Deficiency of cartilage‐specific Y‐box binding protein 1 represses NF‐κB signaling and alleviates osteoarthritis progression

Objective To explore the role of Y‐box binding protein 1 (YBX1) in the pathogenesis of osteoarthritis (OA). Methods The proteome and phosphoproteome were compared between the intact and osteoarthritic regions of the cartilage from patients undergoing total knee arthroplasty, establishing a connection between the pathology and YBX1 upregulation. Normal C57BL/6 and cartilage‐specific Ybx1 ‐deficient mice underwent medial meniscal destabilization surgery; the behavior, micro‐computed tomography, and histology were compared. YBX1 was overexpressed in the C28/I2 cell line, and potential binding partners were identified using immunoprecipitation and mass spectrometry. MedChemExpress drug libraries were screened for potential small‐molecule inhibitors of YBX1, and candidates were injected intra‐articularly into a mouse OA model. Results The total YBX1 and YBX1 phosphorylated levels at S102 were higher in the osteoarthritic than intact human cartilage. Ybx1 knockout in chondrocytes alleviated disease progression in an OA mouse model. Upregulation of YBX1 in chondrocytes activated NF‐κB signaling. Phosphorylation of YBX1 at S102 promoted its entry into the nucleus, where it inhibited NF‐κB‐repressing factor (NKRF), upregulating target genes of NF‐κB. Virtual drug screening identified hesperidin methychalcone and mulberroside A as candidates for inhibiting S102 phosphorylation, alleviating disease progression in an injury‐induced OA mouse model. Conclusion YBX1 contributes to OA progression by inhibiting NKRF, activating NF‐κB signaling; therefore targeting YBX1 is a potential therapeutic strategy for the treatment of OA.