Effect of chondrogenesis related miR-4287 on expression of aggrecanase-1 in human chondrocytes_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

SUN Hong ^1,2 , ZHANG Zhiqi ¹ , HUANG Zhiyu ¹ , MAO Guping ¹ , YU Baoxi ¹ , ZHANG Chengyun ¹ ,  FU Ming ¹

1. Department of Joint Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou Guangdong, 510080, P.R.China;
2. Department of Orthopedics, the Affiliated Hospital of Guizhou Medical University, Guiyang Guizhou, 550004, P.R.China;

Corresponding author：

FU Ming, Email: ming_fu@126.com

Keywords：

Osteoarthritis; miR-4287; interleukin 1β; aggrecanase-1; chondrocytes

DOI：

10.7507/1002-1892.201704065

Video：

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Objective To investigate the effect and mechanism of miR-4287, a chondrogenesis associated microRNA, regulated the expression of aggrecanase-1 (a disintegrin and metalloproteinase with thrombospondin motif 4, ADAMTS4) in human chondrocytes. Methods First, the voluntarily donated normal and osteoarthritic knee articular cartilages were used to detect the expressions of miR-4287 and ADAMTS4 mRNA by real-time fluorescence quantitative PCR. Then, chondrocytes were isolated from knee articular cartilages. The effect of IL-1β on the expression of miR-4287 and ADAMTS4 mRNA was validated by the first generation of osteoarthritic chondrocytes. To confirm the influence of IL-1β signal pathways on the expression of miR-4287 and ADAMTS4 mRNA, osteoarthritic chondrocytes were pretreated with MAPK signal pathway inhibitor SP600125, NF-κB pathway inhibitor SN50, and finally stimulated with IL-1β. Chondro cytes were transfected with miR-4287 mimics and mimics negative control, inhibitors and inhibitors negative control respectively to value the effect of miR-4287 on ADAMTS4 expression. Luciferase reporter assay was used to verify the direct interaction between miR-4287 and putative site in the 3-untranslated region (3’UTR) of ADAMTS4 mRNA. Results Compared with normal knee articular cartilages, the miR-4287 expression was markedly diminished and conversely ADAMTS4 mRNA expression was raised in osteoarthritis cartilages (P<0.05). Stimulation with IL-1β led to a reduction in miR-4287 expression and upregulation in ADAMTS4 mRNA expression, showing significant difference when compared with the untreated groups (P<0.05). Pretreatment with IL-1β signal pathway inhibitors induced miR-4287 expression and attenuated ADAMTS4 mRNA expression in human chondrocytes, which were significantly different from that of unstimulated cells (P<0.05). ADAMTS4 mRNA and protein were suppressed by transfection with miR-4287 mimics (P<0.05) and elevated by transfection with miR-4287 inhibitors (P<0.05). As luciferase reporter assay showed, overexpression miR-4287 failed to alter the luciferase activity of a reporter construct containing either wild or mutant 3’UTR of ADAMTS4 mRNA (P>0.05). Conclusion miR-4287, a chondrogenesis associated microRNA, may play an important role in cartilage degeneration. miRNA-4287 is able to regulate ADAMTS4 expression in human chondrocytes, but not by means of directly targeted the ADAMTS4 mRNA 3’UTR. The exact mechanisms need to be further addressed.

Citation： SUN Hong, ZHANG Zhiqi, HUANG Zhiyu, MAO Guping, YU Baoxi, ZHANG Chengyun, FU Ming. Effect of chondrogenesis related miR-4287 on expression of aggrecanase-1 in human chondrocytes. Chinese Journal of Reparative and Reconstructive Surgery, 2017, 31(12): 1468-1473. doi: 10.7507/1002-1892.201704065 Copy

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14.	Goto A, Dobashi Y, Tsubochi H, et al. MicroRNAs associated with increased AKT gene number in human lung carcinoma. Hum Pathol, 2016, 56: 1-10.
15.	Sun Y, Luo DY, Zhu YC, et al. MiR 3180-5p promotes proliferation in human bladder smooth muscle cell by targeting PODN under hydrodynamic pressure. Sci Rep, 2016, 6: 33042.
16.	Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol, 2011, 23(5): 471-478.
17.	Park SJ, Cheon EJ, Kim HA. MicroRNA-558 regulates the expression of cyclooxygenase-2 and IL-1β-induced catabolic effects in human articular chondrocytes. Osteoarthritis Cartilage, 2013, 21(7): 981-989.
18.	Park SJ, Cheon EJ, Lee MH, et al. MicroRNA-127-5p regulates matrix metalloproteinase 13 expression and interleukin-1β-induced catabolic effects in human chondrocytes. Arthritis Rheum, 2013, 65(12): 3141-3152.
19.	Mirzamohammadi F, Papaioannou G, Kobayashi T. MicroRNAs in cartilage development, homeostasis, and disease. Curr Osteoporos Rep, 2014, 12(4): 410-419.
20.	Matsukawa T, Sakai T, Yonezawa T, et al. MicroRNA-125b regulates the expression of aggrecanase-1 (ADAMTS-4) in human osteoarthritic chondrocytes. Arthritis Res Ther, 2013, 15(1): R28.
21.	Ji Q, Xu X, Xu Y, et al. miR-105/Runx2 axis mediates FGF2-induced ADAMTS expression in osteoarthritis cartilage. J Mol Med (Berl), 2016, 94(6): 681-694.
22.	Wang X, Guo Y, Wang C, et al. MicroRNA-142-3p Inhibits Chondrocyte Apoptosis and Inflammation in Osteoarthritis by Targeting HMGB1. Inflammation, 2016, 39(5): 1718-1728.

1. Heinegärd D, Saxne T. The role of the cartilage matrix in osteoarthritis. Nat Rev Rheumatol, 2011, 7(1): 50-56.
2. Song RH, Tortorella MD, Malfait AM, et al. Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum, 2007, 56(2): 575-585.
3. 冀全博, 徐亚梦, 王岩. miRNA 与骨关节炎软骨基质降解的研究进展. 中国修复重建外科杂志, 2016, 30(11): 1431-1436.
4. Miyaki S, Asahara H. Macro view of microRNA function in osteoarthritis. Nat Rev Rheumatol, 2012, 8(9): 543-552.
5. Meng F, Zhang Z, Chen W, et al. MicroRNA-320 regulates matrix metalloproteinase-13 expression in chondrogenesis and interleukin-1β-induced chondrocyte responses. Osteoarthritis Cartilage, 2016, 24(5): 932-941.
6. Chen W, Chen L, Zhang Z, et al. MicroRNA-455-3p modulates cartilage development and degeneration through modification of histone H3 acetylation. Biochim Biophys Acta, 2016, 1863(12): 2881-2891.
7. Mao G, Zhang Z, Huang Z, et al. MicroRNA-92a-3p regulates the expression of cartilage-specific genes by directly targeting histone deacetylase 2 in chondrogenesis and degradation. Osteoarthritis Cartilage, 2017, 25(4): 521-532.
8. Zhang Z, Kang Y, Zhang Z, et al. Expression of microRNAs during chondrogenesis of human adipose-derived stem cells. Osteoarthritis Cartilage, 2012, 20(12): 1638-1646.
9. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell, 2009, 136(2): 215-233.
10. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet, 2004, 5(7): 522-531.
11. Mirzamohammadi F, Papaioannou G, Kobayashi T. MicroRNAs in cartilage development, homeostasis, and disease. Curr Osteoporos Rep, 2014, 12(4): 410-419.
12. Le LT, Swingler TE, Clark IM. Review: the role of microRNAs in osteoarthritis and chondrogenesis. Arthritis Rheum, 2013, 65(8): 1963-1974.
13. Lee JM, Kang J, Lee E, et al. Chronic Kidney Disease in the Second-Generation Drug-Eluting Stent Era: Pooled Analysis of the Korean Multicenter Drug-Eluting Stent Registry. JACC Cardiovasc Interv, 2016, 9(20): 2097-2109.
14. Goto A, Dobashi Y, Tsubochi H, et al. MicroRNAs associated with increased AKT gene number in human lung carcinoma. Hum Pathol, 2016, 56: 1-10.
15. Sun Y, Luo DY, Zhu YC, et al. MiR 3180-5p promotes proliferation in human bladder smooth muscle cell by targeting PODN under hydrodynamic pressure. Sci Rep, 2016, 6: 33042.
16. Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol, 2011, 23(5): 471-478.
17. Park SJ, Cheon EJ, Kim HA. MicroRNA-558 regulates the expression of cyclooxygenase-2 and IL-1β-induced catabolic effects in human articular chondrocytes. Osteoarthritis Cartilage, 2013, 21(7): 981-989.
18. Park SJ, Cheon EJ, Lee MH, et al. MicroRNA-127-5p regulates matrix metalloproteinase 13 expression and interleukin-1β-induced catabolic effects in human chondrocytes. Arthritis Rheum, 2013, 65(12): 3141-3152.
19. Mirzamohammadi F, Papaioannou G, Kobayashi T. MicroRNAs in cartilage development, homeostasis, and disease. Curr Osteoporos Rep, 2014, 12(4): 410-419.
20. Matsukawa T, Sakai T, Yonezawa T, et al. MicroRNA-125b regulates the expression of aggrecanase-1 (ADAMTS-4) in human osteoarthritic chondrocytes. Arthritis Res Ther, 2013, 15(1): R28.
21. Ji Q, Xu X, Xu Y, et al. miR-105/Runx2 axis mediates FGF2-induced ADAMTS expression in osteoarthritis cartilage. J Mol Med (Berl), 2016, 94(6): 681-694.
22. Wang X, Guo Y, Wang C, et al. MicroRNA-142-3p Inhibits Chondrocyte Apoptosis and Inflammation in Osteoarthritis by Targeting HMGB1. Inflammation, 2016, 39(5): 1718-1728.

Chinese Journal of Reparative and Reconstructive Surgery

Effect of chondrogenesis related miR-4287 on expression of aggrecanase-1 in human chondrocytes

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