Intra-Articular miR-199a-5p Attenuates Post-traumatic Ankle Cartilage Degeneration With Reduced IHH Expression and Hypertrophic-Catabolic Marker Expression.

Abstract

BackgroundPost-traumatic ankle osteoarthritis (TAA) is driven by injury-related inflammation, cartilage matrix loss, and chondrocyte phenotypic instability. Indian hedgehog (IHH) is implicated in hypertrophic and catabolic cartilage remodeling, but whether local miR-199a-5p administration is associated with changes in IHH-related expression patterns in traumatic ankle cartilage remains incompletely defined.MethodsForty-eight male Sprague-Dawley rats were randomized to sham, TAA model, miR-199a-5p agomir, or negative-control agomir groups. TAA-like cartilage degeneration was induced by medial malleolar fracture followed by unrestricted cage activity. From week 2, rats received weekly intra-articular saline, miR-199a-5p agomir, or negative-control agomir for six weeks. Longitudinal inflammation, function, and ankle circumference ratio were assessed, followed by radiography, histology, OARSI scoring, ELISA, Western blotting, and RT-qPCR at week 8.ResultsThe fracture model caused persistent swelling and functional impairment, radiographic post-traumatic changes, cartilage surface disruption, proteoglycan depletion, increased IL-1β/TNF-α production, increased IHH/RUNX2/MMP-13 expression, and reduced SOX9/COL2A1 expression. miR-199a-5p agomir treatment partially improved function, reduced inflammatory scores and cytokine levels, lowered OARSI scores, and was associated with lower IHH expression and a less hypertrophic/catabolic marker profile. The negative-control agomir showed no comparable protective pattern.ConclusionsIntra-articular miR-199a-5p agomir attenuated experimental TAA-like cartilage degeneration. The protective phenotype was associated with reduced inflammation, lower IHH expression, attenuation of hypertrophic/catabolic marker expression, and partial restoration of cartilage matrix-related markers. Direct miR-199a-5p binding to IHH, downstream GLI activation, and local miRNA tissue accumulation were not tested and require further study.