Research progress on signaling molecules involved in articular cartilage repair_Journal of Biomedical Engineering

Authors：

TU Pengcheng ¹ , GUO Yang ^1,2 , ZHENG Suyang ¹ , PAN Yalan ¹ , WANG Lining ¹ ,  MA Yong ^1,2

1. Nanjing University of Chinese Medicine, Nanjing 210023, P.R.China;
2. Department of Traumatology & Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, P.R.China;

Corresponding author：

Keywords：

cartilage repair; signaling pathway; articular cartilage; signaling molecules; tissue engineering

DOI：

10.7507/1001-5515.201806021

Video：

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After the articular cartilage injury, the metabolic level is increased during the progressive degeneration, the chondrocytes secrete a variety of inflammatory factors, and the original cell phenotype is gradually changed. For a long time, a large number of researchers have done a lot of researches to promote anabolism of chondrocytes and to maintain the stability of chondrocyte phenotype. There are many molecular signaling pathways involved in the process of promoting cartilage repair. This review focuses on the key signaling molecules in articular cartilage repair, such as transforming growth factor-beta and bone morphogenetic protein, and reveals their roles in the process of cartilage injury and repair, so that researchers in related fields can understand the molecular mechanism of cartilage injury and repair widely and deeply. Based on this, they may find promising targets and biological methods for the treatment of cartilage injury.

Citation： TU Pengcheng, GUO Yang, ZHENG Suyang, PAN Yalan, WANG Lining, MA Yong. Research progress on signaling molecules involved in articular cartilage repair. Journal of Biomedical Engineering, 2019, 36(2): 343-348. doi: 10.7507/1001-5515.201806021 Copy

1.	Tang Qiang, Hao Liang, Peng Yuanxiang, et al. RNAi silencing of IL-1β and TNF-α in the treatment of post-traumatic arthritis in rabbits. Chem Biol Drug Des, 2015, 86(6): 1466-1470.
2.	Chen Weishen, Sheng Puyi, Huang Zhiyu, et al. MicroRNA-381 regulates chondrocyte hypertrophy by inhibiting histone deacetylase 4 expression. Int J Mol Sci, 2016, 17(9): e1377.
3.	Yin Feng, Cai Junfeng, Zen Wen, et al. Cartilage regeneration of adipose-derived stem cells in the TGF-β 1-immobilized PLGA-gelatin scaffold. Stem Cell Reviews and Reports, 2015, 11(3): 453-459.
4.	Chen R, Mian M, Fu M, et al. Attenuation of the progression of articular cartilage degeneration by inhibition of TGF-β1 signaling in a mouse model of osteoarthritis. American Journal of Pathology, 2015, 185(11): 2875-2885.
5.	Jin Meihua, Lee J, Lee K Y, et al. Alteration of TGF-β-ALK-Smad signaling in hyperoxia-induced bronchopulmonary dysplasia model of newborn rats. Exp Lung Res, 2016, 42(7): 354-364.
6.	Wang Y J, Shen M, Wang M, et al. Inhibition of the TGF-β1/Smad signaling pathway protects against cartilage injury and osteoarthritis in a rat mode. Life Sci, 2017, 189: 106-113.
7.	van der Kraan P M. Age-related alterations in TGF beta signaling as a causal factor of cartilage degeneration in osteoarthritis. Biomed Mater Eng, 2014, 24(1 Suppl): S75-S80.
8.	Crecente-Campo J, Borrajo E, Vidal A, et al. New scaffolds encapsulating TGF-b3/BMP-7 combinations driving strong chondrogenic differentiation. Eur J Pharm Biopharm, 2017, 114: 69-78.
9.	Fu H D, Wang H R, Li D H. BMP7 accelerates the differentiation of rabbit mesenchymal stem cells into cartilage through the Wnt/βcatenin pathway. Exp Ther Med, 2017, 14(6): 5424-5428.
10.	Xia Xiaopeng, Li Jing, Xia Bo, et al. Matrigel scaffold combined with Ad-hBMP7-transfected chondrocytes improves the repair of rabbit cartilage defect. Exp Ther Med, 2017, 13(2): 542-550.
11.	Shang Xifu, Wang Jinwu, Luo Zhengliang, et al. Notch signaling indirectly promotes chondrocyte hypertrophy via regulation of BMP signaling and cell cycle arrest. Sci Rep, 2016, 6: 25594.
12.	Nasrabadi D, Rezaeiani S, Eslaminejad M B, et al. Improved protocol for chondrogenic differentiation of bone marrow derived mesenchymal stem cells -effect of PTHrP and FGF-2 on TGFβ1/BMP2-induced chondrocytes hypertrophy. Stem Cell Reviews and Reports, 2018, 14(5): 755-766.
13.	Gigout A, Guehring H, Froemel D, et al. Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix. Osteoarthritis and Cartilage, 2017, 25(11): 1858-1867.
14.	Howard D, Wardale J, Guehring H, et al. Delivering rhFGF-18 via a bilayer collagen membrane to enhance microfracture treatment of chondral defects in a large animal model. Journal of Orthopaedic Research, 2015, 33(8): 1120-1127.
15.	Nummenmaa E, Hämäläinen M, Moilanen T, et al. Effects of FGF-2 and FGF receptor antagonists on MMP enzymes, aggrecan, and type II collagen in primary human OA chondrocytes. Scand J Rheumatol, 2015, 44(4): 321-330.
16.	Yang Wenyu, Cao Yiting, Zhang Zhe, et al. Targeted delivery of FGF2 to subchondral bone enhanced the repair of articular cartilage defect. Acta Biomater, 2018, 69: 170-182.
17.	Shi Shuiliang, Wang Congrong, Acton A J, et al. Role of sox9 in growth factor regulation of articular chondrocytes. J Cell Biochem, 2015, 116(7): 1391-1400.
18.	Mullen L M, Best S M, Ghose S, et al. Bioactive IGF-1 release from collagen-GAG scaffold to enhance cartilage repair in vitro. J Mater Sci: Mater Med, 2015, 26(1): 2.
19.	Ikeda Y, Sakaue M, Chijimatsu R, et al. IGF-1 gene transfer to human synovial MSCs promotes their chondrogenic differentiation potential without induction of the hypertrophic phenotype. Stem Cells Int, 2017: 5804147.
20.	Loeser R F, Gandhi U, Long D L, et al. Aging and oxidative stress reduce the response of human articular chondrocytes to insulin-like growth factor-1 and osteogenic protein 1. Arthritis Rheumatology, 2014, 66(8): 2201-2209.
21.	Zhou Quan, Li Baojun, Zhao Jiali, et al. IGF-I induces adipose derived mesenchymal cell chondrogenic differentiation in vitro and enhances chondrogenesis in vivo. In Vitro Cell Dev Biol Anim, 2016, 52(3): 356-364.
22.	Uchimura T, Foote A T, Smith E L, et al. Insulin-Like growth factor II (IGF-II) inhibits IL-1b-Induced cartilage matrix loss and promotes cartilage integrity in experimental osteoarthritis. J Cell Biochem, 2015, 116(12): 2858-2869.
23.	Bechtold T E, Saunders C, Decker R S, et al. Osteophyte formation and matrix mineralization in a TMJ osteoarthritis mouse model are associated with ectopic hedgehog signaling. Matrix Biology, 2016, 52-54: 339-354.
24.	Thompson C L, Patel R, Kelly T A, et al. Hedgehog signalling does not stimulate cartilage catabolism and is inhibited by Interleukin-1β. Arthritis Res Ther, 2015, 17: 373.
25.	Han X, Zhuang Y, Zhang Z, et al. Regulatory mechanisms of the Ihh/PTHrP signaling pathway in fibrochondrocytes in entheses of pig achilles tendon. Stem Cells Int, 2016, 26: 8235172.
26.	Shi Juan, Chi Shuhong, Xue J, et al. Emerging role and therapeutic implication of Wnt signaling pathways in autoimmune diseases. Journal of Immunology Research, 2016: 9392132.
27.	Usami Y, Gunawardena A T, Iwamoto M, et al. Wnt signaling in cartilage development and diseases: lessons from animal studies. Lab Invest, 2016, 96(2): 186-196.
28.	Chung R, Wong D, Macsai C, et al. Roles of Wnt/β-catenin signalling pathway in the bony repair of injured growth plate cartilage in young rats. Bone, 2013, 52(2): 651-658.
29.	Lietman C, Wu B, Lechner S, et al. Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. JCI Insight, 2018, 3(3): e96308.
30.	Zhou Nian, Hu Ning, Liao Junyi, et al. HIF-1α as a Regulator of BMP2-induced chondrogenic differentiation, osteogenic differentiation, and endochondral ossification in stem cells. Cellular Physiology and Biochemistry, 2015, 36(1): 44-60.
31.	Zhang F J, Luo W, Lei G H. Role of HIF-1α and HIF-2α in osteoarthritis. Joint Bone Spine, 2015, 82(3): 144-147.
32.	Saito T, Fukai A, Mabuchi A, et al. Transcriptional regulation of endochondral ossification by HIF-2 alpha during skeletal growth and osteoarthritis development. Nat Med, 2010, 16(6): 678-686.
33.	Hwang H S, Park S J, Lee M H, et al. MicroRNA-365 regulates IL-1β-induced catabolic factor expression by targeting HIF-2 alpha in primary chondrocytes. Sci Rep, 2017, 7(1): 17889.
34.	Li Wen, Liu Yanhui, Ding Wanghui, et al. Expression of hypoxia inducible factor-2 alpha in overloaded- stress induced destruction of mandibular condylar chondrocytes. Arch Oral Biol, 2017, 77: 51-54.
35.	Sun Heyan, Hu Kongzu, Yin Zongsheng. Inhibition of the p38-MAPK signaling pathway suppresses the apoptosis and expression of proinflammatory cytokines in human osteoarthritis chondrocytes. Cytokine, 2017, 90: 135-143.
36.	Chen Zhijun, Yue S X, Zhou Guang, et al. ERK1 and ERK2 regulate chondrocyte terminal differentiation during endochondral bone formation. Journal of Bone and Mineral Research, 2015, 30(5): 765-774.
37.	Li Xing, Guo Yuanqing, Huang Shuai, et al. Coenzyme Q10 prevents the interleukin-1 beta induced inflammatory response via inhibition of MAPK signaling pathways in rat articular chondrocytes. Drug Dev Res, 2017, 78(8): 403-410.
38.	Yan Huimin, Duan Xin, Pan Hua, et al. Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc Natl Acad Sci USA, 2016, 113(41): E6199-E6208.
39.	Sun Zhongyi, Yin Zhanmin, Liu Chao, et al. IL-1β promotes ADAMTS enzyme-mediated aggrecan degradation through NF-κB in human intervertebral disc. J Orthop Surg Res, 2015, 10: 159.
40.	Hirata M, Kugimiya F, Fukai A, et al. C/EBPb and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2a as the inducer in chondrocytes. Hum Mol Genet, 2012, 21(5): 1111-1123.
41.	Xu Xilin, Lv Hang, Li Xiaodong, et al. Danshen attenuates osteoarthritis-related cartilage degeneration through inhibition of NF-kappa B signaling pathway in vivo and in vitro. Biochemistry and Cell Biology, 2017, 95(6): 644-651.
42.	Chen Di, Shen Jie, Zhao Weiwei, et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Research, 2017, 5: 16044.

1. Tang Qiang, Hao Liang, Peng Yuanxiang, et al. RNAi silencing of IL-1β and TNF-α in the treatment of post-traumatic arthritis in rabbits. Chem Biol Drug Des, 2015, 86(6): 1466-1470.
2. Chen Weishen, Sheng Puyi, Huang Zhiyu, et al. MicroRNA-381 regulates chondrocyte hypertrophy by inhibiting histone deacetylase 4 expression. Int J Mol Sci, 2016, 17(9): e1377.
3. Yin Feng, Cai Junfeng, Zen Wen, et al. Cartilage regeneration of adipose-derived stem cells in the TGF-β 1-immobilized PLGA-gelatin scaffold. Stem Cell Reviews and Reports, 2015, 11(3): 453-459.
4. Chen R, Mian M, Fu M, et al. Attenuation of the progression of articular cartilage degeneration by inhibition of TGF-β1 signaling in a mouse model of osteoarthritis. American Journal of Pathology, 2015, 185(11): 2875-2885.
5. Jin Meihua, Lee J, Lee K Y, et al. Alteration of TGF-β-ALK-Smad signaling in hyperoxia-induced bronchopulmonary dysplasia model of newborn rats. Exp Lung Res, 2016, 42(7): 354-364.
6. Wang Y J, Shen M, Wang M, et al. Inhibition of the TGF-β1/Smad signaling pathway protects against cartilage injury and osteoarthritis in a rat mode. Life Sci, 2017, 189: 106-113.
7. van der Kraan P M. Age-related alterations in TGF beta signaling as a causal factor of cartilage degeneration in osteoarthritis. Biomed Mater Eng, 2014, 24(1 Suppl): S75-S80.
8. Crecente-Campo J, Borrajo E, Vidal A, et al. New scaffolds encapsulating TGF-b3/BMP-7 combinations driving strong chondrogenic differentiation. Eur J Pharm Biopharm, 2017, 114: 69-78.
9. Fu H D, Wang H R, Li D H. BMP7 accelerates the differentiation of rabbit mesenchymal stem cells into cartilage through the Wnt/βcatenin pathway. Exp Ther Med, 2017, 14(6): 5424-5428.
10. Xia Xiaopeng, Li Jing, Xia Bo, et al. Matrigel scaffold combined with Ad-hBMP7-transfected chondrocytes improves the repair of rabbit cartilage defect. Exp Ther Med, 2017, 13(2): 542-550.
11. Shang Xifu, Wang Jinwu, Luo Zhengliang, et al. Notch signaling indirectly promotes chondrocyte hypertrophy via regulation of BMP signaling and cell cycle arrest. Sci Rep, 2016, 6: 25594.
12. Nasrabadi D, Rezaeiani S, Eslaminejad M B, et al. Improved protocol for chondrogenic differentiation of bone marrow derived mesenchymal stem cells -effect of PTHrP and FGF-2 on TGFβ1/BMP2-induced chondrocytes hypertrophy. Stem Cell Reviews and Reports, 2018, 14(5): 755-766.
13. Gigout A, Guehring H, Froemel D, et al. Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix. Osteoarthritis and Cartilage, 2017, 25(11): 1858-1867.
14. Howard D, Wardale J, Guehring H, et al. Delivering rhFGF-18 via a bilayer collagen membrane to enhance microfracture treatment of chondral defects in a large animal model. Journal of Orthopaedic Research, 2015, 33(8): 1120-1127.
15. Nummenmaa E, Hämäläinen M, Moilanen T, et al. Effects of FGF-2 and FGF receptor antagonists on MMP enzymes, aggrecan, and type II collagen in primary human OA chondrocytes. Scand J Rheumatol, 2015, 44(4): 321-330.
16. Yang Wenyu, Cao Yiting, Zhang Zhe, et al. Targeted delivery of FGF2 to subchondral bone enhanced the repair of articular cartilage defect. Acta Biomater, 2018, 69: 170-182.
17. Shi Shuiliang, Wang Congrong, Acton A J, et al. Role of sox9 in growth factor regulation of articular chondrocytes. J Cell Biochem, 2015, 116(7): 1391-1400.
18. Mullen L M, Best S M, Ghose S, et al. Bioactive IGF-1 release from collagen-GAG scaffold to enhance cartilage repair in vitro. J Mater Sci: Mater Med, 2015, 26(1): 2.
19. Ikeda Y, Sakaue M, Chijimatsu R, et al. IGF-1 gene transfer to human synovial MSCs promotes their chondrogenic differentiation potential without induction of the hypertrophic phenotype. Stem Cells Int, 2017: 5804147.
20. Loeser R F, Gandhi U, Long D L, et al. Aging and oxidative stress reduce the response of human articular chondrocytes to insulin-like growth factor-1 and osteogenic protein 1. Arthritis Rheumatology, 2014, 66(8): 2201-2209.
21. Zhou Quan, Li Baojun, Zhao Jiali, et al. IGF-I induces adipose derived mesenchymal cell chondrogenic differentiation in vitro and enhances chondrogenesis in vivo. In Vitro Cell Dev Biol Anim, 2016, 52(3): 356-364.
22. Uchimura T, Foote A T, Smith E L, et al. Insulin-Like growth factor II (IGF-II) inhibits IL-1b-Induced cartilage matrix loss and promotes cartilage integrity in experimental osteoarthritis. J Cell Biochem, 2015, 116(12): 2858-2869.
23. Bechtold T E, Saunders C, Decker R S, et al. Osteophyte formation and matrix mineralization in a TMJ osteoarthritis mouse model are associated with ectopic hedgehog signaling. Matrix Biology, 2016, 52-54: 339-354.
24. Thompson C L, Patel R, Kelly T A, et al. Hedgehog signalling does not stimulate cartilage catabolism and is inhibited by Interleukin-1β. Arthritis Res Ther, 2015, 17: 373.
25. Han X, Zhuang Y, Zhang Z, et al. Regulatory mechanisms of the Ihh/PTHrP signaling pathway in fibrochondrocytes in entheses of pig achilles tendon. Stem Cells Int, 2016, 26: 8235172.
26. Shi Juan, Chi Shuhong, Xue J, et al. Emerging role and therapeutic implication of Wnt signaling pathways in autoimmune diseases. Journal of Immunology Research, 2016: 9392132.
27. Usami Y, Gunawardena A T, Iwamoto M, et al. Wnt signaling in cartilage development and diseases: lessons from animal studies. Lab Invest, 2016, 96(2): 186-196.
28. Chung R, Wong D, Macsai C, et al. Roles of Wnt/β-catenin signalling pathway in the bony repair of injured growth plate cartilage in young rats. Bone, 2013, 52(2): 651-658.
29. Lietman C, Wu B, Lechner S, et al. Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. JCI Insight, 2018, 3(3): e96308.
30. Zhou Nian, Hu Ning, Liao Junyi, et al. HIF-1α as a Regulator of BMP2-induced chondrogenic differentiation, osteogenic differentiation, and endochondral ossification in stem cells. Cellular Physiology and Biochemistry, 2015, 36(1): 44-60.
31. Zhang F J, Luo W, Lei G H. Role of HIF-1α and HIF-2α in osteoarthritis. Joint Bone Spine, 2015, 82(3): 144-147.
32. Saito T, Fukai A, Mabuchi A, et al. Transcriptional regulation of endochondral ossification by HIF-2 alpha during skeletal growth and osteoarthritis development. Nat Med, 2010, 16(6): 678-686.
33. Hwang H S, Park S J, Lee M H, et al. MicroRNA-365 regulates IL-1β-induced catabolic factor expression by targeting HIF-2 alpha in primary chondrocytes. Sci Rep, 2017, 7(1): 17889.
34. Li Wen, Liu Yanhui, Ding Wanghui, et al. Expression of hypoxia inducible factor-2 alpha in overloaded- stress induced destruction of mandibular condylar chondrocytes. Arch Oral Biol, 2017, 77: 51-54.
35. Sun Heyan, Hu Kongzu, Yin Zongsheng. Inhibition of the p38-MAPK signaling pathway suppresses the apoptosis and expression of proinflammatory cytokines in human osteoarthritis chondrocytes. Cytokine, 2017, 90: 135-143.
36. Chen Zhijun, Yue S X, Zhou Guang, et al. ERK1 and ERK2 regulate chondrocyte terminal differentiation during endochondral bone formation. Journal of Bone and Mineral Research, 2015, 30(5): 765-774.
37. Li Xing, Guo Yuanqing, Huang Shuai, et al. Coenzyme Q10 prevents the interleukin-1 beta induced inflammatory response via inhibition of MAPK signaling pathways in rat articular chondrocytes. Drug Dev Res, 2017, 78(8): 403-410.
38. Yan Huimin, Duan Xin, Pan Hua, et al. Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc Natl Acad Sci USA, 2016, 113(41): E6199-E6208.
39. Sun Zhongyi, Yin Zhanmin, Liu Chao, et al. IL-1β promotes ADAMTS enzyme-mediated aggrecan degradation through NF-κB in human intervertebral disc. J Orthop Surg Res, 2015, 10: 159.
40. Hirata M, Kugimiya F, Fukai A, et al. C/EBPb and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2a as the inducer in chondrocytes. Hum Mol Genet, 2012, 21(5): 1111-1123.
41. Xu Xilin, Lv Hang, Li Xiaodong, et al. Danshen attenuates osteoarthritis-related cartilage degeneration through inhibition of NF-kappa B signaling pathway in vivo and in vitro. Biochemistry and Cell Biology, 2017, 95(6): 644-651.
42. Chen Di, Shen Jie, Zhao Weiwei, et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Research, 2017, 5: 16044.

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