MicroRNA-29a Counteracts Synovitis in Knee Osteoarthritis Pathogenesis by Targeting VEGF

Jih-Yang Ko,Yu-Shan Chen,Mel S Lee,Wei-Shiung Lian,Yi-Chih Sun,Wen-Tsan Weng,Feng-Sheng Wang

doi:10.1038/s41598-017-03616-w

Jih-Yang Ko, Yu-Shan Chen + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-03616-w

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Abstract

Synovitis contributes to the development of osteoarthritis (OA) of the knee. MicroRNAs regulate joint microenvironment homeostasis and deterioration. This study was undertaken to characterize the actions of microRNA-29a (miR-29a) to synovial remodeling in OA joints. Synovial specimens isolated from patients with end-stage OA knees showed abundant fibrotic matrix and vessel histopathology concomitant with weak miR-29a expression. In vitro, miR-29a knockdown caused synovial fibroblasts to exhibit high expressions of collagen III, TGF-β1, MMP9, MMP13, and ADAMTS5, whereas miR-29a overexpression diminished these joint-deleterious factors. In collagenase-mediated OA pathogenesis, miR-29a-overexpressing transgenic mice showed minor responses to hyperplasia, macrophage infiltration, fibrosis, hyperangiogenesis, and VEGF expression in synovial lesions. These effects mitigated articular cartilage loss and gait aberrance of injured joints. Intra-articular administration of miR-29a precursor lessened the collagenase aggravation of excessive synovial remodeling reactions and thereby sustained joint tissue integrity. miR-29a lowered VEGF production and angiogenic activities in synovial fibroblasts through targeting the 3′-UTR of VEGF. Taken together, miR-29a deficiency exacerbated synovitis pathogenesis in the end-stage OA knees. miR-29a signaling fends off excessive synovial angiogenesis and fibrosis, which delays joint destruction. This study sheds new light on the protective effects against synovial deterioration and the therapeutic advantage of miR-29a in OA knees.

Highlights

MicroRNAs constitute 18−25 nucleotides that participate in tissue development and pathogenesis through disrupting the mRNA expression of the target[8]
We investigated whether miR-29 expression was relevant to the occurrence of synovial fibrosis within end-stage OA knees
Synovial fibrosis is a prominently deleterious reaction linked to the prevalence of symptomatic pain[25] and biomechanical dysfunction[26] of affected joints in the pathogenesis of OA

Summary

Introduction

MicroRNAs constitute 18−25 nucleotides that participate in tissue development and pathogenesis through disrupting the mRNA expression of the target[8]. MiR-210 signaling is involved in the connective tissue growth factor-mediated angiogenic activities of OA synovial fibroblasts[14]. Of microRNAs, the miR-29 family is observed to modulate angiogenic reactions, immune responses, and metabolic activities in various tissues . MiR-29 deficiency worsens the pathogenesis of fibrotic matrix accumulation in the bleomycin induction of systemic sclerosis[18] It regulates carbon tetrachloride19- and bile duct ligation-injured liver fibrosis[20]. This study was undertaken to analyze the association of miR-29 expression and synovial fibrosis within end-stage OA knees and investigate the fibrogenic and angiogenic activities of synovial fibroblasts in response to miR-29a signaling. Using miR-29a transgenic mice and exogenous miR-29a treatment, we characterized the synovial integrity, articular cartilage morphology, and gait profiles during collagenase-mediated OA knee pathogenesis

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