受体活性修饰蛋白1促进成骨作用的研究进展
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摘要
生理状态下,骨吸收与骨形成过程的动态平衡对维持骨组织功能至关重要。而在骨损伤状态下,如何通过促进骨形成,抑制骨吸收从而促进骨愈合过程一直是该领域研究的热点。近年来,受体活性修饰蛋白-1(RAMP1)在骨代谢过程中的调节作用已受到越来越多的关注。RAMP1广泛存在于骨组织中,它可以与不同的G蛋白偶联受体(GPCR)结合,修饰受体行为,调节相应的配体作用。此外,它还能进一步参与到受体介导的信号转导中,影响成骨相关细胞内蛋白的相互作用,从而影响成骨相关细胞增殖、迁移、分化等生物学特性。本文就近年来RAMP1促进成骨作用的研究作一综述。
Under physiological conditions,the dynamic balance between bone resorption and bone formation is necessary to maintain bone tissue function. However, whether we can further accelerate or improve osteogenesis process during bone wound healing has been widely explored. Receptor activity-modifying protein-1(RAMP1) has been extensively investigated because of its extensive biological activities, especially its effects on bone fracture repair. RAMP1 is commonly found in bone tissues and can interact with G-protein coupled receptors to modify their activities. RAMP1 also has a broader role in regulating receptor trafficking and signaling, affecting the biological characteristics of osteoblasts,such as proliferation, migration, and differentiation. Thus, this review summarizes recent studies about the effects of RAMP1 on osteogenesis.
Under physiological conditions,the dynamic balance between bone resorption and bone formation is necessary to maintain bone tissue function. However, whether we can further accelerate or improve osteogenesis process during bone wound healing has been widely explored. Receptor activity-modifying protein-1(RAMP1) has been extensively investigated because of its extensive biological activities, especially its effects on bone fracture repair. RAMP1 is commonly found in bone tissues and can interact with G-protein coupled receptors to modify their activities. RAMP1 also has a broader role in regulating receptor trafficking and signaling, affecting the biological characteristics of osteoblasts,such as proliferation, migration, and differentiation. Thus, this review summarizes recent studies about the effects of RAMP1 on osteogenesis.
引文
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[2] Cooper RR. Nerves in cortical bone[J]. Science,1968, 160(3825):327-328.
[3] Bjurholm A, Kreicbergs A, Brodin E, et al. Substance P-and CGRP-immunoreactive nerves in bone[J]. Peptides,1988, 9(1):165-171.
[4] Bahney CS, Hu DP, Taylor AJ, et al. Stem cellderived endochondral cartilage stimulates bone healing by tissue transformation[J]. J Bone Miner Res,2014, 29(5):1269-1282.
[5] Zhang ZM, Dickerson IM, Russo AF. Calcitonin gene-related peptide receptor activation by receptor activity-modifying protein-1 gene transfer to vascular smooth muscle cells[J]. Endocrinology, 2006, 147(4):1932-1940.
[6] Zhang ZM, Winborn CS, Marquez de Prado B, et al.Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion[J]. J Neurosci,2007, 27(10):2693-2703.
[7] Zhang YF, Xu JK, Ruan YC, et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats[J].Nat Med, 2016, 22(10):1160-1169.
[8] Hay DL, Walker CS. CGRP and its receptors[J].Headache, 2017, 57(4):625-636.
[9] Blixt FW, Radziwon-Balicka A, Edvinsson L, et al.Distribution of CGRP and its receptor components CLR and RAMP1 in the rat retina[J]. Exp Eye Res,2017, 161:124-131.
[10] Zheng LF,Wang R,Xu YZ,et al. Calcitonin generelated peptide dynamics in rat dorsal root ganglia and spinal cord following different sciatic nerve injuries[J]. Brain Res, 2008, 1187:20-32.
[11] Toth CC, Willis D, Twiss JL, et al. Locally synthesized calcitonin gene-related peptide has a critical role in peripheral nerve regeneration[J]. J Neuropathol Exp Neurol, 2009, 68(3):326-337.
[12] Xiang L,Ma L,Wei N,et al. Effect of lentiviral vector overexpression a-calcitonin gene-related peptide on titanium implant osseointegration in a-CGRP-deficient mice[J]. Bone, 2017, 94:135-140.
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[17] Booe JM, Walker CS, Barwell J, et al. Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G proteincoupled receptor[J]. Mol Cell, 2015, 58(6):1040-1052.
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[19] Klein KR, Matson BC, Caron KM. The expanding repertoire of receptor activity modifying protein(RAMP)function[J]. Crit Rev Biochem Mol Biol,2016,51(1):65-71.
[20] Yuan J, Gilbert ER, Cline MA. The central anorexigenic mechanism of amylin in Japanese quail(Coturnix japonica)involves pro-opiomelanocortin,calcitonin receptor, and the arcuate nucleus of the hypothalamus[J]. Comp Biochem Physiol A Mol Integr Physiol, 2017, 210:28-34.
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[26] Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB[J]. Nat Rev Mol Cell Biol, 2001, 2(8):599-609.
[27] Koga T, Matsui Y,Asagiri M, et al. NFAT and Osterix cooperatively regulate bone formation[J]. Nat Med,2005, 11(8):880-885.
[28] Komori T. Signaling networks in RUNX2-dependent bone development[J]. J Cell Biochem, 2011,112(3):750-755.
[29] Yoo YM, Kwag JH, Kim KH, et al. Effects of neuropeptides and mechanical loading on bone cell resorption in vitro[J]. Int J Mol Sci, 2014, 15(4):5874-5883.
[30] Liang W, Zhuo XL, Tang ZF, et al. Calcitonin generelated peptide stimulates proliferation and osteogenic differentiation of osteoporotic rat-derived bone mesenchymal stem cells[J]. Mol Cell Biochem,2015, 402(1/2):101-110.
[31] Mach DB, Rogers SD, Sabino MC, et al. Origins of skeletal pain:sensory and sympathetic innervation of the mouse femur[J]. Neuroscience, 2002, 113(1):155-166.
[32] Ballica R,Valentijn K,Khachatryan A, et al. Targeted expression of calcitonin gene-related peptide to osteoblasts increases bone density in mice[J]. J Bone Miner Res, 1999, 14(7):1067-1074.
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[34] Huebner AK, Schinke T,Priemel M, et al. Calcitonin deficiency in mice progressively results in high bone turnover[J]. J Bone Miner Res, 2006, 21(12):1924-1934.
[35] Li Y,Tan YH, Zhang G, et al. Effects of calcitonin gene-related peptide on the expression and activity of nitric oxide synthase during mandibular bone healing in rabbits:an experimental study[J]. J Oral Maxillofac Surg, 2009, 67(2):273-279.
[36] Hilairet S, Belanger C, Bertrand J, et al. Agonist-promoted internalization of a ternary complex between calcitonin receptor-like receptor, receptor activitymodifying protein 1(RAMP1), and beta-arrestin[J].J Biol Chem,2001,276(45):42182-42190.
[37] McLatchie LM,Fraser NJ,Main MJ,et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor[J]. Nature, 1998,393(6683):333-339.
[38] Marquez-Rodas I, Xavier FE, Arroyo-Villa I, et al.Increased expression in calcitonin-like receptor induced by aldosterone in cerebral arteries from spontaneously hypertensive rats does not correlate with functional role of CGRP receptor[J]. Regul Pept,2008, 146(1/2/3):125-130.
[39] Togari A, Arai M,Mizutani S, et al. Expression of mRNAs for neuropeptide receptors and beta-adrenergic receptors in human osteoblasts and human osteogenic sarcoma cells[J]. Neurosci Lett, 1997,233(2/3):125-128.
[40] Kawase T, Okuda K, Burns DM. Immature human osteoblastic MG63 cells predominantly express a subtype 1-like CGRP receptor that inactivates extra-cellular signal response kinase by a cAMP-dependent mechanism[J]. Eur J Pharmacol, 2003, 470(3):125-137.
[41] Uzan B, de Vernejoul MC, Cressent M. RAMPs and CRLR expressions in osteoblastic cells after dexamethasone treatment[J]. Biochem Biophys Res Commun,2004, 321(4):802-808.
[42] Villa I,Mrak E,Rubinacci A,et al. CGRP inhibits osteoprotegerin production in human osteoblast-like cells via cAMP/PKA-dependent pathway[J]. Am J Physiol Cell Physiol, 2006, 291(3):C529-C537.
[43] Russo AF,Kuburas A,Kaiser EA,et al. A potential preclinical migraine model:CGRP-sensitized mice[J]. Mol Cell Pharmacol, 2009. 1(5):264-270.
[44] Bohn KJ,Li BL,Huang XF, et al. CGRP receptor activity in mice with global expression of human receptor activity modifying protein 1[J]. Br J Pharmacol, 2017, 174(12):1826-1840.
[45] Zhao ZL, Fu XB,Zhang G, et al. The influence of RAMP1 overexpression on CGRP-induced osteogenic differentiation in MG-63 cells in vitro:an experimental study[J]. J Cell Biochem, 2013,114(2):314-322.
[46]蒋章,张慧宇,张纲,等.RAMP1-siRNAX对CGRP促MG-63细胞增殖作用影响的实验研究[J].实用口腔医学杂志,2015, 31(3):339-342.Jiang Z,Zhang HY, Zhang G, et al. Experimental study on the effect of RAMP1-siRNA on CGRP-induced proliferation of MG-63 cells[J]. J Pract Stomatol,2015,31(3):339-342.
[47] Kurashige C, Hosono K, Matsuda H, et al. Roles of receptor activity-modifying protein 1 in angiogenesis and lymphangiogenesis during skin wound healing in mice[J]. FASEB J, 2014, 28(3):1237-1247.
[48] Mishima T, Ito Y, Nishizawa N, et al. RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice[J]. J Surg Res, 2017, 219:50-60.
[49] Erdling A, Sheykhzade M, Edvinsson L. Differential inhibitory response to telcagepant on aCGRP induced vasorelaxation and intracellular Ca~(2+)levels in the perfused and non-perfused isolated rat middle cerebral artery[J]. J Headache Pain,2017, 18(1):61.
[50] Kawashima-Takeda N,Ito Y,Nishizawa N,et al.RAMP1 suppresses mucosal injury from dextransodium sulfate-induced colitis in mice[J]. J Gastroenterol Hepatol, 2017, 32(4):809-818.
[51] Umeda Y, Takamiya M, Yoshizaki H, et al. Inhibition of mitogen-stimulated T lymphocyte proliferation by calcitonin gene-related peptide[J]. Biochem Biophys Res Commun,1988, 154(1):227-235.
[52] Wang F, Millet I, Bottomly K, et al. Calcitonin generelated peptide inhibits interleukin 2 production by murine T lymphocytes[J]. J Biol Chem, 1992, 267(29):21052-21057.
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[54] Cheng L, Khan M, Mudge AW. Calcitonin generelated peptide promotes Schwann cell proliferation[J]. J Cell Biol, 1995, 129(3):789-796.
[55] Ichinose M, Sawada M. Enhancement of phagocytosis by calcitonin gene-related peptide(CGRP)in cultured mouse peritoneal macrophages[J]. Peptides,1996, 17(8):1405-1414.
[56] Vignery A, McCarthy TL. The neuropeptide calcitonin gene-related peptide stimulates insulin-like growth factor I production by primary fetal rat osteo-blasts[J]. Bone,1996, 18(4):331-335.
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[2] Cooper RR. Nerves in cortical bone[J]. Science,1968, 160(3825):327-328.
[3] Bjurholm A, Kreicbergs A, Brodin E, et al. Substance P-and CGRP-immunoreactive nerves in bone[J]. Peptides,1988, 9(1):165-171.
[4] Bahney CS, Hu DP, Taylor AJ, et al. Stem cellderived endochondral cartilage stimulates bone healing by tissue transformation[J]. J Bone Miner Res,2014, 29(5):1269-1282.
[5] Zhang ZM, Dickerson IM, Russo AF. Calcitonin gene-related peptide receptor activation by receptor activity-modifying protein-1 gene transfer to vascular smooth muscle cells[J]. Endocrinology, 2006, 147(4):1932-1940.
[6] Zhang ZM, Winborn CS, Marquez de Prado B, et al.Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion[J]. J Neurosci,2007, 27(10):2693-2703.
[7] Zhang YF, Xu JK, Ruan YC, et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats[J].Nat Med, 2016, 22(10):1160-1169.
[8] Hay DL, Walker CS. CGRP and its receptors[J].Headache, 2017, 57(4):625-636.
[9] Blixt FW, Radziwon-Balicka A, Edvinsson L, et al.Distribution of CGRP and its receptor components CLR and RAMP1 in the rat retina[J]. Exp Eye Res,2017, 161:124-131.
[10] Zheng LF,Wang R,Xu YZ,et al. Calcitonin generelated peptide dynamics in rat dorsal root ganglia and spinal cord following different sciatic nerve injuries[J]. Brain Res, 2008, 1187:20-32.
[11] Toth CC, Willis D, Twiss JL, et al. Locally synthesized calcitonin gene-related peptide has a critical role in peripheral nerve regeneration[J]. J Neuropathol Exp Neurol, 2009, 68(3):326-337.
[12] Xiang L,Ma L,Wei N,et al. Effect of lentiviral vector overexpression a-calcitonin gene-related peptide on titanium implant osseointegration in a-CGRP-deficient mice[J]. Bone, 2017, 94:135-140.
[13] Hilairet S, Foord SM, Marshall FH, et al. Proteinprotein interaction and not glycosylation determines the binding selectivity of heterodimers between the calcitonin receptor-like receptor and the receptor activity-modifying proteins[J]. J Biol Chem, 2001,276(31):29575-29581.
[14] Hay DL, Poyner DR, Smith DM. Desensitisation of adrenomedullin and CGRP receptors[J]. Regul Pept,2003, 112(1/2/3):139-145.
[15] Udawela M,Hay DL,Sexton PM. The receptor activity modifying protein family of G protein coupled receptor accessory proteins[J]. Semin Cell Dev Biol,2004, 15(3):299-308.
[16] Qi T, Hay DL. Structure-function relationships of the N-terminus of receptor activity-modifying proteins[J]. Br J Pharmacol, 2010,159(5):1059-1068.
[17] Booe JM, Walker CS, Barwell J, et al. Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G proteincoupled receptor[J]. Mol Cell, 2015, 58(6):1040-1052.
[18] Hay DL,Walker CS,Gingell JJ,et al. Receptor activity-modifying proteins; multifunctional G protein-coupled receptor accessory proteins[J]. Biochem Soc Trans, 2016, 44(2):568-573.
[19] Klein KR, Matson BC, Caron KM. The expanding repertoire of receptor activity modifying protein(RAMP)function[J]. Crit Rev Biochem Mol Biol,2016,51(1):65-71.
[20] Yuan J, Gilbert ER, Cline MA. The central anorexigenic mechanism of amylin in Japanese quail(Coturnix japonica)involves pro-opiomelanocortin,calcitonin receptor, and the arcuate nucleus of the hypothalamus[J]. Comp Biochem Physiol A Mol Integr Physiol, 2017, 210:28-34.
[21] Edvinsson L. The trigeminovascular pathway:role of CGRP and CGRP receptors in migraine[J]. Headache, 2017,57(Suppl 2):47-55.
[22] Hay DL, Garelja ML, Poyner DR, et al. Update on the pharmacology of calcitonin/CGRP family of peptides:IUPHAR Review 25[J]. Br J Pharmacol,2018, 175(1):3-17.
[23] Booe JM,Warner ML,Roehrkasse AM,et al. Probing the mechanism of receptor activity-modifying protein modulation of GPCR ligand selectivity through rational design of potent adrenomedullin and calcitonin gene-related peptide antagonists[J]. Mol Pharmacol, 2018, 93(4):355-367.
[24] Hay DL, Pioszak AA. Receptor activity-modifying proteins(RAMPs):new insights and roles[J]. Annu Rev Pharmacol Toxicol,2016, 56:469-487.
[25] Pawlak JB, Wetzel-Strong SE, Dunn MK, et al. Cardiovascular effects of exogenous adrenomedullin and CGRP in Ramp and Calcrl deficient mice[J]. Peptides, 2017, 88:1-7.
[26] Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB[J]. Nat Rev Mol Cell Biol, 2001, 2(8):599-609.
[27] Koga T, Matsui Y,Asagiri M, et al. NFAT and Osterix cooperatively regulate bone formation[J]. Nat Med,2005, 11(8):880-885.
[28] Komori T. Signaling networks in RUNX2-dependent bone development[J]. J Cell Biochem, 2011,112(3):750-755.
[29] Yoo YM, Kwag JH, Kim KH, et al. Effects of neuropeptides and mechanical loading on bone cell resorption in vitro[J]. Int J Mol Sci, 2014, 15(4):5874-5883.
[30] Liang W, Zhuo XL, Tang ZF, et al. Calcitonin generelated peptide stimulates proliferation and osteogenic differentiation of osteoporotic rat-derived bone mesenchymal stem cells[J]. Mol Cell Biochem,2015, 402(1/2):101-110.
[31] Mach DB, Rogers SD, Sabino MC, et al. Origins of skeletal pain:sensory and sympathetic innervation of the mouse femur[J]. Neuroscience, 2002, 113(1):155-166.
[32] Ballica R,Valentijn K,Khachatryan A, et al. Targeted expression of calcitonin gene-related peptide to osteoblasts increases bone density in mice[J]. J Bone Miner Res, 1999, 14(7):1067-1074.
[33] Gangula PR,Zhao H,Supowit SC, et al. Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene knockout mice[J]. Hypertension, 2000, 35(1 Pt 2):470-475.
[34] Huebner AK, Schinke T,Priemel M, et al. Calcitonin deficiency in mice progressively results in high bone turnover[J]. J Bone Miner Res, 2006, 21(12):1924-1934.
[35] Li Y,Tan YH, Zhang G, et al. Effects of calcitonin gene-related peptide on the expression and activity of nitric oxide synthase during mandibular bone healing in rabbits:an experimental study[J]. J Oral Maxillofac Surg, 2009, 67(2):273-279.
[36] Hilairet S, Belanger C, Bertrand J, et al. Agonist-promoted internalization of a ternary complex between calcitonin receptor-like receptor, receptor activitymodifying protein 1(RAMP1), and beta-arrestin[J].J Biol Chem,2001,276(45):42182-42190.
[37] McLatchie LM,Fraser NJ,Main MJ,et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor[J]. Nature, 1998,393(6683):333-339.
[38] Marquez-Rodas I, Xavier FE, Arroyo-Villa I, et al.Increased expression in calcitonin-like receptor induced by aldosterone in cerebral arteries from spontaneously hypertensive rats does not correlate with functional role of CGRP receptor[J]. Regul Pept,2008, 146(1/2/3):125-130.
[39] Togari A, Arai M,Mizutani S, et al. Expression of mRNAs for neuropeptide receptors and beta-adrenergic receptors in human osteoblasts and human osteogenic sarcoma cells[J]. Neurosci Lett, 1997,233(2/3):125-128.
[40] Kawase T, Okuda K, Burns DM. Immature human osteoblastic MG63 cells predominantly express a subtype 1-like CGRP receptor that inactivates extra-cellular signal response kinase by a cAMP-dependent mechanism[J]. Eur J Pharmacol, 2003, 470(3):125-137.
[41] Uzan B, de Vernejoul MC, Cressent M. RAMPs and CRLR expressions in osteoblastic cells after dexamethasone treatment[J]. Biochem Biophys Res Commun,2004, 321(4):802-808.
[42] Villa I,Mrak E,Rubinacci A,et al. CGRP inhibits osteoprotegerin production in human osteoblast-like cells via cAMP/PKA-dependent pathway[J]. Am J Physiol Cell Physiol, 2006, 291(3):C529-C537.
[43] Russo AF,Kuburas A,Kaiser EA,et al. A potential preclinical migraine model:CGRP-sensitized mice[J]. Mol Cell Pharmacol, 2009. 1(5):264-270.
[44] Bohn KJ,Li BL,Huang XF, et al. CGRP receptor activity in mice with global expression of human receptor activity modifying protein 1[J]. Br J Pharmacol, 2017, 174(12):1826-1840.
[45] Zhao ZL, Fu XB,Zhang G, et al. The influence of RAMP1 overexpression on CGRP-induced osteogenic differentiation in MG-63 cells in vitro:an experimental study[J]. J Cell Biochem, 2013,114(2):314-322.
[46]蒋章,张慧宇,张纲,等.RAMP1-siRNAX对CGRP促MG-63细胞增殖作用影响的实验研究[J].实用口腔医学杂志,2015, 31(3):339-342.Jiang Z,Zhang HY, Zhang G, et al. Experimental study on the effect of RAMP1-siRNA on CGRP-induced proliferation of MG-63 cells[J]. J Pract Stomatol,2015,31(3):339-342.
[47] Kurashige C, Hosono K, Matsuda H, et al. Roles of receptor activity-modifying protein 1 in angiogenesis and lymphangiogenesis during skin wound healing in mice[J]. FASEB J, 2014, 28(3):1237-1247.
[48] Mishima T, Ito Y, Nishizawa N, et al. RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice[J]. J Surg Res, 2017, 219:50-60.
[49] Erdling A, Sheykhzade M, Edvinsson L. Differential inhibitory response to telcagepant on aCGRP induced vasorelaxation and intracellular Ca~(2+)levels in the perfused and non-perfused isolated rat middle cerebral artery[J]. J Headache Pain,2017, 18(1):61.
[50] Kawashima-Takeda N,Ito Y,Nishizawa N,et al.RAMP1 suppresses mucosal injury from dextransodium sulfate-induced colitis in mice[J]. J Gastroenterol Hepatol, 2017, 32(4):809-818.
[51] Umeda Y, Takamiya M, Yoshizaki H, et al. Inhibition of mitogen-stimulated T lymphocyte proliferation by calcitonin gene-related peptide[J]. Biochem Biophys Res Commun,1988, 154(1):227-235.
[52] Wang F, Millet I, Bottomly K, et al. Calcitonin generelated peptide inhibits interleukin 2 production by murine T lymphocytes[J]. J Biol Chem, 1992, 267(29):21052-21057.
[53] Asahina A, Hosoi J, Murphy GF, et al. Calcitonin generelated peptide modulates Langerhans cell antigenpresenting function[J]. Proc Assoc Am Physicians,1995, 107(2):242-244.
[54] Cheng L, Khan M, Mudge AW. Calcitonin generelated peptide promotes Schwann cell proliferation[J]. J Cell Biol, 1995, 129(3):789-796.
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