-step, PU.1-dependent mechanism for developmentally regulated chromatin remodeling and transcription of the c-fins gene. Mol Cell Biol,2007.27(3):p.878-87.
[1]Roodman, G.D., Cell biology of the osteoclast. Exp Hematol,1999.27(8):p. 1229-41.
[2]Vaananen, H.K., et al., Osteoclast lineage and function. Arch Biochem Biophys,2008.473(2):p.132-8.
[3]Quinn, J.M., et al., Modulation of osteoclast formation. Biochem Biophys Res Commun,2005.328(3):p.739-45.
[4]Klemsz, M.J., et al., The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell,1990.61(1):p.113-24.
[5]Krysinska, H., et al., A two-step, PU.1-dependent mechanism for developmentally regulated chromatin remodeling and transcription of the c-fms gene. Mol Cell Biol,2007.27(3):p.878-87.
[6]DeKoter, R.P., et al.,, PU.1 regulates both cytokine-dependent proliferation and differentiation of granulocyte/macrophage progenitors. EMBO J,1998. 17(15):p.4456-68.
[7]Tondravi, M.M., et al., Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature,1997.386(6620):p.81-4.
[8]Kwon, O.H., et al., The hematopoietic transcription factor PU.1 regulates RANK gene expression in myeloid progenitors. Biochem Biophys Res Commun,2005.335(2):p.437-46.
[9]Ishii, J., et al., Lipopolysaccharide suppresses RANK gene expression in macrophages by down-regulating PU.l and MITF. J Cell Biochem,2008. 105(3):p.896-904.
[10]Crotti, T.N., et al., PU.1 and NFATcl mediate osteoclastic induction of the mouse beta3 integrin promoter. J Cell Physiol,2008.215(3):p.636-44.
[11]So, H., et al., Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. J Biol Chem,2003.278(26):p.24209-16.
[12]Mansky, K.C., et al., The microphthalmia transcription factor (MITF) contains two N-terminal domains required for transactivation of osteoclast target promoters and rescue of mi mutant osteoclasts. J Leukoc Biol,2002.71(2):p. 295-303.
[13]Hu, R., et al., Eos, MITF, and PU.1 recruit corepressors to osteoclast-specific genes in committed myeloid progenitors. Mol Cell Biol,2007.27(11):p. 4018-27.
[14]Sharma, S.M., et al., MITF and PU.1 recruit p38 MAPK and NFATcl to target genes during osteoclast differentiation. J Biol Chem,2007.282(21):p. 15921-9.
[15]Otero, K., et al., Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP 12 and beta-catenin. Nat Immunol,2009.10(7):p.734-43.
[16]Curry, J.M., et al., M-CSF signals through the MAPK/ERK pathway via Spl to induce VEGF production and induces angiogenesis in vivo. PLoS One, 2008.3(10):p. e3405.
[17]Jack, G.D., et al.,, M-CSF elevates c-Fos and phospho-C/EBPalpha(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification. Blood,2009.114(10):p. 2172-80.
[18]Chang, M., et al., Phosphatidylinostitol-3 kinase and phospholipase C enhance CSF-1-dependent macrophage survival by controlling glucose uptake. Cell Signal,2009.21(9):p.1361-9.
[19]Felix, R., et al., Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology,1990.127(5):p. 2592-4.
[20]Wiktor-Jedrzejczak, W., et al., Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A,1990.87(12):p.4828-32.
[21]Fuller, K., et al., Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts. J Exp Med,1993.178(5):p. 1733-44.
[22]Arai, F., et al., Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med,1999.190(12):p.1741-54.
[23]Begg, S.K., et al., Delayed hematopoietic development in osteopetrotic (op/op) mice. J Exp Med,1993.177(1):p.237-42.
[24]Faccio, R., et al., Localization and possible role of two different alpha v beta 3 integrin conformations in resting and resorbing osteoclasts. J Cell Sci,2002. 115(Pt 14):p.2919-29.
[25]Faccio, R., et al., c-Fms and the alphavbeta3 integrin collaborate during osteoclast differentiation. J Clin Invest,2003.111(5):p.749-58.
[26]Elsegood, C.L., et al., M-CSF induces the stable interaction of cFms with alphaVbeta3 integrin in osteoclasts. Int J Biochem Cell Biol,2006.38(9):p. 1518-29.
[27]Dai, X.M., et al., Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood,2002.99(1):p.111-20.
[28]Nakamura, I., et al., Involvement of alpha(v)beta3 integrins in osteoclast function. J Bone Miner Metab,2007.25(6):p.337-44.
[29]Schoch, S., et al., Modular structure of cAMP response element binding protein 2 (CREB2). Neurochem Int,2001.38(7):p.601-8.
[30]Xiao, G., et al., Cooperative interactions between activating transcription factor 4 and Runx2/Cbfal stimulate osteoblast-specific osteocalcin gene expression. J Biol Chem,2005.280(35):p.30689-96.
[31]Tanaka, T., et al., Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres. Genes Cells,1998.3(12):p.801-10.
[32]Masuoka, H.C., et al.,, Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood,2002.99(3):p. 736-45.
[33]Song, H., et al., Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. J Biol Chem,2008.283(52):p.36687-97.
[34]Yang, X., et al., ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell,2004. 117(3):p.387-98.
[35]Elefteriou, F., et al., Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature,2005.434(7032):p.514-20.
[36]Yu, S., et al., Parathyroid hormone increases activating transcription factor 4 expression and activity in osteoblasts:requirement for osteocalcin gene expression. Endocrinology,2008.149(4):p.1960-8.
[37]Yu, S., et al., Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone. PLoS One,2009.4(10):p. e7583.
[38]Seo, J., et al., Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes,2009.58(11):p.2565-73.
[39]Hinoi, E., et al., An Osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion. Ann N Y Acad Sci,2009.1173 Suppl 1:p. E20-30.
[40]Elefteriou, F., et al., ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab,2006.4(6):p. 441-51.
[41]Matsumoto, M., et al., Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATcl and PU.1. J Biol Chem,2004.279(44):p.45969-79.
[42]Yavropoulou, M.P., et al., Osteoclastogenesis-Current knowledge and future perspectives. J Musculoskelet Neuronal Interact,2008.8(3):p.204-16.
[43]Ikeda, F., et al., Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest,2004.114(4): p.475-84.
[44]Yang, X., et al., ATF4, the osteoblast accumulation of which is determined post-translationally, can induce osteoblast-specific gene expression in non-osteoblastic cells. J Biol Chem,2004.279(45):p.47109-14.
[45]Sugatani, T., et al., Aktl/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem,2005.280(5):p.3583-9.
[46]Kawamura, N., et al., Regulation of bone mass by PI3 kinase/Akt signalin. Nippon Rinsho,2007.65 Suppl 9:p.67-70.
[47]Yang, F.C., et al., Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. J Clin Invest,2006.116(11):p.2880-91.
[48]Yasuda, H., et al., Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A,1998.95(7):p.3597-602.
[49]Kong, Y.Y., et al., OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature,1999.397(6717):p. 315-23.
[50]Rho, J., et al., Osteoimmunology:interactions of the immune and skeletal systems. Mol Cells,2004.17(1):p.1-9.
[51]Sankar, U., et al., RANKL coordinates cell cycle withdrawal and differentiation in osteoclasts through the cyclin-dependent kinase inhibitors p27KIP1 and p21CIP1.J Bone Miner Res,2004.19(8):p.1339-48.
[52]Sundaram, K., et al., FGF-2 stimulation of RANK ligand expression in Paget's disease of bone. Mol Endocrinol,2009.23(9):p.1445-54.
[53]Li, P., et al., RANK signaling is not required for TNFalpha-mediated increase in CD 11 (hi) osteoclast precursors but is essential for mature osteoclast formation in TNFalpha-mediated inflammatory arthritis. J Bone Miner Res, 2004.19(2):p.207-13.
[54]Kanazawa, K., et al., Self-assembled RANK induces osteoclastogenesis ligand-independently. J Bone Miner Res,2005.20(11):p.2053-60.
[55]Taguchi, Y, et al., A unique domain in RANK is required for Gab2 and PLCgamma2 binding to establish osteoclastogenic signals. Genes Cells,2009. 14(11):p.1331-45.
[56]Shinohara, M., et al., Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell,2008.132(5):p. 794-806.
[57]Islam, S., et al., Receptor activator of nuclear factor-kappa B ligand induces osteoclast formation in RAW 264.7 macrophage cells via augmented production of macrophage-colony-stimulating factor. Microbiol Immunol, 2008.52(12):p.585-90.
[58]Horowitz, M.C., et al., Control of osteoclastogenesis and bone resorption by members of the TNF family of receptors and ligands. Cytokine Growth Factor Rev,2001.12(1):p.9-18.
[59]Simonet, W.S., et al., Osteoprotegerin:a novel secreted protein involved in the regulation of bone density. Cell,1997.89(2):p.309-19.
[60]Boyce, B.F., et al., TNF-alpha and pathologic bone resorption. Keio J Med, 2005.54(3):p.127-31.
[61]Kobayashi, K., et al., Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med,2000.191(2):p.275-86.
[62]Azuma, Y., et al., Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem,2000.275(7):p.4858-64.
[63]Mormann, M., et al., Lipopolysaccharides (LPS) induce the differentiation of human monocytes to osteoclasts in a tumour necrosis factor (TNF) alpha-dependent manner:a link between infection and pathological bone resorption. Mol Immunol,2008.45(12):p.3330-7.
[64]Arai, S., et al., Osteoclastogenesis-related antigen, a novel molecule on mouse stromal cells, regulates osteoclastogenesis. J Bone Miner Res,2003.18(4):p. 686-95.
[65]Kim, N., et al., A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med,2002.195(2):p.201-9.
[66]Herman, S., et al., Induction of osteoclast-associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis. Arthritis Rheum,2008.58(10): p.3041-50.
[67]Yamada, T., et al., Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells. Blood,2003. 101(6):p.2227-34.
[68]Bai, S., et al., NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem,2008. 283(10):p.6509-18.
[69]Fukushima, H., et al., The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Mol Cell Biol,2008.28(20):p.6402-12.
[70]Naito, A., et al., Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells,1999.4(6): p.353-62.
[71]Lomaga, M.A., et al., TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev,1999.13(8):p.1015-24.
[72]Kaji, K., et al., Tumor necrosis factor alpha-induced osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6. J Bone Miner Res, 2001.16(9):p.1593-9.
[73]Asagiri, M., et al., The molecular understanding of osteoclast differentiation. Bone,2007.40(2):p.251-64.
[74]Kobayashi, N., et al., Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J,2001.20(6):p.1271-80.
[75]Wu, H., et al., TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays,2003.25(11):p.1096-105.
[76]Bai, S., et al., Tumor necrosis factor receptor-associated factor 6 is an intranuclear transcriptional coactivator in osteoclasts. J Biol Chem,2008. 283(45):p.30861-7.
[77]Bai, S., et al., FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner. J Clin Invest,2005.115(10):p.2742-51.
[78]Kanazawa, K., et al., TRAF5 functions in both RANKL-and TNFalpha-induced osteoclastogenesis. J Bone Miner Res,2003.18(3):p. 443-50.
[79]Kanazawa, K., et al., TRAF2 is essential for TNF-alpha-induced osteoclastogenesis. J Bone Miner Res,2005.20(5):p.840-7.
[80]Xing, L., et al., NF-kappaB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK-and cytokine-mediated osteoclastogenesis. J Bone Miner Res,2002.17(7):p. 1200-10.
[81]Yamashita, T., et al., NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATcl. J Biol Chem,2007. 282(25):p.18245-53.
[82]Takatsuna, H., et al., Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATcl. J Bone Miner Res,2005.20(4):p.653-62.
[83]Asagiri, M., et al., Autoamplification of NFATcl expression determines its essential role in bone homeostasis. J Exp Med,2005.202(9):p.1261-9.
[84]Battaglino, R., et al., c-myc is required for osteoclast differentiation. J Bone Miner Res,2002.17(5):p.763-73.
[85]Chinenov, Y., et al., Close encounters of many kinds:Fos-Jun interactions that mediate transcription regulatory specificity. Oncogene,2001.20(19):p. 2438-52.
[86]Wang, Z.Q., et al., Bone and haernatopoietic defects in mice lacking c-fos. Nature,1992.360(6406):p.741-5.
[87]Grigoriadis, A.E., et al., c-Fos:a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science,1994.266(5184):p. 443-8.
[88]Matsuo, K., et al., Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem,2004.279(25):p. 26475-80.
[89]Takayanagi, H., The role of NFAT in osteoclast formation. Ann N Y Acad Sci, 2007.1116:p.227-37.
[90]Liu, Q., et al., Interaction between TAK1-TAB1-TAB2 and RCANl-calcineurin defines a signalling nodal control point. Nat Cell Biol, 2009.11(2):p.154-61.
[91]Macian, F., et al., Partners in transcription:NFAT and AP-1. Oncogene,2001. 20(19):p.2476-89.
[92]Ranger, A.M., et al., The transcription factor NF-ATc is essential for cardiac valve formation. Nature,1998.392(6672):p.186-90.
[93]Takayanagi, H., et al., Induction and activation of the transcription, factor NFATcl (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell,2002.3(6):p.889-901.
[94]Winslow, M.M., et al., Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell,2006.10(6):p.771-82.
[95]Aliprantis, A.O., et al., NFATcl in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest,2008.
[96]Crotti, T.N., et al., NFATcl directly induces the human beta3 integrin gene in osteoclast differentiation. J Musculoskelet Neuronal Interact,2005.5(4):p. 335-7.
[97]Kim, K., et al., NFATcl induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol Endocrinol,2008.22(1):p.176-85.
[98]Mundy, G.R., et al., Boning up on ephrin signaling. Cell,2006.126(3):p. 441-3.
[99]Zhao, C., et al., Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab,2006.4(2):p.111-21.
[100]Ma, T., et al., Human interleukin-1-induced murine osteoclastogenesis is dependent on RANKL, but independent of TNF-alpha. Cytokine,2004.26(3): p.138-44.
[101]Onoe, Y., et al., IL-13 and IL-4 inhibit bone resorption by suppressing cyclooxygenase-2-dependent prostaglandin synthesis in osteoblasts. J Immunol,1996.156(2):p.758-64.
[102]Barton, B.E., et al., IL-3 induces differentiation of bone marrow precursor cells to osteoclast-like cells. J Immunol,1989.143(10):p.3211-6.
[103]Axmann, R., et al., Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum,2009.60(9):p. 2747-56.
[104]Ogata, Y., et al., A novel role of IL-15 in the development of osteoclasts: inability to replace its activity with IL-2. J Immunol,1999.162(5):p. 2754-60.
[105]Huang, H., et al., IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells:implications for bone remodeling. Cell Death Differ,2009.16(10):p.1332-43.
[106]Li, X., et al., IL-23 induces receptor activator of NF-kappaB ligand expression in fibroblast-like synoviocytes via STAT3 and NF-kappaB signal pathways. Immunol Lett,2009.
[107]Kamel Mohamed, S.G., et al., Interleukin-4 inhibits RANKL-induced expression of NFATcl and c-Fos:a possible mechanism for downregulation of osteoclastogenesis. Biochem Biophys Res Commun,2005.329(3):p.839-45.
[108]Mohamed, S.G., et al., Interleukin-10 inhibits RANKL-mediated expression of NFATcl in part via suppression of c-Fos and c-Jun in RAW264.7 cells and mouse bone marrow cells. Bone,2007.41(4):p.592-602.
[109]Okahashi, N., et al., Osteoclast differentiation is associated with transient upregulation of cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(KIP1). J Cell Biochem,2001.80(3):p.339-45.
[110]Ogasawara, T., et al., Osteoclast differentiation by RANKL requires NF-kappaB-mediated downregulation of cyclin-dependent kinase 6 (Cdk6). J Bone Miner Res,2004.19(7):p.1128-36.
[111]Yagi, M., et al., Role of DC-STAMP in cellular fusion of osteoclasts and macrophage giant cells. J Bone Miner Metab,2006.24(5):p.355-8.
[112]Yagi, M., et al., Induction of DC-STAMP by alternative activation and downstream signaling mechanisms. J Bone Miner Res,2007.22(7):p. 992-1001.
[113]Ainola, M., et al., Involvement of ADAM8 in osteoclastogenesis and pathological bone destruction. Ann Rheum Dis,2008.
[114]Abe, E., et al., Meltrin-alpha, a fusion protein involved in multinucleated giant cell and osteoclast formation. Calcif Tissue Int,1999.64(6):p.508-15.
[115]Lum, L., et al., Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem,1999.274(19):p.13613-8.
[116]Choi, S.J., et al., ADAM8:a novel osteoclast stimulating factor. J Bone Miner Res,2001.16(5):p.814-22.
[117]Ma, G, et al., Increased expression and processing of ADAM 12 (meltrin-alpha) in osteolysis associated with aseptic loosening of total hip replacement implants. J Rheumatol,2005.32(10):p.1943-50.
[118]Mbalaviele, G., et al., The role of cadherin in the generation of multinucleated osteoclasts from mononuclear precursors in murine marrow. J Clin Invest, 1995.95(6):p.2757-65.
[119]Ilvesaro, J.M., et al., Inhibition of bone resorption in vitro by a peptide containing the cadherin cell adhesion recognition sequence HAV is due to prevention of sealing zone formation. Exp Cell Res,1998.242(1):p.75-83.
[120]Monaghan, H., et al., Adenomatous polyposis coli (APC), beta-catenin, and cadherin are expressed in human bone and cartilage. Histopathology,2001. 39(6):p.611-9.
[121]Mbalaviele, G., et al., Cadherin-6 mediates the heterotypic interactions between the hemopoietic osteoclast cell lineage and stromal cells in a murine model of osteoclast differentiation. J Cell Biol,1998.141(6):p.1467-76.
[122]Castro, C.H., et al., Targeted expression of a dominant-negative N-cadherin in vivo delays peak bone mass and increases adipogenesis. J Cell Sci,2004. 117(Pt 13):p.2853-64.
[123]Stains, J.P., et al., Cell-cell interactions in regulating osteogenesis and osteoblast function. Birth Defects Res C Embryo Today,2005.75(1):p. 72-80.
[124]Shin, C.S., et al., Dominant negative N-cadherin inhibits osteoclast differentiation by interfering with beta-catenin regulation of RANKL, independent of cell-cell adhesion. J Bone Miner Res,2005.20(12):p. 2200-12.
[125]Lai, C.F., et al., Accentuated ovariectomy-induced bone loss and altered osteogenesis in heterozygous N-cadherin null mice. J Bone Miner Res,2006. 21(12):p.1897-906.
[126]Chabadel, A., et al., CD44 and beta3 integrin organize two functionally distinct actin-based domains in osteoclasts. Mol Biol Cell,2007.18(12):p. 4899-910.
[127]Sterling, H., et al., CD44 occupancy prevents macrophage multinucleation. J Cell Biol,1998.143(3):p.837-47.
[128]Kania, J.R., et al., CD44 antibodies inhibit osteoclast formation. J Bone Miner Res,1997.12(8):p.1155-64.
[129]de Vries, T.J., et al., Effect of CD44 deficiency on in vitro and in vivo osteoclast formation. J Cell Biochem,2005.94(5):p.954-66.
[130]Hayer, S., et al., CD44 is a determinant of inflammatory bone loss. J Exp Med, 2005.201(6):p.903-14.
[131]Spessotto, P., et al., Hyaluronan-CD44 interaction hampers migration of osteoclast-like cells by down-regulating MMP-9. J Cell Biol,2002.158(6):p. 1133-44.
[132]Ariyoshi, W., et al., Mechanisms involved in enhancement of osteoclast formation and function by low molecular weight hyaluronic acid. J Biol Chem, 2005.280(19):p.18967-72.
[133]Cao, J.J., et al., Hyaluronan increases RANKL expression in bone marrow stromal cells through CD44. J Bone Miner Res,2005.20(1):p.30-40.
[134]Duong, L.T., et al., Integrins and signaling in osteoclast function. Matrix Biol, 2000.19(2):p.97-105.
[135]Nakamura, I., et al., Osteoclast integrin alphaVbeta3 is present in the clear zone and contributes to cellular polarization. Cell Tissue Res,1996.286(3):p. 507-15.
[136]Crippes, B.A., et al., Antibody to beta3 integrin inhibits osteoclast-mediated bone resorption in the thyroparathyroidectomized rat. Endocrinology,1996. 137(3):p.918-24.
[137]Schaffner, P., et al., Structure and function of RGD peptides involved in bone biology. Cell Mol Life Sci,2003.60(1):p.119-32.
[138]Zou, W., et al., Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J Cell Biol, 2007.176(6):p.877-88.
[139]Chellaiah, M.A., et al., The integrin alpha(v)beta(3) and CD44 regulate the actions of osteopontin on osteoclast motility. Calcif Tissue Int,2003.72(3):p. 197-205.
[140]Wiwanitkit, V., Effect of interleukin-2 and tumor necrosis factor-alpha on osteopontin:molecular function and biological process. Pediatr Int,2008. 50(2):p.213-5.
[141]Chellaiah, M.A., et al., Rho-dependent Rho kinase activation increases CD44 surface expression and bone resorption in osteoclasts. J Biol Chem,2003. 278(31):p.29086-97.
[142]Hayashi, H., et al., The role of Mac-1 (CDllb/CD18) in osteoclast differentiation induced by receptor activator of nuclear factor-kappaB ligand. FEBS Lett,2008.582(21-22):p.3243-8.
[143]Cipriano, D.J., et al., Structure and regulation of the vacuolar ATPases. Biochim Biophys Acta,2008.1777(7-8):p.599-604.
[144]Zaidi, M., et al., Osteoclastogenesis, bone resorption, and osteoclast-based therapeutics. J Bone Miner Res,2003.18(4):p.599-609.
[145]Kornak, U., et al., Loss of the C1C-7 chloride channel leads to osteopetrosis in mice and man. Cell,2001.104(2):p.205-15.
[146]Feng, S., et al., Atp6vlc1 is an essential component of the osteoclast proton pump and in F-actin ring formation in osteoclasts. Biochem J,2009.417(1):p. 195-203.
[147]Smith, A.N., et al., The d subunit plays a central role in human vacuolar H(+)-ATPases. J Bioenerg Biomembr,2008.40(4):p.371-80.
[148]Feng, H., et al., Myocyte enhancer factor 2 and microphthalmia-associated transcription factor cooperate with NFATcl to transactivate the V-ATPase d2 promoter during RANKL-induced osteoclastogenesis. J Biol Chem,2009. 284(21):p.14667-76.
[149]Dew, G., et al., Localisation of matrix metalloproteinases and TIMP-2 in resorbing mouse bone. Cell Tissue Res,2000.299(3):p.385-94.
[150]Ortega, N., et al., How proteases regulate bone morphogenesis. Ann N Y Acad Sci,2003.995:p.109-16.
[151]Engsig, M.T., et al., Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones. J Cell Biol,2000.151(4):p.879-89.
[152]Sundaram, K., et al., RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Exp Cell Res,2007.313(1):p.168-78.
[153]Everts, V., et al., Functional heterogeneity of osteoclasts:matrix metalloproteinases participate in osteoclastic resorption of calvarial bone but not in resorption of long bone. FASEB J,1999.13(10):p.1219-30.
[154]Li, Y.P., et al., Characterization of mouse cathepsin K gene, the gene promoter, and the gene expression. J Bone Miner Res,1999.14(4):p.487-99.
[155]Soderstrom, M., et al., Cathepsin expression during skeletal development. Biochim Biophys Acta,1999.1446(1-2):p.35-46.
[156]Gelb, B.D., et al., Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science,1996.273(5279):p.1236-8.
[157]Johnson, M.R., et al., A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. Genome Res,1996.6(11):p.1050-5.
[158]Saftig, P., et al., Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci U S A,1998.95(23):p. 13453-8.
[159]Pennypacker, B., et al., Bone density, strength, and formation in adult cathepsin K (-/-) mice. Bone,2008.
[160]Fujisaki, K., et al., Receptor activator of NF-kappaB ligand induces the expression of carbonic anhydrase Ⅱ, cathepsin K, and matrix metalloproteinase-9 in osteoclast precursor RAW264.7 cells. Life Sci,2007. 80(14):p.1311-8.
[161]Pang, M., et al., AP-1 stimulates the cathepsin K promoter in RAW 264.7 cells. Gene,2007.403(1-2):p.151-8.
[162]Wilson, S.R., et al., Cathepsin K activity dependent regulation of osteoclast actin ring formation and bone resorption. J Biol Chem,2008.
[163]Stoch, S.A., et al., Cathepsin K inhibitors:a novel target for osteoporosis therapy. Clin Pharmacol Ther,2008.83(1):p.172-6.
[164]Kim, S.H., et al., Effect of novel N-cyano-tetrahydro-pyridazine compounds, a class of cathepsin K inhibitors, on the bone resorptive activity of mature osteoclasts. Bioorg Med Chem Lett,2008.18(14):p.3988-91.