Lin28a induces SOX9 and chondrocyte reprogramming via HMGA2 and blunts cartilage loss in mice

Among tissues undergoing permanent stress, cartilage has low regenerative capacity. Irreversible cartilage lesions characterize osteoarthritis (OA), in which cartilage loss is not followed by tissue repair. We investigated the physiopatological role of LIN28a, an RNA binding protein, in cartilage in adults. Lin28a was detected in only damaged cartilage of humans and mice. Here, inducible conditional cartilage deletion of Lin28a upregulates Mmp13 expression in sham mice and exacerbates cartilage destruction in OA mice. Lin28a-specific cartilage overexpression protects mice against cartilage breakdown, stimulates chondrocyte proliferation and the expression of Prg4 and Sox9, but reduces the expression of Mmp13. Lin28a overexpression inhibits Let-7b and Let-7c miRNA levels, facilitates the expression of HMGA2, and thereby activates the transcription of Sox9, a factor required for chondrocyte reprogramming. Finally, administration of siRNA against HMGA2 inhibits the cartilage protective eff...