Progress of research on the relationship between calcitonin gene-related peptide and RANK/RANKL/OPG system in the bone reconstruction_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

WANG Shiyao ^1,2 , XU Shaoce ^1,2 , SHI Zhengwei ^1,2 , WU Jianchao ^1,2 , LEI Shuanhu ¹ ,  WANG Yuliang ¹

1. Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou Gansu, 730000, P.R.China;
2. Orthopedics Key Laboratory of Gansu Province, Lanzhou Gansu, 730000, P.R.China;

Corresponding author：

WANG Yuliang, Email: wyl60918@sina.com

Keywords：

Bone reconstruction; osteoblast; osteoclast; calcitonin gene-related peptide; receptor activator of nuclear factor κB; receptor activator of nuclear factor κB ligand; osteoprotegerin

DOI：

10.7507/1002-1892.201811137

Video：

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Objective To summarize the research progress on the calcitonin gene-related peptide (CGRP) and receptor activator of nuclear factor κB (RANK)/receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) system during bone reconstruction to provide theoretical basis for further research on the prevention and treatment of bone-related diseases.Methods The relevant research results at home and abroad in recent years were analyzed and summarized.Results CGRP and RANK/RANKL/OPG system play important regulatory roles in the bone reconstruction.Conclusion At present, the research on the mechanism of CGRP and RANK/RANKL/OPG system in bone reconstruction is insufficient. Therefore, it is necessary to study further on the process and interrelation of CGRP and RANK/RANKL/OPG system in bone reconstruction to confirm their mechanism, which will bring new ideas and methods for the treatment of bone related diseases in clinic.

Citation： WANG Shiyao, XU Shaoce, SHI Zhengwei, WU Jianchao, LEI Shuanhu, WANG Yuliang. Progress of research on the relationship between calcitonin gene-related peptide and RANK/RANKL/OPG system in the bone reconstruction. Chinese Journal of Reparative and Reconstructive Surgery, 2019, 33(4): 511-515. doi: 10.7507/1002-1892.201811137 Copy

1.	Iacobini C, Blasetti Fantauzzi C, Bedini R, et al. Galectin-3 is essential for proper bone cell differentiation and activity, bone remodeling and biomechanical competence in mice. Metabolism, 2018, 83: 149-158.
2.	李菊, 郭晓东, 李明政, 等. 蛋白质因子在调控骨改建过程中的作用机制研究进展. 中国修复重建外科杂志, 2019, 33(1): 115-123.
3.	Tang P, Duan C, Wang Z, et al. NPY and CGRP inhibitor influence on ERK pathway and macrophage aggregation during fracture healing. Cell Physiol Biochem, 2017, 41(4): 1457-1467.
4.	K?ttstorfer J, Thomas A, Gregori M, et al. Are OPG and RANKL involved in human fracture healing? J Orthop Res, 2014, 32(12): 1557-1561.
5.	Kauther MD, Xu J, Wedemeyer C. Alpha-calcitonin gene-related peptide can reverse the catabolic influence of UHMWPE particles on RANKL expression in primary human osteoblasts. Int J Biol Sci, 2010, 6(6): 525-536.
6.	Imai S, Rauvala H, Konttinen YT, et al. Efferent targets of osseous CGRP‐immunoreactive nerve fiber before and after bone destruction in adjuvant arthritic rat: an ultramorphological study on their terminal‐target relations. J Bone Miner Res, 1997, 12(7): 1018-1027.
7.	Imai S, Matsusue Y. Neuronal regulation of bone metabolism and anabolism: calcitonin gene-related peptide-, substance P-, and tyrosine hydroxylase-containing nerves and the bone. Microsc Res Tech, 2002, 58(2): 61-69.
8.	Villa I, Dal Fiume C, Maestroni A, et al. Human osteoblast-like cell proliferation induced by calcitonin-related peptides involves PKC activity. Am J Physiol Endocrinol Metab, 2003, 284(3): E627-633.
9.	Cornish J, Callon KE, Bava U, et al. Effects of calcitonin, amylin, and calcitonin gene-related peptide on osteoclast development. Bone, 2001, 29(2): 162-168.
10.	Wang L, Shi X, Zhao R, et al. Calcitonin-gene-related peptide stimulates stromal cell osteogenic differentiation and inhibits RANKL induced NF-κB activation, osteoclastogenesis and bone resorption. Bone, 2010, 46(5): 1369-1379.
11.	孙东良, 陈通, 付爱军, 等. 颅脑损伤合并股骨闭合性骨折大鼠模型的建立及骨痂中降钙素基因相关肽的表达及意义. 中国煤炭工业医学杂志, 2014, 17(7): 1123-1126.
12.	Li X, Qin L, Bergenstock M, et al. Parathyroid hormone stimulates osteoblastic expression of MCP-1 to recruit and increase the fusion of pre/osteoclasts. J Biol Chem, 2007, 282(45): 33098-33106.
13.	Han N, Zhang DY, Wang TB, et al. Calcitonin gene-related peptide induces proliferation and monocyte chemoattractant protein-1 expression via extracellular signal-regulated kinase activation in rat osteoblasts. Chin Med J (Engl), 2010, 123(13): 1748-1753.
14.	Hukkanen M, Konttinen YT, Santavirta S, et al. Rapid proliferation of calcitonin gene-related peptide-immunoreactive nerves during healing of rat tibial fracture suggests neural involvement in bone growth and remodelling. Neuroscience, 1993, 54(4): 969-979.
15.	姚建华, 时述山, 李亚非, 等. 脊髓损伤大鼠胫骨骨痂中降钙素基因相关肽的改变. 中华实验外科杂志, 2000, 17(4): 342-343.
16.	Quinn JM, Saleh H. Modulation of osteoclast function in bone by the immune system. Mol Cell Endocrinol, 2009, 310(1-2): 40-51.
17.	Huang YL, Liu YW, Huang YJ, et al. A special ingredient (VtR) containing oligostilbenes isolated from vitis thunbergii prevents bone loss in ovariectomized mice: in vitro and in vivo study. Evid Based Complement Alternat Med, 2013, 2013: 409421.
18.	Malliga DE, Wagner D, Fahrleitner-Pammer A. The role of osteoprotegerin (OPG) receptor activator for nuclear factor kappaB ligand (RANKL) in cardiovascular pathology-a review. Wien Med Wochenschr, 2011, 161(23-24): 565-570.
19.	Yasuda H. Bone and bone related biochemical examinations. Bone and collagen related metabolites. Receptor activator of NF-kappaB ligand (RANKL). Clini Calcium, 2006, 16(6): 964-970.
20.	Ryser MD, Qu Y, Komarova SV. Osteoprotegerin in bone metastases: mathematical solution to the puzzle. PLoS Comput Biol, 2012, 8(10): e1002703.
21.	Quinn JM, Itoh K, Udagawa N, et al. Transforming growth factor beta affects osteoclast differentiation via direct and indirect actions. J Bone Mineral Res, 2001, 16(10): 1787-1794.
22.	Teitelbaum SL. Bone resorption by osteoclasts. Science, 2000, 289(5484): 1504-1508.
23.	Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature, 2003, 423(6937): 337-342.
24.	Wada T, Nakashima T, Hiroshi N, et al. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med, 2006, 12(1): 17-25.
25.	Enomoto T, Furuya Y, Tomimori Y, et al. Establishment of a new murine model of hypercalcemia with anorexia by overexpression of soluble receptor activator of NF-κB ligand using an adenovirus vector. J Bone Miner Metab, 2011, 29(4): 414-421.
26.	Weitzmann MN. The role of inflammatory cytokines, the RANKL/OPG axis, and the immunoskeletal interface in physiological bone turnover and osteoporosis. Scientifica (Cairo), 2013, 2013: 125705.
27.	O’Brien EA, Williams JH, Marshall MJ. Osteoprotegerin is produced when prostaglandin synthesis is inhibited causing osteoclasts to detach from the surface of mouse parietal bone and attach to the endocranial membrane. Bone, 2001, 28(2): 208-214.
28.	Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol, 2005, 5(6): 618-625.
29.	熊燕琴, 周筠, 雷涛. 骨代谢信号通路的研究进展. 中国骨质疏松杂志, 2014, 20(2): 200-204.
30.	武文杰, 刘浩, 娄纪纲, 等. 国产人工颈椎间盘界面压力对假体-骨界面骨整合的影响. 中国修复重建外科杂志, 2017, 31(4): 443-450.
31.	Shimizu‐Ishiura M, Kawana F, Sasaki T. Osteoprotegerin administration reduces femural bone loss in ovariectomized mice via impairment of osteoclast structure and function. J Electron Microsc (Tokyo), 2002, 51(5): 315-325.
32.	Kim HH, Lee DE, Shin JN, et al. Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett, 1999, 443(3): 297-302.
33.	Naito A, Azuma S, Tanaka S, et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells, 1999, 4(6): 353-362.
34.	曾立, 徐永明, 邢更彦. 脂多糖对破骨细胞生成及骨吸收功能作用及其机制研究. 中国修复重建外科杂志, 2018, 32(5): 568-574.
35.	Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys, 2008, 473(2): 139-146.
36.	Kon T, Cho TJ, Aizawa T, et al. Expression of osteoprotegerin, receptor activator of NF‐κB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Mineral Res, 2001, 16(6): 1004-1014.
37.	Wang XF, Zhang YK, Yu ZS, et al. The role of the serum RANKL/OPG ratio in the healing of intertrochanteric fractures in elderly patients. Mol Med Rep, 2013, 7(4): 1169-1172.
38.	严斌, 何沛恒, 罗震, 等. 骨保护素与 RANKL 在骨折愈合期的表达及其意义. 实用医学杂志, 2016, 32(9): 1464-1467.
39.	Cheung J, Mak YT, Papaioannou S, et al. Interleukin-6(IL-6), IL-1, receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin production by human osteoblastic cells: comparison of the effects of 17-beta oestradiol and raloxifene. J Endocrinol, 2003, 177(3): 423-433.
40.	Fu Q, Jilka RL, Manolagas SC, et al. Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. J Biol Chem, 2002, 277(50): 48868-48875.
41.	Villa I, Melzi R, Pagani F, et al. Effects of calcitonin gene-related peptide and amylin on human osteoblast-like cells proliferation. Eur J Pharmacol, 2000, 409(3): 273-278.
42.	Ishizuka K, Hirukawa K, Nakamura H, et al. Inhibitory effect of CGRP on osteoclast formation by mouse bone marrow cells treated with isoproterenol. Neurosci Let, 2005, 379(1): 47-51.
43.	He H, Chai J, Zhang S, et al. CGRP may regulate bone metabolism through stimulating osteoblast differentiation and inhibiting osteoclast formation. Mol Med Rep, 2016, 13(5): 3977-3984.
44.	肖啸, 胡冰. 不同浓度降钙素基因相关肽对大鼠成骨细胞 OPG mRNA 表达的影响. 医学研究杂志, 2013, 42(9): 106-109.
45.	Villa I, Mrak E, Rubinacci A, et al. CGRP inhibits osteoprotegerin production in human osteoblast-like cells via cAMP/PKA-dependent pathway. Am J Physiol Cell Physiol, 2006, 291(3): C529-537.
46.	徐琳, 葛永玲, 郑宇浩, 等. H89 抑制降钙素基因相关肽促兔成骨细胞OPG表达的实验研究. 西北国防医学杂志, 2011, 32(4): 274-275.

1. Iacobini C, Blasetti Fantauzzi C, Bedini R, et al. Galectin-3 is essential for proper bone cell differentiation and activity, bone remodeling and biomechanical competence in mice. Metabolism, 2018, 83: 149-158.
2. 李菊, 郭晓东, 李明政, 等. 蛋白质因子在调控骨改建过程中的作用机制研究进展. 中国修复重建外科杂志, 2019, 33(1): 115-123.
3. Tang P, Duan C, Wang Z, et al. NPY and CGRP inhibitor influence on ERK pathway and macrophage aggregation during fracture healing. Cell Physiol Biochem, 2017, 41(4): 1457-1467.
4. K?ttstorfer J, Thomas A, Gregori M, et al. Are OPG and RANKL involved in human fracture healing? J Orthop Res, 2014, 32(12): 1557-1561.
5. Kauther MD, Xu J, Wedemeyer C. Alpha-calcitonin gene-related peptide can reverse the catabolic influence of UHMWPE particles on RANKL expression in primary human osteoblasts. Int J Biol Sci, 2010, 6(6): 525-536.
6. Imai S, Rauvala H, Konttinen YT, et al. Efferent targets of osseous CGRP‐immunoreactive nerve fiber before and after bone destruction in adjuvant arthritic rat: an ultramorphological study on their terminal‐target relations. J Bone Miner Res, 1997, 12(7): 1018-1027.
7. Imai S, Matsusue Y. Neuronal regulation of bone metabolism and anabolism: calcitonin gene-related peptide-, substance P-, and tyrosine hydroxylase-containing nerves and the bone. Microsc Res Tech, 2002, 58(2): 61-69.
8. Villa I, Dal Fiume C, Maestroni A, et al. Human osteoblast-like cell proliferation induced by calcitonin-related peptides involves PKC activity. Am J Physiol Endocrinol Metab, 2003, 284(3): E627-633.
9. Cornish J, Callon KE, Bava U, et al. Effects of calcitonin, amylin, and calcitonin gene-related peptide on osteoclast development. Bone, 2001, 29(2): 162-168.
10. Wang L, Shi X, Zhao R, et al. Calcitonin-gene-related peptide stimulates stromal cell osteogenic differentiation and inhibits RANKL induced NF-κB activation, osteoclastogenesis and bone resorption. Bone, 2010, 46(5): 1369-1379.
11. 孙东良, 陈通, 付爱军, 等. 颅脑损伤合并股骨闭合性骨折大鼠模型的建立及骨痂中降钙素基因相关肽的表达及意义. 中国煤炭工业医学杂志, 2014, 17(7): 1123-1126.
12. Li X, Qin L, Bergenstock M, et al. Parathyroid hormone stimulates osteoblastic expression of MCP-1 to recruit and increase the fusion of pre/osteoclasts. J Biol Chem, 2007, 282(45): 33098-33106.
13. Han N, Zhang DY, Wang TB, et al. Calcitonin gene-related peptide induces proliferation and monocyte chemoattractant protein-1 expression via extracellular signal-regulated kinase activation in rat osteoblasts. Chin Med J (Engl), 2010, 123(13): 1748-1753.
14. Hukkanen M, Konttinen YT, Santavirta S, et al. Rapid proliferation of calcitonin gene-related peptide-immunoreactive nerves during healing of rat tibial fracture suggests neural involvement in bone growth and remodelling. Neuroscience, 1993, 54(4): 969-979.
15. 姚建华, 时述山, 李亚非, 等. 脊髓损伤大鼠胫骨骨痂中降钙素基因相关肽的改变. 中华实验外科杂志, 2000, 17(4): 342-343.
16. Quinn JM, Saleh H. Modulation of osteoclast function in bone by the immune system. Mol Cell Endocrinol, 2009, 310(1-2): 40-51.
17. Huang YL, Liu YW, Huang YJ, et al. A special ingredient (VtR) containing oligostilbenes isolated from vitis thunbergii prevents bone loss in ovariectomized mice: in vitro and in vivo study. Evid Based Complement Alternat Med, 2013, 2013: 409421.
18. Malliga DE, Wagner D, Fahrleitner-Pammer A. The role of osteoprotegerin (OPG) receptor activator for nuclear factor kappaB ligand (RANKL) in cardiovascular pathology-a review. Wien Med Wochenschr, 2011, 161(23-24): 565-570.
19. Yasuda H. Bone and bone related biochemical examinations. Bone and collagen related metabolites. Receptor activator of NF-kappaB ligand (RANKL). Clini Calcium, 2006, 16(6): 964-970.
20. Ryser MD, Qu Y, Komarova SV. Osteoprotegerin in bone metastases: mathematical solution to the puzzle. PLoS Comput Biol, 2012, 8(10): e1002703.
21. Quinn JM, Itoh K, Udagawa N, et al. Transforming growth factor beta affects osteoclast differentiation via direct and indirect actions. J Bone Mineral Res, 2001, 16(10): 1787-1794.
22. Teitelbaum SL. Bone resorption by osteoclasts. Science, 2000, 289(5484): 1504-1508.
23. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature, 2003, 423(6937): 337-342.
24. Wada T, Nakashima T, Hiroshi N, et al. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med, 2006, 12(1): 17-25.
25. Enomoto T, Furuya Y, Tomimori Y, et al. Establishment of a new murine model of hypercalcemia with anorexia by overexpression of soluble receptor activator of NF-κB ligand using an adenovirus vector. J Bone Miner Metab, 2011, 29(4): 414-421.
26. Weitzmann MN. The role of inflammatory cytokines, the RANKL/OPG axis, and the immunoskeletal interface in physiological bone turnover and osteoporosis. Scientifica (Cairo), 2013, 2013: 125705.
27. O’Brien EA, Williams JH, Marshall MJ. Osteoprotegerin is produced when prostaglandin synthesis is inhibited causing osteoclasts to detach from the surface of mouse parietal bone and attach to the endocranial membrane. Bone, 2001, 28(2): 208-214.
28. Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol, 2005, 5(6): 618-625.
29. 熊燕琴, 周筠, 雷涛. 骨代谢信号通路的研究进展. 中国骨质疏松杂志, 2014, 20(2): 200-204.
30. 武文杰, 刘浩, 娄纪纲, 等. 国产人工颈椎间盘界面压力对假体-骨界面骨整合的影响. 中国修复重建外科杂志, 2017, 31(4): 443-450.
31. Shimizu‐Ishiura M, Kawana F, Sasaki T. Osteoprotegerin administration reduces femural bone loss in ovariectomized mice via impairment of osteoclast structure and function. J Electron Microsc (Tokyo), 2002, 51(5): 315-325.
32. Kim HH, Lee DE, Shin JN, et al. Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett, 1999, 443(3): 297-302.
33. Naito A, Azuma S, Tanaka S, et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells, 1999, 4(6): 353-362.
34. 曾立, 徐永明, 邢更彦. 脂多糖对破骨细胞生成及骨吸收功能作用及其机制研究. 中国修复重建外科杂志, 2018, 32(5): 568-574.
35. Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys, 2008, 473(2): 139-146.
36. Kon T, Cho TJ, Aizawa T, et al. Expression of osteoprotegerin, receptor activator of NF‐κB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Mineral Res, 2001, 16(6): 1004-1014.
37. Wang XF, Zhang YK, Yu ZS, et al. The role of the serum RANKL/OPG ratio in the healing of intertrochanteric fractures in elderly patients. Mol Med Rep, 2013, 7(4): 1169-1172.
38. 严斌, 何沛恒, 罗震, 等. 骨保护素与 RANKL 在骨折愈合期的表达及其意义. 实用医学杂志, 2016, 32(9): 1464-1467.
39. Cheung J, Mak YT, Papaioannou S, et al. Interleukin-6(IL-6), IL-1, receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin production by human osteoblastic cells: comparison of the effects of 17-beta oestradiol and raloxifene. J Endocrinol, 2003, 177(3): 423-433.
40. Fu Q, Jilka RL, Manolagas SC, et al. Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. J Biol Chem, 2002, 277(50): 48868-48875.
41. Villa I, Melzi R, Pagani F, et al. Effects of calcitonin gene-related peptide and amylin on human osteoblast-like cells proliferation. Eur J Pharmacol, 2000, 409(3): 273-278.
42. Ishizuka K, Hirukawa K, Nakamura H, et al. Inhibitory effect of CGRP on osteoclast formation by mouse bone marrow cells treated with isoproterenol. Neurosci Let, 2005, 379(1): 47-51.
43. He H, Chai J, Zhang S, et al. CGRP may regulate bone metabolism through stimulating osteoblast differentiation and inhibiting osteoclast formation. Mol Med Rep, 2016, 13(5): 3977-3984.
44. 肖啸, 胡冰. 不同浓度降钙素基因相关肽对大鼠成骨细胞 OPG mRNA 表达的影响. 医学研究杂志, 2013, 42(9): 106-109.
45. Villa I, Mrak E, Rubinacci A, et al. CGRP inhibits osteoprotegerin production in human osteoblast-like cells via cAMP/PKA-dependent pathway. Am J Physiol Cell Physiol, 2006, 291(3): C529-537.
46. 徐琳, 葛永玲, 郑宇浩, 等. H89 抑制降钙素基因相关肽促兔成骨细胞OPG表达的实验研究. 西北国防医学杂志, 2011, 32(4): 274-275.

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Chinese Journal of Reparative and Reconstructive Surgery

Progress of research on the relationship between calcitonin gene-related peptide and RANK/RANKL/OPG system in the bone reconstruction

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