Background/Purpose:  Intensive synovitis is a prominent feature that progressively aggravated excessive fibrosis reactions relative to joint stiffness in the pathogenesis of osteoarthritis (OA). MicroRNA-29a (miR-29a) is reported to modulate overabundant fibrotic matrix accumulation during tissue deterioration. This study is undertaken to verify whether miR-29a expression was linked to synovial fibrosis in end-stage knee OA and tested whether miR-29a signaling affected fibrogenic reactions in synovial fibroblasts and synovial remodeling and joint integrity during OA development.

Methods:  Synovial tissues and fibroblasts were harvested from 20 patients with end-stage knee OA. For non-OA group, synovial specimens were biopsied from 10 patients with femoral neck fracture. Knee joints in mice that overexpressed miR-29a were subjected to superpatellar injection of collagenase to provoke OA. miR-29a and fibrogenic factor expression were quantified by RT-quantitative PCR and in situ hybridization. Synovial fibrosis and joint injury were analyzed by Masson’s trichrome staining, immunohistochemistry and histomorphometry.

Results:  Synovial tissues within end-stage knee OA exhibited 52% declines in miR-29a expression in conjunction with 2.1-3.3-fold increases in fibrotic matrix deposition, capillary vessel formation, and membrane thickness compared to non-OA group. In vitro, miR-29a signaling interruption led to 1.8-2.6-fold increases in joint-deleterious factors collagen III, TGF-β1, MMP3, MMP9, ADAMTS5, and VEGF expression within synovial fibroblast cultures. Gain of miR-29a signaling enabled cell cultures to have 42-67% reductions in baseline expression of joint-deleterious factors. Of note, miR-29a transgenic mice exhibited moderate responses to the collagenase exacerbation of fibrosis, macrophage infiltration, and hypervascularization within synovial microenvironment. These synovium-protecting effects remarkably shielded knee joints from articular cartilage deterioration histopathology and gait irregularity. Likewise, exogenous miR-29a administration via intra-articular injection delayed the progression of excessive synovial angiogenesis, inflammation and fibrosis, a protective regime that improved joint damage and walking patterns of injured knees. Luciferase reporter analyses revealed that miR-29a directly targeted 3’-untranslated region (3’-UTR) of VEGF, which suppressed VEGF production and angiogenic activities in synovial fibroblasts cultures.

Conclusion:  miR-29a deficiency is relevant to the occurrence of excessive synovial fibrosis within end-stage OA knees. miR-29a signaling is indispensable to fend off fibrogenic, angiogenic, and cartilage degradation factor expression in synovial fibroblast cultures. Gain of miR-29a function facilitates the maintenance of synovium homeostasis that alleviates OA knee pathogenesis. This study sheds a new light on the anabolic actions and therapeutic potential of miR-29a signaling to synovial integrity during OA progression.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/microrna-29a-curtails-synovitis-in-the-development-of-knee-osteoarthritis-by-disrupting-vegf/