胰岛素样生长因子1增强骨形态形成蛋白9介导的间充质干细胞成骨分化及成骨作用的研究
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摘要
骨骼是少数几个在个体成熟后仍保留有潜在再生能力的器官之一,亦是唯一一种在整个生命周期中都保持持续重塑功能的组织。高效的骨再生能力对临床上治疗许多骨骼肌肉系统疾病具有重要意义,如节段性骨缺损、骨不连及脊柱融合失败等。胚胎发育时,骨发生是一个连续的、涉及众多细胞活动的演化过程。在骨骼系统发育过程中,骨发生有两种主要的方式,膜内成骨和软骨内成骨。而骨折后的骨再生过程则是一个类似于软骨内成骨的连续过程,其起始于间充质干细胞(Mesenchymal stem cells,MSCs)的化学趋化与增殖。间充质干细胞在生物组织工程和再生医学领域有着十分巨大的潜力和广泛的应用前景。MSCs依附于骨髓间充质细胞,可向成骨、成软骨、成脂及成肌等多方向分化。
研究表明,有数条信号通路对干细胞的自我更新及种系维持起作用。骨形态形成蛋白(Bone morphogenetic proteins,BMPs)在胚胎发育过程中对细胞的增值和分化起重要调节作用,其在干细胞生物学中也扮演重要角色。BMPs属于转化生长因子(Transforming growth factor,TGF)超家族,在人体内至少有15中不同的亚型存在。BMPs基因表达的异常可导致发育过程中多种骨骼和非骨骼系统畸形的发生。BMPs通过与BMP受体异二聚体结合并相互作用来激活其信号通路。BMP受体(BMP receptor,BMPR)具有两种亚型,I型BMP受体(BMPR type I,BMPR-I)和II型BMP受体(BMPR type II,BMPR-II)。活化的受体激酶可磷酸化转录因子Smad1、Smad5或Smad8,磷酸化的这些R-Smad因子将于Smad4结合,定位转移至细胞核内,与其它协同活化因子一道促进目的基因的表达。本实验是前期系统的研究了14种不同BMPs,发现BMP9是其中可在体内、外诱导间充质干细胞成骨分化作用最强的BMPs因子。本实验的研究还进一步揭示了BMP9对BMP介导的MSCs向成骨细胞分化过程中的一系列下游基因具有重要的调节作用。
BMP9(亦被称为生长分化因子2,GDF2)最早在胚鼠肝脏中发现,其功能主要包括介导和维持胚胎基底前脑胆碱能神经的胆碱能表型,抑制肝糖原产生和介导脂代谢相关关键酶的表达,刺激鼠肝性杀菌多肽1的合成等。虽然人们对BMP9在骨骼肌肉系统内的作用和功能的认识并不深入,但是其潜在的诱导成骨活性显示出其可作为一种高效的再生因子的可能性。根据本实验前期研究的结果,我们相信其它生长因子可对BMP9介导的骨形成产生协同作用,从而更有效的诱导、促进成果过程。
在本文中,作者针对胰岛素样生长因子1(Insulin-like growth factor 1, IGF1)在BMP9介导的成骨过程中的作用进行了研究。作为IGF信号通路的成员之一,IGF1在胚胎生长、发育过程中具有重要作用。IGF1通过与IGF1受体结合,可活化PI3K/AKT通路或MAPK通路。Igf1基因敲除小鼠的出生重量较野生型小鼠低40%,这说明IGF1在胚胎发育中起重要作用。在本研究中,作者发现间充质干细胞的内源性IGF1量非常低。外源性表达IGF1可明显增强间充质干细胞内BMP9介导的早期成骨指标——碱性磷酸酶(Alkaline phosphatase,ALP)的活性。对间充质干细胞内由BMP9介导的中、晚期成骨指标——骨钙素(Osteocalcin,OCN)、骨桥素(Osteopotin,OPN),IGF1亦有明显的促进其合成表达的作用。同时,Alizarin Red S染色显示IGF1还可增强BMP介导的间充质干细胞钙化的作用。在干细胞异位移植成骨实验中,IGF1可增强BMP9介导的干细胞异位成骨能力。利用胚胎鼠肢体组织培养,我们发现IGF1自身可增加胚鼠肢体骨软骨增值区(Proliferation Zone)的活性和软骨肥大区(Hypertrophic Zone)的扩展;IGF1、BMP9共同使用可对胚胎骨的生长和成骨分化有更强的促进作用。
在对IGF1增强BMP9介导间充质干细胞成骨作用的机制研究中,作者发现外源性IGFBP3、IGFBP4和IGFBP5可以导致IGF1对BMP9介导的ALP活性的增强作用失效。进一步,IGF1可增强BMP9介导的BMPR-Smad报告子活性、Smad1/5/8的磷酸化及其向核内定向转移的程度。然而,BMP9单纯作用并不能明显介导AKT的磷酸化活化,PI3K特异性抑制剂LY294002不仅可阻断IGF1对BMP9介导的成骨信号的促进作用,亦可直接抑制BMP的活性,说明在间充质干细胞内BMP9与IGF1可能通过PI3K/pAKT通路来实现两者间的交叉调控。
Bone is one of the few organs that retains the potential for regeneration into adult life, and is the only tissue that can undergo continual remodeling throughout life. Efficacious bone regeneration would have an important impact on the clinical management of many bone and musculoskeletal disorders, such as with segmental bone loss, fracture non-union, and failed spinal fusion. Osteogenesis is a sequential cascade that recapitulates most, if not all, of the cellular events occurring during embryonic skeletal development. During skeletogenesis, bone formation can occur through two different pathways, intramembranous ossification or endochondral ossification. Bone regeneration following a fracture progresses through sequential phases similar to endochondral ossification, starting with chemotaxis and proliferation of mesenchymal stem cells. Mesenchymal stem cells (MSCs) hold great promise for tissue bioengineering and regenerative medicine. MSCs are adherent marrow stromal cells that can self-renew and differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages.
Several signaling pathways have been implicated in regulating stem cell self-renewal and lineage commitment. Bone morphogenetic proteins (BMPs) play an important role in regulating cell proliferation and differentiation during development and have been shown to play an important role in stem cell biology. BMPs belong to the TGF superfamily and consist of at least 15 members in humans. Genetic disruptions of BMPs have resulted in various skeletal and extraskeletal abnormalities during development. BMPs fulfill their signaling activity by interacting with the heterodimeric complex of two transmembrane serine/threonine kinase receptors, BMPR type I and BMPR type II. The activated receptor kinases phosphorylate the transcription factors Smads 1, 5, or 8, which in turn form a heterodimeric complex with Smad4 in the nucleus and activate the expression of target genes in concert with other co-activators. Upon analyzing the 14 types of BMPs, we found that BMP9 is one of the most potent BMPs in inducing osteogenic differentiation of mesenchymal stem cells (MSCs) both in vitro and in vivo. We further demonstrated that BMP9 regulates a distinct set of downstream targets that may play a role in regulating BMP-induced osteoblast differentiation of MSCs.
BMP9 (also known as growth differentiation factor 2, or GDF-2) was first identified in the developing mouse liver, and its possible roles include inducing and maintaining the cholinergic phenotype of embryonic basal forebrain cholinergic neurons, inhibiting hepatic glucose production and inducing the expression of key enzymes of lipid metabolism, and stimulating murine hepcidin 1 expression. Although the functional role of BMP9 in the skeletal system remains to be fully understood, the potent osteogenic activity of BMP9 suggests that it may be used as an efficacious bone regeneration agent. It is conceivable that other growth factors may act synergistically or enhance BMP9-induced bone formation.
Here, we sought to investigate the effect of insulin-like growth factor 1 (IGF1) on BMP9-induced bone formation. As a member of the IGF signaling system, IGF1 plays an important role in prenatal growth and development. IGF1 transduces its signaling through IGF-receptors and activates the phosphatidylinositol-3-kinase (PI3K)/Akt pathway or the mitogen-activated protein kinase (MAPK) pathway. The Igf1 null mice exhibit a 40% decrease in birth weight compared to their wild-type littermates, suggesting an important role of IGF1 in development. We have found that endogenous IGF1 expression is relatively low in MSCs. Exogenous expression of IGF1 can potentiate BMP9-induced early osteogenic marker alkaline phosphatase (ALP) activity and the expression of later markers, such as osteocalcin (OCN) and osteopontin (OPN) in MSCs. IGF1 is shown to augment BMP9-induced ectopic bone formation in stem cell implantation studies. Using perinatal limb explant culture, we have demonstrated that IGF1 enhances BMP9-induced endochondral ossification, while IGF1 itself can promote the expansion of hypertropic chondrocyte zone of the cultured limb explants. Exogenous expression of IGFBP3, IGFBP4 and IGFBP5, leads to inhibition of the IGF1 effect on BMP9-induced ALP activity and matrix mineralization in MSCs. Furthermore, IGF1 is shown to enhance the BMP9-induced BMPR-Smad reporter activity and the nuclear translocation of Smad1/5/8. While BMP9 stimulation does not significantly induce AKT phosphorylation, PI3K inhibitor LY294002 abolishes the IGF1 potentiation effect on BMP9-mediated osteogenic signaling, and can directly inhibit BMP9 activity, suggesting that BMP9 may cross-talk with IGF1 through PI3K/AKT signaling pathway during osteogenic differentiation of MSCs.
研究表明,有数条信号通路对干细胞的自我更新及种系维持起作用。骨形态形成蛋白(Bone morphogenetic proteins,BMPs)在胚胎发育过程中对细胞的增值和分化起重要调节作用,其在干细胞生物学中也扮演重要角色。BMPs属于转化生长因子(Transforming growth factor,TGF)超家族,在人体内至少有15中不同的亚型存在。BMPs基因表达的异常可导致发育过程中多种骨骼和非骨骼系统畸形的发生。BMPs通过与BMP受体异二聚体结合并相互作用来激活其信号通路。BMP受体(BMP receptor,BMPR)具有两种亚型,I型BMP受体(BMPR type I,BMPR-I)和II型BMP受体(BMPR type II,BMPR-II)。活化的受体激酶可磷酸化转录因子Smad1、Smad5或Smad8,磷酸化的这些R-Smad因子将于Smad4结合,定位转移至细胞核内,与其它协同活化因子一道促进目的基因的表达。本实验是前期系统的研究了14种不同BMPs,发现BMP9是其中可在体内、外诱导间充质干细胞成骨分化作用最强的BMPs因子。本实验的研究还进一步揭示了BMP9对BMP介导的MSCs向成骨细胞分化过程中的一系列下游基因具有重要的调节作用。
BMP9(亦被称为生长分化因子2,GDF2)最早在胚鼠肝脏中发现,其功能主要包括介导和维持胚胎基底前脑胆碱能神经的胆碱能表型,抑制肝糖原产生和介导脂代谢相关关键酶的表达,刺激鼠肝性杀菌多肽1的合成等。虽然人们对BMP9在骨骼肌肉系统内的作用和功能的认识并不深入,但是其潜在的诱导成骨活性显示出其可作为一种高效的再生因子的可能性。根据本实验前期研究的结果,我们相信其它生长因子可对BMP9介导的骨形成产生协同作用,从而更有效的诱导、促进成果过程。
在本文中,作者针对胰岛素样生长因子1(Insulin-like growth factor 1, IGF1)在BMP9介导的成骨过程中的作用进行了研究。作为IGF信号通路的成员之一,IGF1在胚胎生长、发育过程中具有重要作用。IGF1通过与IGF1受体结合,可活化PI3K/AKT通路或MAPK通路。Igf1基因敲除小鼠的出生重量较野生型小鼠低40%,这说明IGF1在胚胎发育中起重要作用。在本研究中,作者发现间充质干细胞的内源性IGF1量非常低。外源性表达IGF1可明显增强间充质干细胞内BMP9介导的早期成骨指标——碱性磷酸酶(Alkaline phosphatase,ALP)的活性。对间充质干细胞内由BMP9介导的中、晚期成骨指标——骨钙素(Osteocalcin,OCN)、骨桥素(Osteopotin,OPN),IGF1亦有明显的促进其合成表达的作用。同时,Alizarin Red S染色显示IGF1还可增强BMP介导的间充质干细胞钙化的作用。在干细胞异位移植成骨实验中,IGF1可增强BMP9介导的干细胞异位成骨能力。利用胚胎鼠肢体组织培养,我们发现IGF1自身可增加胚鼠肢体骨软骨增值区(Proliferation Zone)的活性和软骨肥大区(Hypertrophic Zone)的扩展;IGF1、BMP9共同使用可对胚胎骨的生长和成骨分化有更强的促进作用。
在对IGF1增强BMP9介导间充质干细胞成骨作用的机制研究中,作者发现外源性IGFBP3、IGFBP4和IGFBP5可以导致IGF1对BMP9介导的ALP活性的增强作用失效。进一步,IGF1可增强BMP9介导的BMPR-Smad报告子活性、Smad1/5/8的磷酸化及其向核内定向转移的程度。然而,BMP9单纯作用并不能明显介导AKT的磷酸化活化,PI3K特异性抑制剂LY294002不仅可阻断IGF1对BMP9介导的成骨信号的促进作用,亦可直接抑制BMP的活性,说明在间充质干细胞内BMP9与IGF1可能通过PI3K/pAKT通路来实现两者间的交叉调控。
Bone is one of the few organs that retains the potential for regeneration into adult life, and is the only tissue that can undergo continual remodeling throughout life. Efficacious bone regeneration would have an important impact on the clinical management of many bone and musculoskeletal disorders, such as with segmental bone loss, fracture non-union, and failed spinal fusion. Osteogenesis is a sequential cascade that recapitulates most, if not all, of the cellular events occurring during embryonic skeletal development. During skeletogenesis, bone formation can occur through two different pathways, intramembranous ossification or endochondral ossification. Bone regeneration following a fracture progresses through sequential phases similar to endochondral ossification, starting with chemotaxis and proliferation of mesenchymal stem cells. Mesenchymal stem cells (MSCs) hold great promise for tissue bioengineering and regenerative medicine. MSCs are adherent marrow stromal cells that can self-renew and differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages.
Several signaling pathways have been implicated in regulating stem cell self-renewal and lineage commitment. Bone morphogenetic proteins (BMPs) play an important role in regulating cell proliferation and differentiation during development and have been shown to play an important role in stem cell biology. BMPs belong to the TGF superfamily and consist of at least 15 members in humans. Genetic disruptions of BMPs have resulted in various skeletal and extraskeletal abnormalities during development. BMPs fulfill their signaling activity by interacting with the heterodimeric complex of two transmembrane serine/threonine kinase receptors, BMPR type I and BMPR type II. The activated receptor kinases phosphorylate the transcription factors Smads 1, 5, or 8, which in turn form a heterodimeric complex with Smad4 in the nucleus and activate the expression of target genes in concert with other co-activators. Upon analyzing the 14 types of BMPs, we found that BMP9 is one of the most potent BMPs in inducing osteogenic differentiation of mesenchymal stem cells (MSCs) both in vitro and in vivo. We further demonstrated that BMP9 regulates a distinct set of downstream targets that may play a role in regulating BMP-induced osteoblast differentiation of MSCs.
BMP9 (also known as growth differentiation factor 2, or GDF-2) was first identified in the developing mouse liver, and its possible roles include inducing and maintaining the cholinergic phenotype of embryonic basal forebrain cholinergic neurons, inhibiting hepatic glucose production and inducing the expression of key enzymes of lipid metabolism, and stimulating murine hepcidin 1 expression. Although the functional role of BMP9 in the skeletal system remains to be fully understood, the potent osteogenic activity of BMP9 suggests that it may be used as an efficacious bone regeneration agent. It is conceivable that other growth factors may act synergistically or enhance BMP9-induced bone formation.
Here, we sought to investigate the effect of insulin-like growth factor 1 (IGF1) on BMP9-induced bone formation. As a member of the IGF signaling system, IGF1 plays an important role in prenatal growth and development. IGF1 transduces its signaling through IGF-receptors and activates the phosphatidylinositol-3-kinase (PI3K)/Akt pathway or the mitogen-activated protein kinase (MAPK) pathway. The Igf1 null mice exhibit a 40% decrease in birth weight compared to their wild-type littermates, suggesting an important role of IGF1 in development. We have found that endogenous IGF1 expression is relatively low in MSCs. Exogenous expression of IGF1 can potentiate BMP9-induced early osteogenic marker alkaline phosphatase (ALP) activity and the expression of later markers, such as osteocalcin (OCN) and osteopontin (OPN) in MSCs. IGF1 is shown to augment BMP9-induced ectopic bone formation in stem cell implantation studies. Using perinatal limb explant culture, we have demonstrated that IGF1 enhances BMP9-induced endochondral ossification, while IGF1 itself can promote the expansion of hypertropic chondrocyte zone of the cultured limb explants. Exogenous expression of IGFBP3, IGFBP4 and IGFBP5, leads to inhibition of the IGF1 effect on BMP9-induced ALP activity and matrix mineralization in MSCs. Furthermore, IGF1 is shown to enhance the BMP9-induced BMPR-Smad reporter activity and the nuclear translocation of Smad1/5/8. While BMP9 stimulation does not significantly induce AKT phosphorylation, PI3K inhibitor LY294002 abolishes the IGF1 potentiation effect on BMP9-mediated osteogenic signaling, and can directly inhibit BMP9 activity, suggesting that BMP9 may cross-talk with IGF1 through PI3K/AKT signaling pathway during osteogenic differentiation of MSCs.
引文
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[1] Haid, R.W., Jr., C.L. Branch, Jr., J.T. Alexander, et al., Posterior lumbar interbody fusion using recombinant human bone morphogenetic protein type 2 with cylindrical interbody cages. Spine J, 2004. 4(5): p. 527-38; discussion 538-9.
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[1] Borrelli, J., Jr., W.D. Prickett, and W.M. Ricci, Treatment of nonunions and osseous defects with bone graft and calcium sulfate. Clin Orthop Relat Res, 2003(411): p. 245-54.
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[1] Haid, R.W., Jr., C.L. Branch, Jr., J.T. Alexander, et al., Posterior lumbar interbody fusion using recombinant human bone morphogenetic protein type 2 with cylindrical interbody cages. Spine J, 2004. 4(5): p. 527-38; discussion 538-9.
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[5] Luo, J., Z.L. Deng, X. Luo, et al., A protocol for rapid generation of recombinantadenoviruses using the AdEasy system. Nat Protoc, 2007. 2(5): p. 1236-47.
[6] Cheng, H., W. Jiang, F.M. Phillips, et al., Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am, 2003. 85-A(8): p. 1544-52.
[7] Kang, Q., M.H. Sun, H. Cheng, et al., Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery. Gene Ther, 2004. 11(17): p. 1312-20.
[8] Luo, J., M.H. Sun, Q. Kang, et al., Gene therapy for bone regeneration. Curr Gene Ther, 2005. 5(2): p. 167-79.
[9] Peng, Y., Q. Kang, H. Cheng, et al., Transcriptional characterization of bone morphogenetic proteins (BMPs)-mediated osteogenic signaling. J Cell Biochem, 2003. 90(6): p. 1149-65.
[10] Deng, Z.L., K.A. Sharff, N. Tang, et al., Regulation of osteogenic differentiation during skeletal development. Front Biosci, 2008. 13: p. 2001-21.
[11] Kang, Q. and T.C. He, A Comprehensive Analysis of the Dual Roles of BMPs in Regulating Adipogenic and Osteogenic Differentiation of Mesenchymal Progenitor Cells. Stem Cells Dev, 2008.
[12] Luu, H.H., W.X. Song, X. Luo, et al., Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells. J Orthop Res, 2007. 25(5): p. 665-77.
[13] Phillips, F.M., P.M. Bolt, T.C. He, et al., Gene therapy for spinal fusion. Spine J, 2005. 5(6 Suppl): p. 250S-258S.
[14] Brissenden, J.E., A. Ullrich, and U. Francke, Human chromosomal mapping of genes for insulin-like growth factors I and II and epidermal growth factor. Nature, 1984. 310(5980): p. 781-4.
[15] Blum, W.F., K. Albertsson-Wikland, S. Rosberg, et al., Serum levels of insulin-likegrowth factor I (IGF-I) and IGF binding protein 3 reflect spontaneous growth hormone secretion. J Clin Endocrinol Metab, 1993. 76(6): p. 1610-6.
[16] Rotwein, P., A.M. Gronowski, and M.J. Thomas, Rapid nuclear actions of growth hormone. Horm Res, 1994. 42(4-5): p. 170-5.
[17] Thomas, M.J., K. Kikuchi, D.P. Bichell, et al., Rapid activation of rat insulin-like growth factor-I gene transcription by growth hormone reveals no alterations in deoxyribonucleic acid-protein interactions within the major promoter. Endocrinology, 1994. 135(4): p. 1584-92.
[18] Giustina, A., Does growth hormone replacement therapy improve cardiac function? Nat Clin Pract Endocrinol Metab, 2007. 3(9): p. 614-5.
[19] Mazziotti, G., A. Giustina, E. Canalis, et al., Glucocorticoid-induced osteoporosis: clinical and therapeutic aspects. Arq Bras Endocrinol Metabol, 2007. 51(8): p. 1404-12.
[20] Baroncelli, G.I., S. Bertelloni, F. Sodini, et al., Acquisition of bone mass in normal individuals and in patients with growth hormone deficiency. J Pediatr Endocrinol Metab, 2003. 16 Suppl 2: p. 327-35.
[21] Monson, J.P., W.M. Drake, P.V. Carroll, et al., Influence of growth hormone on accretion of bone mass. Horm Res, 2002. 58 Suppl 1: p. 52-6.
[22] Kudo, Y., M. Iwashita, Y. Takeda, et al., Evidence for modulation of osteocalcin containing gamma-carboxyglutamic acid residues synthesis by insulin-like growth factor-I and vitamin K2 in human osteosarcoma cell line MG-63. Eur J Endocrinol, 1998. 138(4): p. 443-8.
[23] Johansson, H., S. Gandini, B. Bonanni, et al., Relationships between circulating hormone levels, mammographic percent density and breast cancer risk factors in postmenopausal women. Breast Cancer Res Treat, 2008. 108(1): p. 57-67.
[24] Wozney, J.M., V. Rosen, A.J. Celeste, et al., Novel regulators of bone formation: molecular clones and activities. Science, 1988. 242(4885): p. 1528-34.
[25] Celeste, A.J., J.A. Iannazzi, R.C. Taylor, et al., Identification of transforming growth factor beta family members present in bone-inductive protein purified from bovine bone. Proc Natl Acad Sci U S A, 1990. 87(24): p. 9843-7.
[26] Rosen, V., J. Nove, J.J. Song, et al., Responsiveness of clonal limb bud cell lines to bone morphogenetic protein 2 reveals a sequential relationship between cartilage and bone cell phenotypes. J Bone Miner Res, 1994. 9(11): p. 1759-68.
[27] Chen, P., S. Vukicevic, T.K. Sampath, et al., Osteogenic protein-1 promotes growth and maturation of chick sternal chondrocytes in serum-free cultures. J Cell Sci, 1995. 108 ( Pt 1): p. 105-14.
[28] Smajilagic, A., M.Y. Al-Khalil, A. Redjic, et al., Recombinant human bone morphogenetic protein-7 and bone marrow as a substitute for bone graft in reconstruction defect of rabbit mandible. Saudi Med J, 2005. 26(9): p. 1398-402.
[29] Tsuda, H., T. Wada, T. Yamashita, et al., Enhanced osteoinduction by mesenchymal stem cells transfected with a fiber-mutant adenoviral BMP2 gene. J Gene Med, 2005. 7(10): p. 1322-34.
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