The role of Wnt signaling pathway in osteoarthritis via the dual-targeted regulation of cartilage and subchondral bone_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LIAN Qiangqiang ¹ , CHI Bojing ¹ ,  ZHANG Liu ^1,2 ,  TIAN Faming ^1,3

1. North China University of Science and Technology, Tangshan Hebei, 063210, P.R.China;
2. Department of Orthopedics, Emergency Management General Hospital, National Mine Medical Security Center, Beijing, 100028, P.R.China;
3. Medical Research Center, Hebei Key Laboratory for Organ Fibrosis, North China University of Science and Technology, Tangshan Hebei, 063210, P.R.China;

Corresponding author：

ZHANG Liu, Email: zhliu130@sohu.com; TIAN Faming, Email: tfm9911316@163.com

Keywords：

Osteoarthritis; Wnt signaling pathway; β-catenin; articular cartilage; subchondral bone

DOI：

10.7507/1002-1892.201909088

Video：

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Objective To summarize the active changes of Wnt signaling pathway in osteoarthritis (OA) as well as the influence and mechanism of dual-targeted regulation on cartilage and subchondral bone and the role of crosstalk between them on OA process.Methods The relevant literature concerning the articular cartilage, subchondral bone, and crosstalk between them in OA and non-OA states by Wnt signaling pathway in vivo and vitro experimental studies and clinical studies in recent years was reviewed, and the mechanism was analyzed and summarized.Results Wnt signaling can regulate the differentiation and function of chondrocytes and osteoblasts through the classic β-catenin-dependent or non-classical β-catenin-independent Wnt signaling pathway and its cross-linking with other signaling pathways, thereby affecting the cartilage and bone metabolism. Moreover, Wnt signaling pathway can activate the downstream protein Wnt1-inducible-signaling pathway protein 1 to regulate the progress of OA and it also can be established gap junctions between different cells in cartilage and subchondral bone to communicate molecules directly to regulate OA occurrence and development. Intra-articular injection of Wnt signaling inhibitor SM04690 can inhibit the progress of OA, and overexpression of Wnt signaling pathway inhibitor Dickkopf in osteoblasts can antagonize the role of vascular endothelial growth factor work on chondrocytes and inhibit the catabolism of its matrix.Conclusion The regulation of metabolism and function of cartilage and subchondral bone and crosstalk between them is through interactions among Wnt signaling pathway and molecules of other signaling. Therefore, it plays an vital role in the occurrence and development of OA and is expected to become a new target of OA treatment through intervention and regulation of Wnt signaling pathway.

Citation： LIAN Qiangqiang, CHI Bojing, ZHANG Liu, TIAN Faming. The role of Wnt signaling pathway in osteoarthritis via the dual-targeted regulation of cartilage and subchondral bone. Chinese Journal of Reparative and Reconstructive Surgery, 2020, 34(6): 797-803. doi: 10.7507/1002-1892.201909088 Copy

1.	Zhao Y, Liu H, Zhao C, et al. Paracrine interactions involved in human induced pluripotent stem cells differentiation into chondrocytes. Curr Stem Cell Res Ther, 2019. [Epub ahead of print].
2.	王方兴, 薛华明, 马童, 等. 人工单髁关节置换术治疗超高龄膝关节骨关节炎患者的近期疗效. 中国修复重建外科杂志, 2019, 33(8): 947-952.
3.	Martel-Pelletier J, Barr AJ, Cicuttini FM, et al. Osteoarthritis. Nat Rev Dis Primers, 2016, 2: 16072.
4.	刘康妍, 郑聪, 胡海澜. 骨关节炎流行病学研究. 中华关节外科杂志 (电子版), 2017, 11(3): 320-323.
5.	Aspden RM, Saunders FR. Osteoarthritis as an organ disease: from the cradle to the grave. Eur Cell Mater, 2019, 37: 74-87.
6.	陈闻波, 蔡江瑜, 孙亚英, 等. 应用干细胞旁分泌效应治疗膝部骨关节炎的研究进展. 中国修复重建外科杂志, 2019, 33(1): 1446-1451.
7.	Kwan Tat S, Lajeunesse D, Pelletier JP, et al. Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Pract Res Clin Rheumatol, 2010, 24(1): 51-70.
8.	Zhou Y, Wang T, Hamilton JL, et al. Wnt/β-catenin signaling in osteoarthritis and in other forms of arthritis. Curr Rheumatol Rep, 2017, 19(9): 53.
9.	Rigoglou S, Papavassiliou AG. The NF-κB signalling pathway in osteoarthritis. Int J Biochem Cell Biol, 2013, 45(11): 2580-2584.
10.	Malemud CJ. Negative Regulators of JAK/STAT signaling in rheumatoid arthritis and osteoarthritis. Int J Mol Sci, 2017, 18(3): E484.
11.	Zhai G, Doré J, Rahman P. TGF-β signal transduction pathways and osteoarthritis. Rheumatol Int, 2015, 35(8): 1283-1292.
12.	Usami Y, Gunawardena AT, Iwamoto M, et al. Wnt signaling in cartilage development and diseases: lessons from animal studies. Lab Invest, 2016, 96(2): 186-196.
13.	Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell, 2017, 169(6): 985-999.
14.	MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 2009, 17(1): 9-26.
15.	Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell, 2012, 149(6): 1192-1205.
16.	Clevers H. Wnt/beta-catenin signaling in development and disease. Cell, 2006, 127(3): 469-480.
17.	Wang Y, Fan X, Xing L, et al. Wnt signaling: a promising target for osteoarthritis therapy. Cell Commun Signal, 2019, 17(1): 97.
18.	Funck-Brentano T, Bouaziz W, Marty C, et al. DKK-1-mediated inhibition of Wnt signaling in bone ameliorates osteoarthritis in mice. Arthritis Rheumatol, 2014, 66(11): 3028-3039.
19.	Yuan X, Liu H, Huang H, et al. The key role of canonical Wnt/β-catenin signaling in cartilage chondrocytes. Curr Drug Targets, 2016, 17(4): 475-484.
20.	Ma B, Landman EB, Miclea RL, et al. WNT signaling and cartilage: of mice and men. Calcif Tissue Int, 2013, 92(5): 399-411.
21.	Chen K, Quan H, Chen G, et al. Spatio-temporal expression patterns of Wnt signaling pathway during the development of temporomandibular condylar cartilage. Gene Expr Patterns, 2017, 25-26: 149-158.
22.	Zhang Y, Sheu TJ, Hoak D, et al. CCN1 regulates chondrocyte maturation and cartilage development. J Bone Miner Res, 2016, 31(3): 549-559.
23.	Huang X, Zhong L, Hendriks J, et al. The effects of the WNT-signaling modulators BIO and PKF118-310 on the chondrogenic differentiation of human mesenchymal stem cells. Int J Mol Sci, 2018, 19(2): E561.
24.	Regard JB, Zhong Z, Williams BO, et al. Wnt signaling in bone development and disease: making stronger bone with Wnts. Cold Spring Harb Perspect Biol, 2012, 4(12): a007997.
25.	Yang T, Zhang J, Cao Y, et al. Wnt5a/Ror2 mediates temporomandibular joint subchondral bone remodeling. J Dent Res, 2015, 94(6): 803-812.
26.	Esen E, Chen J, Karner CM, et al. WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab, 2013, 17(5): 745-755.
27.	Heilmann A, Schinke T, Bindl R, et al. The Wnt serpentine receptor Frizzled-9 regulates new bone formation in fracture healing. PLoS One, 2013, 8(12): e84232.
28.	Houschyar KS, Tapking C, Borrelli MR, et al. Wnt pathway in bone repair and regeneration-what do we know so far. Front Cell Dev Biol, 2019, 6: 170.
29.	Zhang R, Oyajobi BO, Harris SE, et al. Wnt/β-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone, 2013, 52(1): 145-156.
30.	Rudnicki MA, Williams BO. Wnt signaling in bone and muscle. Bone, 2015, 80: 60-66.
31.	Roberts JL, Liu G, Paglia DN, et al. Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation. Ann N Y Acad Sci, 2020, 1463(1): 45-59.
32.	Alam I, Reilly AM, Alkhouli M, et al. Bone mass and strength are significantly improved in mice overexpressing human WNT16 in osteocytes. Calcif Tissue Int, 2017, 100(4): 361-373.
33.	Loeser RF, Goldring SR, Scanzello CR, et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum, 2012, 64(6): 1697-1707.
34.	Troeberg L, Nagase H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta, 2012, 1824(1): 133-145.
35.	Hou L, Shi H, Wang M, et al. MicroRNA-497-5p attenuates IL-1β-induced cartilage matrix degradation in chondrocytes via Wnt/β-catenin signal pathway. Int J Clin Exp Pathol, 2019, 12(8): 3108-3118.
36.	Liu X, Wang L, Ma C, et al. Exosomes derived from platelet-rich plasma present a novel potential in alleviating knee osteoarthritis by promoting proliferation and inhibiting apoptosis of chondrocyte via Wnt/β-catenin signaling pathway. J Orthop Surg Res, 2019, 14(1): 470.
37.	Nalesso G, Thomas BL, Sherwood JC, et al. WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis. Ann Rheum Dis, 2017, 76(1): 218-226.
38.	Monteagudo S, Cornelis FMF, Aznar-Lopez C, et al. DOT1L safeguards cartilage homeostasis and protects against osteoarthritis. Nat Commun, 2017, 8: 15889.
39.	Gu Y, Ren K, Wang L, et al. Loss of Klotho contributes to cartilage damage by derepression of canonical Wnt/β-catenin signaling in osteoarthritis mice. Aging (Albany NY), 2019, 11(24): 12793-12809.
40.	Deshmukh V, Hu H, Barroga C, et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage, 2018, 26(1): 18-27.
41.	Yazici Y, McAlindon TE, Fleischmann R, et al. A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study. Osteoarthritis Cartilage, 2017, 25(10): 1598-1606.
42.	van den Bosch MH, Blom AB, Sloetjes AW, et al. Induction of canonical Wnt signaling by synovial overexpression of selected Wnts leads to protease activity and early osteoarthritis-like cartilage damage. Am J Pathol, 2015, 185(7): 1970-1980.
43.	Meo Burt P, Xiao L, Hurley MM. FGF23 regulates Wnt/β-catenin signaling-mediated osteoarthritis in mice overexpressing high-molecular-weight FGF2. Endocrinology, 2018, 159(6): 2386-2396.
44.	Chan BY, Fuller ES, Russell AK, et al. Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthritis Cartilage, 2011, 19(7): 874-885.
45.	Martineau X, Abed É, Martel-Pelletier J, et al. Alteration of Wnt5a expression and of the non-canonical Wnt/PCP and Wnt/PKC-Ca²⁺ pathways in human osteoarthritis osteoblasts. PLoS One, 2017, 12(8): e0180711.
46.	Weng LH, Wang CJ, Ko JY, et al. Control of DKK-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees. Arthritis Rheum, 2010, 62(5): 1393-1402.
47.	Thysen S, Luyten FP, Lories RJ. Loss of Frzb and Sfrp1 differentially affects joint homeostasis in instability-induced osteoarthritis. Osteoarthritis Cartilage, 2015, 23(2): 275-279.
48.	肖志锋, 林定坤. 骨关节炎软骨内骨化病理研究进展. 中国修复重建外科杂志, 2016, 30(12): 1556-1561.
49.	Kobayashi Y, Uehara S, Udagawa N, et al. Regulation of bone metabolism by Wnt signals. J Biochem, 2016, 159(4): 387-392.
50.	Carpintero-Fernandez P, Gago-Fuentes R, Wang HZ, et al. Intercellular communication via gap junction channels between chondrocytes and bone cells. Biochim Biophys Acta Biomembr, 2018, 1860(12): 2499-2505.
51.	Prasadam I, Crawford R, Xiao Y. Aggravation of ADAMTS and matrix metalloproteinase production and role of ERK1/2 pathway in the interaction of osteoarthritic subchondral bone osteoblasts and articular cartilage chondrocytes—possible pathogenic role in osteoarthritis. J Rheumatol, 2012, 39(3): 621-634.
52.	Chen P, Xia C, Mo J, et al. Interpenetrating polymer network scaffold of sodium hyaluronate and sodium alginate combined with berberine for osteochondral defect regeneration. Mater Sci Eng C Mater Biol Appl, 2018, 91: 190-200.
53.	Li X, Yang J, Liu D, et al. Knee loading inhibits osteoclast lineage in a mouse model of osteoarthritis. Sci Rep, 2016, 6: 24668.

1. Zhao Y, Liu H, Zhao C, et al. Paracrine interactions involved in human induced pluripotent stem cells differentiation into chondrocytes. Curr Stem Cell Res Ther, 2019. [Epub ahead of print].
2. 王方兴, 薛华明, 马童, 等. 人工单髁关节置换术治疗超高龄膝关节骨关节炎患者的近期疗效. 中国修复重建外科杂志, 2019, 33(8): 947-952.
3. Martel-Pelletier J, Barr AJ, Cicuttini FM, et al. Osteoarthritis. Nat Rev Dis Primers, 2016, 2: 16072.
4. 刘康妍, 郑聪, 胡海澜. 骨关节炎流行病学研究. 中华关节外科杂志 (电子版), 2017, 11(3): 320-323.
5. Aspden RM, Saunders FR. Osteoarthritis as an organ disease: from the cradle to the grave. Eur Cell Mater, 2019, 37: 74-87.
6. 陈闻波, 蔡江瑜, 孙亚英, 等. 应用干细胞旁分泌效应治疗膝部骨关节炎的研究进展. 中国修复重建外科杂志, 2019, 33(1): 1446-1451.
7. Kwan Tat S, Lajeunesse D, Pelletier JP, et al. Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Pract Res Clin Rheumatol, 2010, 24(1): 51-70.
8. Zhou Y, Wang T, Hamilton JL, et al. Wnt/β-catenin signaling in osteoarthritis and in other forms of arthritis. Curr Rheumatol Rep, 2017, 19(9): 53.
9. Rigoglou S, Papavassiliou AG. The NF-κB signalling pathway in osteoarthritis. Int J Biochem Cell Biol, 2013, 45(11): 2580-2584.
10. Malemud CJ. Negative Regulators of JAK/STAT signaling in rheumatoid arthritis and osteoarthritis. Int J Mol Sci, 2017, 18(3): E484.
11. Zhai G, Doré J, Rahman P. TGF-β signal transduction pathways and osteoarthritis. Rheumatol Int, 2015, 35(8): 1283-1292.
12. Usami Y, Gunawardena AT, Iwamoto M, et al. Wnt signaling in cartilage development and diseases: lessons from animal studies. Lab Invest, 2016, 96(2): 186-196.
13. Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell, 2017, 169(6): 985-999.
14. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 2009, 17(1): 9-26.
15. Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell, 2012, 149(6): 1192-1205.
16. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell, 2006, 127(3): 469-480.
17. Wang Y, Fan X, Xing L, et al. Wnt signaling: a promising target for osteoarthritis therapy. Cell Commun Signal, 2019, 17(1): 97.
18. Funck-Brentano T, Bouaziz W, Marty C, et al. DKK-1-mediated inhibition of Wnt signaling in bone ameliorates osteoarthritis in mice. Arthritis Rheumatol, 2014, 66(11): 3028-3039.
19. Yuan X, Liu H, Huang H, et al. The key role of canonical Wnt/β-catenin signaling in cartilage chondrocytes. Curr Drug Targets, 2016, 17(4): 475-484.
20. Ma B, Landman EB, Miclea RL, et al. WNT signaling and cartilage: of mice and men. Calcif Tissue Int, 2013, 92(5): 399-411.
21. Chen K, Quan H, Chen G, et al. Spatio-temporal expression patterns of Wnt signaling pathway during the development of temporomandibular condylar cartilage. Gene Expr Patterns, 2017, 25-26: 149-158.
22. Zhang Y, Sheu TJ, Hoak D, et al. CCN1 regulates chondrocyte maturation and cartilage development. J Bone Miner Res, 2016, 31(3): 549-559.
23. Huang X, Zhong L, Hendriks J, et al. The effects of the WNT-signaling modulators BIO and PKF118-310 on the chondrogenic differentiation of human mesenchymal stem cells. Int J Mol Sci, 2018, 19(2): E561.
24. Regard JB, Zhong Z, Williams BO, et al. Wnt signaling in bone development and disease: making stronger bone with Wnts. Cold Spring Harb Perspect Biol, 2012, 4(12): a007997.
25. Yang T, Zhang J, Cao Y, et al. Wnt5a/Ror2 mediates temporomandibular joint subchondral bone remodeling. J Dent Res, 2015, 94(6): 803-812.
26. Esen E, Chen J, Karner CM, et al. WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab, 2013, 17(5): 745-755.
27. Heilmann A, Schinke T, Bindl R, et al. The Wnt serpentine receptor Frizzled-9 regulates new bone formation in fracture healing. PLoS One, 2013, 8(12): e84232.
28. Houschyar KS, Tapking C, Borrelli MR, et al. Wnt pathway in bone repair and regeneration-what do we know so far. Front Cell Dev Biol, 2019, 6: 170.
29. Zhang R, Oyajobi BO, Harris SE, et al. Wnt/β-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone, 2013, 52(1): 145-156.
30. Rudnicki MA, Williams BO. Wnt signaling in bone and muscle. Bone, 2015, 80: 60-66.
31. Roberts JL, Liu G, Paglia DN, et al. Deletion of Wnt5a in osteoclasts results in bone loss through decreased bone formation. Ann N Y Acad Sci, 2020, 1463(1): 45-59.
32. Alam I, Reilly AM, Alkhouli M, et al. Bone mass and strength are significantly improved in mice overexpressing human WNT16 in osteocytes. Calcif Tissue Int, 2017, 100(4): 361-373.
33. Loeser RF, Goldring SR, Scanzello CR, et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum, 2012, 64(6): 1697-1707.
34. Troeberg L, Nagase H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta, 2012, 1824(1): 133-145.
35. Hou L, Shi H, Wang M, et al. MicroRNA-497-5p attenuates IL-1β-induced cartilage matrix degradation in chondrocytes via Wnt/β-catenin signal pathway. Int J Clin Exp Pathol, 2019, 12(8): 3108-3118.
36. Liu X, Wang L, Ma C, et al. Exosomes derived from platelet-rich plasma present a novel potential in alleviating knee osteoarthritis by promoting proliferation and inhibiting apoptosis of chondrocyte via Wnt/β-catenin signaling pathway. J Orthop Surg Res, 2019, 14(1): 470.
37. Nalesso G, Thomas BL, Sherwood JC, et al. WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis. Ann Rheum Dis, 2017, 76(1): 218-226.
38. Monteagudo S, Cornelis FMF, Aznar-Lopez C, et al. DOT1L safeguards cartilage homeostasis and protects against osteoarthritis. Nat Commun, 2017, 8: 15889.
39. Gu Y, Ren K, Wang L, et al. Loss of Klotho contributes to cartilage damage by derepression of canonical Wnt/β-catenin signaling in osteoarthritis mice. Aging (Albany NY), 2019, 11(24): 12793-12809.
40. Deshmukh V, Hu H, Barroga C, et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage, 2018, 26(1): 18-27.
41. Yazici Y, McAlindon TE, Fleischmann R, et al. A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study. Osteoarthritis Cartilage, 2017, 25(10): 1598-1606.
42. van den Bosch MH, Blom AB, Sloetjes AW, et al. Induction of canonical Wnt signaling by synovial overexpression of selected Wnts leads to protease activity and early osteoarthritis-like cartilage damage. Am J Pathol, 2015, 185(7): 1970-1980.
43. Meo Burt P, Xiao L, Hurley MM. FGF23 regulates Wnt/β-catenin signaling-mediated osteoarthritis in mice overexpressing high-molecular-weight FGF2. Endocrinology, 2018, 159(6): 2386-2396.
44. Chan BY, Fuller ES, Russell AK, et al. Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthritis Cartilage, 2011, 19(7): 874-885.
45. Martineau X, Abed É, Martel-Pelletier J, et al. Alteration of Wnt5a expression and of the non-canonical Wnt/PCP and Wnt/PKC-Ca²⁺ pathways in human osteoarthritis osteoblasts. PLoS One, 2017, 12(8): e0180711.
46. Weng LH, Wang CJ, Ko JY, et al. Control of DKK-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees. Arthritis Rheum, 2010, 62(5): 1393-1402.
47. Thysen S, Luyten FP, Lories RJ. Loss of Frzb and Sfrp1 differentially affects joint homeostasis in instability-induced osteoarthritis. Osteoarthritis Cartilage, 2015, 23(2): 275-279.
48. 肖志锋, 林定坤. 骨关节炎软骨内骨化病理研究进展. 中国修复重建外科杂志, 2016, 30(12): 1556-1561.
49. Kobayashi Y, Uehara S, Udagawa N, et al. Regulation of bone metabolism by Wnt signals. J Biochem, 2016, 159(4): 387-392.
50. Carpintero-Fernandez P, Gago-Fuentes R, Wang HZ, et al. Intercellular communication via gap junction channels between chondrocytes and bone cells. Biochim Biophys Acta Biomembr, 2018, 1860(12): 2499-2505.
51. Prasadam I, Crawford R, Xiao Y. Aggravation of ADAMTS and matrix metalloproteinase production and role of ERK1/2 pathway in the interaction of osteoarthritic subchondral bone osteoblasts and articular cartilage chondrocytes—possible pathogenic role in osteoarthritis. J Rheumatol, 2012, 39(3): 621-634.
52. Chen P, Xia C, Mo J, et al. Interpenetrating polymer network scaffold of sodium hyaluronate and sodium alginate combined with berberine for osteochondral defect regeneration. Mater Sci Eng C Mater Biol Appl, 2018, 91: 190-200.
53. Li X, Yang J, Liu D, et al. Knee loading inhibits osteoclast lineage in a mouse model of osteoarthritis. Sci Rep, 2016, 6: 24668.

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The role of Wnt signaling pathway in osteoarthritis via the dual-targeted regulation of cartilage and subchondral bone

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