miR‑27 inhibits the NF-κB signaling pathway by targeting leptin in osteoarthritic chondrocytes

Zhou,Bin; Li,Hongwei; Shi,Jide

doi:10.3892/ijmm.2017.3021

miR‑27 inhibits the NF-κB signaling pathway by targeting leptin in osteoarthritic chondrocytes

Authors:
- Bin Zhou
- Hongwei Li
- Jide Shi
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Affiliations: Department of Orthopaedics, The Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
Published online on: June 13, 2017 https://doi.org/10.3892/ijmm.2017.3021
Pages: 523-530

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Abstract

Osteoarthritis (OA) is a chronic degenerative joint disease. An increasing number of studies point to the role of microRNAs (miRNAs or miRs) in the pathogenesis of OA. An earlier study suggested that miR‑27b was associated with OA; however, the precise mechanisms regarding the involvement of the miR‑27 in the progression of OA remain unclear. In the present study, we first analyzed the effects of miR‑27 on OA. In vitro, the degree of miR‑27 expression was decreased in chondrocytes obtained from patients with OA. Transfection with miR‑27 mimic increased the viability of CH8 cells and induced the expression of type-II collagen, type-X collagen, glycosaminoglycan (GAG) and aggrecan (ACAN). The results of luciferase activity assay revealed that miR‑27 directly targeted the 3'-untranslated region (3'-UTR) of leptin. The results of western blot analysis and ELISA indicated that the concentration of leptin was decreased after the CH8 cells were transfected with miR‑27 mimic. In vivo, a rat model of OA was established by anterior cruciate ligament transection (ACLT). When the rats with OA were injected with miR‑27 lentiviral overexpression vector, the results of ELISA revealed that the levels of interleukin (IL)-6 and IL-8 were decreased. The results of western blot analysis revealed that matrix metalloproteinase (MMP)-9 and MMP-13 expression levels were decreased, and the nuclear factor-κB (NF-κB) pathway was inhibited. On the whole, our results suggest that the upregulation of miR‑27 inhibits the pathogenesis of OA by targeting leptin and inhibiting the NF-κB signaling pathway. Thus, miR‑27 exerts protective effects against OA.

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1	Akhtar N, Rasheed Z, Ramamurthy S, Anbazhagan AN, Voss FR and Haqqi TM: MicroRNA-27b regulates the expression of matrix metalloproteinase 13 in human osteoarthritis chondrocytes. Arthritis Rheum. 62:1361–1371. 2010. View Article : Google Scholar : PubMed/NCBI
2	Vonk LA, Kragten AH, Dhert WJ, Saris DB and Creemers LB: Overexpression of hsa-miR-148a promotes cartilage production and inhibits cartilage degradation by osteoarthritic chondrocytes. Osteoarthritis Cartilage. 22:145–153. 2014. View Article : Google Scholar
3	Kerkhof HJ, Bierma-Zeinstra SM, Arden NK, Metrustry S, Castano-Betancourt M, Hart DJ, Hofman A, Rivadeneira F, Oei EH, Spector TD, et al: Prediction model for knee osteoarthritis incidence, including clinical, genetic and biochemical risk factors. Ann Rheum Dis. 73:2116–2121. 2014. View Article : Google Scholar
4	Berenbaum F, Eymard F and Houard X: Osteoarthritis, inflammation and obesity. Curr Opin Rheumatol. 25:114–118. 2013. View Article : Google Scholar
5	Zhang D, Cao X, Li J and Zhao G: MiR-210 inhibits NF-κB signaling pathway by targeting DR6 in osteoarthritis. Sci Rep. 5:127752015. View Article : Google Scholar
6	Marcu KB, Otero M, Olivotto E, Borzí RM and Goldring MB: NF-kappaB signaling: Multiple angles to target OA. Curr Drug Targets. 11:599–613. 2010. View Article : Google Scholar : PubMed/NCBI
7	Chen LX, Lin L, Wang HJ, Wei XL, Fu X, Zhang JY and Yu CL: Suppression of early experimental osteoarthritis by in vivo delivery of the adenoviral vector-mediated NF-kappaBp65-specific siRNA. Osteoarthritis Cartilage. 16:174–184. 2008. View Article : Google Scholar
8	Ushita M, Saito T, Ikeda T, Yano F, Higashikawa A, Ogata N, Chung U, Nakamura K and Kawaguchi H: Transcriptional induction of SOX9 by NF-kappaB family member RelA in chondrogenic cells. Osteoarthritis Cartilage. 17:1065–1075. 2009. View Article : Google Scholar : PubMed/NCBI
9	Zhang P, Zhong ZH, Yu HT and Liu B: Significance of increased leptin expression in osteoarthritis patients. PLoS One. 10:e01232242015. View Article : Google Scholar : PubMed/NCBI
10	Bassi M, Furuya WI, Zoccal DB, Menani JV, Colombari E, Hall JE, da Silva AA, do Carmo JM and Colombari DS: Control of respiratory and cardiovascular functions by leptin. Life Sci. 125:25–31. 2015. View Article : Google Scholar : PubMed/NCBI
11	Wollman L, Powell G, Levine R and Fregosi R: Leptin acutely inhibits respiratory function in neonatal rats (712.18). FASEB J. 28(1 Supplement): 712.182014.
12	Bartell SM, Rayalam S, Ambati S, Gaddam DR, Hartzell DL, Hamrick M, She JX, Della-Fera MA and Baile CA: Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice. J Bone Miner Res. 26:1710–1720. 2011. View Article : Google Scholar : PubMed/NCBI
13	Vuolteenaho K1, Koskinen A, Kukkonen M, Nieminen R, Päivärinta U, Moilanen T and Moilanen E: Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage - mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. Mediators Inflamm. 2009:3458382009. View Article : Google Scholar
14	Ku JH, Lee CK, Joo BS, An BM, Choi SH, Wang TH and Cho HL: Correlation of synovial fluid leptin concentrations with the severity of osteoarthritis. Clin Rheumatol. 28:1431–1435. 2009. View Article : Google Scholar : PubMed/NCBI
15	Honsawek S and Chayanupatkul M: Correlation of plasma and synovial fluid adiponectin with knee osteoarthritis severity. Arch Med Res. 41:593–598. 2010. View Article : Google Scholar
16	Li ZC, Han N, Li X, Li G, Liu YZ, Sun GX, Wang Y, Chen GT and Li GF: Decreased expression of microRNA-130a correlates with TNF-α in the development of osteoarthritis. Int J Clin Exp Pathol. 8:2555–2564. 2015.
17	Song J, Jin EH, Kim D, Kim KY, Chun CH and Jin EJ: MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis. BBA Clin. 3:79–89. 2014. View Article : Google Scholar
18	Song J, Kim D, Chun CH and Jin EJ: miR-370 and miR-373 regulate the pathogenesis of osteoarthritis by modulating one-carbon metabolism via SHMT-2 and MECP-2, respectively. Aging Cell. 14:826–837. 2015. View Article : Google Scholar : PubMed/NCBI
19	Hautier A, Salentey V, Aubert-Foucher E, Bougault C, Beauchef G, Ronzière MC, De Sobarnitsky S, Paumier A, Galéra P, Piperno M, et al: Bone morphogenetic protein-2 stimulates chondrogenic expression in human nasal chondrocytes expanded in vitro. Growth Factors. 26:201–211. 2008. View Article : Google Scholar : PubMed/NCBI
20	Huang JG, Xia C, Zheng XP, Yi TT, Wang XY, Song G and Zhang B: 17β-Estradiol promotes cell proliferation in rat osteoarthritis model chondrocytes via PI3K/Akt pathway. Cell Mol Biol Lett. 16:564–575. 2011. View Article : Google Scholar : PubMed/NCBI
21	Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P and Pottie P: Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum. 48:3118–3129. 2003. View Article : Google Scholar : PubMed/NCBI
22	Lee JJ, Drakaki A, Iliopoulos D and Struhl K: MiR-27b targets PPARγ to inhibit growth, tumor progression and the inflammatory response in neuroblastoma cells. Oncogene. 31:3818–3825. 2012. View Article : Google Scholar
23	Xu W, Liu M, Peng X, Zhou P, Zhou J, Xu K, Xu H and Jiang S: miR-24-3p and miR-27a-3p promote cell proliferation in glioma cells via cooperative regulation of MXI1. Int J Oncol. 42:757–766. 2013.
24	Urbich C, Kaluza D, Frömel T, Knau A, Bennewitz K, Boon RA, Bonauer A, Doebele C, Boeckel JN, Hergenreider E, et al: MicroRNA-27a/b controls endothelial cell repulsion and angiogenesis by targeting semaphorin 6A. Blood. 119:1607–1616. 2012. View Article : Google Scholar
25	Coppari R and Bjørbæk C: Leptin revisited: Its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov. 11:692–708. 2012. View Article : Google Scholar : PubMed/NCBI
26	Terlain B, Presle N, Pottie P, Mainard D and Netter P: Leptin: a link between obesity and osteoarthritis? Bull Acad Natl Med. 190:1421–1437. 1475–1477. 2006.
27	Koskinen A, Vuolteenaho K, Nieminen R, Moilanen T and Moilanen E: Leptin enhances MMP-1, MMP-3 and MMP-13 production in human osteoarthritic cartilage and correlates with MMP-1 and MMP-3 in synovial fluid from OA patients. Clin Exp Rheumatol. 29:57–64. 2011.PubMed/NCBI
28	Mutabaruka MS, Aissa MA, Delalandre A, Lavigne M and Lajeunesse D: Research article Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression. Arthritis Res Ther. 12:R202010. View Article : Google Scholar
29	Stannus OP, Jones G, Quinn SJ, Cicuttini FM, Dore D and Ding C: Research article the association between leptin, interleukin-6, and hip radiographic osteoarthritis in older people: A cross-sectional study. Arthritis Res Ther. 12:R952010. View Article : Google Scholar
30	Lam QLK, Wang S, Ko OKH, Kincade PW and Lu L: Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1. Proc Natl Acad Sci USA. 107:13812–13817. 2010. View Article : Google Scholar : PubMed/NCBI
31	Qi J, Qiao Y, Wang P, Li S, Zhao W and Gao C: microRNA-210 negatively regulates LPS-induced production of proinflammatory cytokines by targeting NF-κB1 in murine macrophages. FEBS Lett. 586:1201–1207. 2012. View Article : Google Scholar : PubMed/NCBI
32	Shukla K, Sharma AK, Ward A, Will R, Hielscher T, Balwierz A, Breunig C, Münstermann E, König R, Keklikoglou I, et al: MicroRNA-30c-2-3p negatively regulates NF-κB signaling and cell cycle progression through downregulation of TRADD and CCNE1 in breast cancer. Mol Oncol. 9:1106–1119. 2015. View Article : Google Scholar : PubMed/NCBI
33	Carrion K, Patel V, Dyo J, Holland A, Gallegos T, Hardiman G, Mohamed S, Leire E, Nigam S, Nizet V and Nigam V: miR-148a is a novel repressor of NF-κB signaling in aortic valve calcification. Circulation. 128:A160672013.