Inflammatory microenvironment promotes extracellular matrix degradation of chondrocytes through ALKBH5-dependent Runx2 m 6 A modification in the pathogenesis of osteoarthritis.

Background: Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the breakdown of cartilage and extracellular matrix (ECM). The degradation of ECM in chondrocytes plays a crucial role in OA pathogenesis, but the underlying molecular mechanisms remain largely unclear.
Methods: A sodium monoiodoacetate (MIA) mouse model was used to mimic OA. ECM integrity was accessed by Hematoxylin and Eosin (H&E) staining, Safranin O/fast green staining, and microcomputerized tomography. Enzyme-linked immunosorbent assay measured circulating proinflammatory cytokines. Reverse transcription-quantitative polymerase chain reaction and western blotting analyzed mRNA and protein expression levels. RNA and chromatin immunoprecipitation evaluated RNA-protein and DNA-protein interactions.
Results: MIA mice showed significant upregulation of the RNA m ⁶ A demethylase ALKBH5 (alkylated DNA repair protein AlkB homolog 5), the transcription factor Runx2 (runt-related transcription factor 2), and matrix-degrading enzymes Mmps (matrix metallopeptidase) and Adamts(s) (a disintegrin and metalloproteinase with thrombospondin motifs). In vitro, proinflammatory cytokines induced these proteins in chondrocytes. Mechanically, Alkbh5 cooperated with Ythdf1 (YTH N6-methyladenosine RNA binding protein 1) in the inflammatory microenvironment to regulate the expression and stability of RUNX2 mRNA. Runx2, in turn, activated the expression of MMPs and ADAMTSs, promoting ECM degradation in chondrocytes, thereby contributing to OA progression. Notably, inhibition of Alkbh5 and Runx2 in MIA-treated mice significantly alleviated the pathological progression of OA.
Conclusion: Our results reveal a novel mechanism of OA pathogenesis and suggest that targeting Alkbh5 and Runx2 may represent a new therapeutic strategy for OA treatment.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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