Full Text:   <2389>

Summary:  <1841>

CLC number: R684.3

On-line Access: 2016-03-07

Received: 2015-11-04

Revision Accepted: 2015-12-27

Crosschecked: 2016-02-15

Cited: 3

Clicked: 3723

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2016 Vol.17 No.3 P.200-208


Roles of microRNA and signaling pathway in osteoarthritis pathogenesis

Author(s):  Bin Xu, Yao-yao Li, Jun Ma, Fu-xing Pei

Affiliation(s):  Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China; more

Corresponding email(s):   spot125@163.com

Key Words:  MicroRNA, Signaling pathway, Osteoarthritis, Pathogenesis

Bin Xu, Yao-yao Li, Jun Ma, Fu-xing Pei. Roles of microRNA and signaling pathway in osteoarthritis pathogenesis[J]. Journal of Zhejiang University Science B, 2016, 17(3): 200-208.

@article{title="Roles of microRNA and signaling pathway in osteoarthritis pathogenesis",
author="Bin Xu, Yao-yao Li, Jun Ma, Fu-xing Pei",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Roles of microRNA and signaling pathway in osteoarthritis pathogenesis
%A Bin Xu
%A Yao-yao Li
%A Jun Ma
%A Fu-xing Pei
%J Journal of Zhejiang University SCIENCE B
%V 17
%N 3
%P 200-208
%@ 1673-1581
%D 2016
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1500267

T1 - Roles of microRNA and signaling pathway in osteoarthritis pathogenesis
A1 - Bin Xu
A1 - Yao-yao Li
A1 - Jun Ma
A1 - Fu-xing Pei
J0 - Journal of Zhejiang University Science B
VL - 17
IS - 3
SP - 200
EP - 208
%@ 1673-1581
Y1 - 2016
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1500267

osteoarthritis (OA) is a common chronic degenerative joint disease, with complicated pathogenic factors and undefined pathogenesis. Various signaling pathways play important roles in OA pathogenesis, including genetic expression, matrix synthesis and degradation, cell proliferation, differentiation, apoptosis, and so on. microRNA (miRNA) is a class of non-coding RNA in Eukaryon, regulating genetic expression on the post-transcriptional level. A great number of miRNAs are involved in the development of OA, and are closely associated with different signaling pathways. This article reviews the roles of miRNAs and signaling pathways in OA, looking toward having a better understanding of its pathogenesis mechanisms and providing new therapeutic targets for its treatment.



Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Abouheif, M.M., Nakasa, T., Shibuya, H., et al., 2010. Silencing microRNA inhibits chondrocyte apoptosis in a rat osteoarthritis model in vitro. Rheumatology (Oxford), 49(11):2054-2060.

[2]Akhtar, N., Rasheed, Z., Ramamurthy, S., et al., 2010. MicroRNA-27b regulates the expression of matrix metalloproteinase human osteoarthritis chondrocytes. Arthritis Rheum., 62(5):1361-1371.

[3]Araldi, E., Schipani, E., 2010. MicroRNA-140 and the silencing of osteoarthritis. Genes Dev., 24(11):1075-1080.

[4]Ashraf, S., Cha, B.H., Kim, J.S., et al., 2015. Regulation of senescence associated signaling mechanisms in chondrocytes for cartilage tissue regeneration. Osteoarthr. Cartilage, 24(2):196-205.

[5]Ballock, R.T., Heydemann, A., Wakefield, L.M., et al., 1993. TGF-β 1 prevents hypertrophy of epiphyseal chondrocytes: regulation of gene expression for cartilage matrix proteins and metalloproteases. Dev. Biol., 158(2):414-429.

[6]Bartel, D.P., 2004. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116(2):281-297.

[7]Bazzoni, F., Rossato, M., Fabbri, M., et al., 2009. Induction and regulatory function of miR human monocytes and neutrophils exposed to proinflammatory signals. PNAS, 106(13):5282-5287.

[8]Bell, D.M., Leung, K.K., Wheatley, S.C., et al., 1997. SOX9 directly regulates the type-II collagen gene. Nat. Genet., 16(2):174-178.

[9]Bernstein, E., Caudy, A.A., Hammond, S.M., et al., 2001. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature, 409(6818):363-366.

[10]Bi, W.M., Deng, J.M., Zhang, Z.P., et al., 1999. Sox9 is required for cartilage formation. Nat. Genet., 22(1):85-89.

[11]Billinghurst, R.C., Dahlberg, L., Ionescu, M., et al., 1997. Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J. Clin. Invest., 99(7):1534-1545.

[12]Calin, G.A., Croce, C.M., 2006. MicroRNA signatures in human cancers. Nat. Rev. Cancer, 6(11):857-866.

[13]Cheng, G., Jin, Y., 2012. MicroRNAs: potentially important regulators for schistosome development and therapeutic targets against schistosomiasis. Parasitology, 139(5):669-679.

[14]Clemmons, D.R., Busby, W.J., Garmong, A., et al., 2002. Inhibition of insulin-like growth factor binding protein 5 proteolysis in articular cartilage and joint fluid results in enhanced concentrations of insulin-like growth factor 1 and is associated with improved osteoarthritis. Arthritis Rheum., 46(3):694-703.

[15]Cobb, B.S., Nesterova, T.B., Thompson, E., et al., 2005. T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer. J. Exp. Med., 201(9):1367-1373.

[16]Dudek, K.A., Lafont, J.E., Martinez-Sanchez, A., et al., 2010. Type II collagen expression is regulated by tissue-specific miR human articular chondrocytes. J. Biol. Chem., 285(32):24381-24387.

[17]Eberhart, J.K., He, X., Swartz, M.E., et al., 2008. MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis. Nat. Genet., 40(3):290-298.

[18]Farh, K.K., Grimson, A., Jan, C., et al., 2005. The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science, 310(5755):1817-1821.

[19]Fosang, A.J., Last, K., Knauper, V., et al., 1996. Degradation of cartilage aggrecan by collagenase-3 (MMP-13). FEBS Lett., 380(1-2):17-20.

[20]Furumatsu, T., Ozaki, T., Asahara, H., 2009. Smad3 activates the Sox9-dependent transcription on chromatin. Int. J. Biochem. Cell Biol., 41(5):1198-1204.

[21]Gantier, M.P., Stunden, H.J., McCoy, C.E., et al., 2012. A miR-19 regulon that controls NF-κB signaling. Nucleic Acids Res., 40(16):8048-8058.

[22]Gilbert, A.M., Bursavich, M.G., Lombardi, S., et al., 2008. N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2). Bioorg. Med. Chem. Lett., 18(24):6454-6457.

[23]Goldring, M.B., Goldring, S.R., 2007. Osteoarthritis. J. Cell. Physiol., 213(3):626-634.

[24]Goldring, M.B., Goldring, S.R., 2010. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann. N. Y. Acad. Sci., 1192(1):230-237.

[25]Grimsrud, C.D., Romano, P.R., D'Souza, M., et al., 2001. BMP signaling stimulates chondrocyte maturation and the expression of Indian hedgehog. J. Orthop. Res., 19(1):18-25.

[26]Gu, Y.J., Ge, P., Mu, Y., et al., 2014. Clinical and laboratory characteristics of patients having amyloidogenic trans-thyretin deposition in osteoarthritic knee joints. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 15(1):92-99.

[27]Guan, Y.J., Yang, X., Wei, L., et al., 2011. MiR-365: a mechanosensitive microRNA stimulates chondrocyte differentiation through targeting histone deacetylase 4. FASEB J., 25(12):4457-4466.

[28]Harfe, B.D., McManus, M.T., Mansfield, J.H., et al., 2005. The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. PNAS, 102(31):10898-10903.

[29]Iliopoulos, D., Malizos, K.N., Oikonomou, P., et al., 2008. Integrative microRNA and proteomic approaches identify novel osteoarthritis genes and their collaborative metabolic and inflammatory networks. PLoS ONE, 3(11):e3740.

[30]Jones, J.I., Gockerman, A., Busby, W.J., et al., 1993. Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I. J. Cell Biol., 121(3):679-687.

[31]Jones, S.W., Watkins, G., Le Good, N., et al., 2009. The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-α and MMP13. Osteoarthr. Cartilage, 17(4):464-472.

[32]Kanellopoulou, C., Muljo, S.A., Kung, A.L., et al., 2005. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes. Dev., 19(4):489-501.

[33]Karlsen, T.A., Jakobsen, R.B., Mikkelsen, T.S., et al., 2014. microRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN. Stem Cells Dev., 23(3):290-304.

[34]Kim, Y.I., Ryu, J.S., Yeo, J.E., et al., 2014. Overexpression of TGF-β1 enhances chondrogenic differentiation and proliferation of human synovium-derived stem cells. Biochem. Biophys. Res. Commun., 450(4):1593-1599.

[35]Knauper, V., Lopez-Otin, C., Smith, B., et al., 1996. Biochemical characterization of human collagenase-3. J. Biol. Chem., 271(3):1544-1550.

[36]Kobayashi, T., Lu, J., Cobb, B.S., et al., 2008. Dicer-dependent pathways regulate chondrocyte proliferation and differentiation. PNAS, 105(6):1949-1954.

[37]Kronenberg, H.M., 2003. Developmental regulation of the growth plate. Nature, 423(6937):332-336.

[38]Lee, Y., Ahn, C., Han, J., et al., 2003. The nuclear RNase III Drosha initiates microRNA processing. Nature, 425(6956):415-419.

[39]Li, X., Wu, J.F., 2010. Recent developments in patent anti-cancer agents targeting the matrix metalloproteinases (MMPs). Recent Pat. Anticancer Drug Discov., 5(2):109-141.

[40]Liang, Z.J., Zhuang, H., Wang, G.X., et al., 2012. MiRNA-140 is a negative feedback regulator of MMP IL-1β-stimulated human articular chondrocyte C28/I2 cells. Inflamm. Res., 61(5):503-509.

[41]Lin, E.A., Kong, L., Bai, X.H., et al., 2009. miR-199a*, a bone morphogenic protein 2-responsive microRNA, regulates chondrogenesis via direct targeting to Smad1. J Biol. Chem., 284(17):11326-11335.

[42]Lu, Y.L., Jing, W., Feng, L.S., et al., 2014. Effects of hypoxic exercise training on microRNA expression and lipid metabolism in obese rat livers. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 15(9):820-829.

[43]Lund, E., Guttinger, S., Calado, A., et al., 2004. Nuclear export of microRNA precursors. Science, 303(5654):95-98.

[44]Martinez-Sanchez, A., Dudek, K.A., Murphy, C.L., 2012. Regulation of human chondrocyte function through direct inhibition of cartilage master regulator SOX9 by microRNA-145 (miRNA-145). J. Biol. Chem., 287(2):916-924.

[45]Matsukawa, T., Sakai, T., Yonezawa, T., et al., 2013. MicroRNA-125b regulates the expression of aggrecanase-1 (ADAMTS-4) in human osteoarthritic chondrocytes. Arthritis Res. Ther., 15(1):R28.

[46]Miyaki, S., Asahara, H., 2012. Macro view of microRNA function in osteoarthritis. Nat. Rev. Rheumatol., 8(9):543-552.

[47]Miyaki, S., Nakasa, T., Otsuki, S., et al., 2009. MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum., 60(9):2723-2730.

[48]Miyaki, S., Sato, T., Inoue, A., et al., 2010. MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev., 24(11):1173-1185.

[49]Nakamura, Y., Inloes, J.B., Katagiri, T., et al., 2011. Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling. Mol. Cell. Biol., 31(14):3019-3028.

[50]Nicolas, F.E., Pais, H., Schwach, F., et al., 2008. Experimental identification of microRNA-140 targets by silencing and overexpressing miR-140. RNA, 14(12):2513-2520.

[51]Nicolas, F.E., Pais, H., Schwach, F., et al., 2011. mRNA expression profiling reveals conserved and non-conserved miR-140 targets. RNA Biol., 8(4):607-615.

[52]Niederberger, E., Geisslinger, G., 2008. The IKK-NF-κB pathway: a source for novel molecular drug targets in pain therapy FASEB J., 22(10):3432-3442.

[53]Oeckinghaus, A., Ghosh, S., 2009. The NF-κB family of transcription factors and its regulation. Cold Spring Harb. Perspect. Biol., 1(4):a000034.

[54]Ohgawara, T., Kubota, S., Kawaki, H., et al., 2009. Regulation of chondrocytic phenotype by micro RNA 18a:involvement of Ccn2/Ctgf as a major target gene. FEBS Lett., 583(6):1006-1010.

[55]Pais, H., Nicolas, F.E., Soond, S.M., et al., 2010. Analyzing mRNA expression identifies Smad3 as a microRNA-140 target regulated only at protein level. RNA, 16(3):489-494.

[56]Park, S.J., Cheon, E.J., Lee, M.H., et al., 2013a. MicroRNA-127-5p regulates matrix metalloproteinase 13 expression and interleukin-1β-induced catabolic effects in human chondrocytes. Arthritis Rheum., 65(12):3141-3152.

[57]Park, S.J., Cheon, E.J., Kim, H.A., 2013b. MicroRNA-558 regulates the expression of cyclooxygenase-2 and IL-1β-induced catabolic effects in human articular chondrocytes. Osteoarthr. Cartilage, 21(7):981-989.

[58]Pelletier, J.P., Martel-Pelletier, J., Altman, R.D., et al., 1983. Collagenolytic activity and collagen matrix breakdown of the articular cartilage in the Pond-Nuki dog model of osteoarthritis. Arthritis Rheum., 26(7):866-874.

[59]Pelletier, J.P., Martel-Pelletier, J., Mehraban, F., et al., 1992. Immunological analysis of proteoglycan structural changes in the early stage of experimental osteoarthritic canine cartilage lesions. J. Orthop. Res., 10(4):511-523.

[60]Rigoglou, S., Papavassiliou, A.G., 2013. The NF-κB signalling pathway in osteoarthritis. Int. J. Biochem. Cell Biol., 45(11):2580-2584.

[61]Roman-Blas, J.A., Stokes, D.G., Jimenez, S.A., 2007. Modulation of TGF-β signaling by proinflammatory cytokines in articular chondrocytes. Osteoarthr. Cartilage, 15(12):1367-1377.

[62]Serra, R., Karaplis, A., Sohn, P., 1999. Parathyroid hormone-related peptide (PTHrP)-dependent and -independent effects of transforming growth factor β (TGF-β) on endochondral bone formation. J. Cell Biol., 145(4):783-794.

[63]Shamoon, M., Hochberg, M.C., 2000. Treatment of osteoarthritis with acetaminophen: efficacy, safety, and comparison with nonsteroidal anti-inflammatory drugs. Curr. Rheumatol. Rep., 2(6):454-458.

[64]Stanczyk, J., Ospelt, C., Karouzakis, E., et al., 2011. Altered expression of microRNA rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum., 63(2):373-381.

[65]Swingler, T.E., Wheeler, G., Carmont, V., et al., 2012. The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis Rheum., 64(6):1909-1919.

[66]Taganov, K.D., Boldin, M.P., Chang, K.J., et al., 2006. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. PNAS, 103(33):12481-12486.

[67]Tardif, G., Hum, D., Pelletier, J.P., et al., 2009. Regulation of the IGFBP-5 and MMP-13 genes by the microRNAs miR-140 and miR in human osteoarthritic chondrocytes. BMC Musculoskelet. Disord., 10(1):148.

[68]Tortorella, M.D., Tomasselli, A.G., Mathis, K.J., et al., 2009. Structural and inhibition analysis reveals the mechanism of selectivity of a series of aggrecanase inhibitors. J. Biol. Chem., 284(36):24185-24191.

[69]Trenkmann, M., Brock, M., Gay, R.E., et al., 2013. Tumor necrosis factor α-induced microRNA activates rheumatoid arthritis synovial fibroblasts through a feedback loop in NF-κB signaling. Arthritis Rheum., 65(4):916-927.

[70]Tuddenham, L., Wheeler, G., Ntounia-Fousara, S., et al., 2006. The cartilage specific microRNA-140 targets histone deacetylase mouse cells. FEBS Lett., 580(17):4214-4217.

[71]van der Kraan, P.M., Goumans, M.J., Blaney, D.E., et al., 2012. Age-dependent alteration of TGF-β signalling in osteoarthritis. Cell Tissue Res., 347(1):257-265.

[72]Wang, W., Luo, Y.P., 2015. MicroRNAs in breast cancer: oncogene and tumor suppressors with clinical potential. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 16(1):18-31.

[73]Wittwer, A.J., Hills, R.L., Keith, R.H., et al., 2007. Substrate-dependent inhibition kinetics of an active site-directed inhibitor of ADAMTS-4 (Aggrecanase 1). Biochemistry, 46(21):6393-6401.

[74]Yang, B., Guo, H., Zhang, Y., et al., 2011. MicroRNA-145 regulates chondrogenic differentiation of mesenchymal stem cells by targeting Sox9. PLoS ONE, 6(7):e21679.

[75]Yang, J., Qin, S., Yi, C., et al., 2011. MiR-140 is co-expressed with Wwp2-C transcript and activated by Sox9 to target Sp maintaining the chondrocyte proliferation. FEBS Lett., 585(19):2992-2997.

[76]Yasuda, T., 2011. Activation of Akt leading to NF-κB up-regulation in chondrocytes stimulated with fibronectin fragment. Biomed. Res., 32(3):209-215.

[77]Yuan, Z.M., Yang, Z.L., Zheng, Q., 2014. Deregulation of microRNA expression in thyroid tumors. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 15(3):212-224.

[78]Zhang, Y., Jia, J., Yang, S., et al., 2014. MicroRNA-21 controls the development of osteoarthritis by targeting GDF chondrocytes. Exp. Mol. Med., 46(2):e79.

[79]Zhao, L., Li, G., Zhou, G.Q., 2009. SOX9 directly binds CREB as a novel synergism with the PKA pathway in BMP-2-induced osteochondrogenic differentiation. J. Bone Miner. Res., 24(5):826-836.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE