Uhrf1 determines osteophyte fate by regulating differentiation of synovial mesenchymal progenitor cells [MBD-seq]

We used mesenchymal progenitor cell-specific Uhrf1 knockout (cKO) mice to evaluate osteophyte development and articular cartilage degeneration 2 and 12 weeks post-DMM (destabilization of the medial meniscus) surgery. Two weeks after DMM, cKO mice exhibited significantly smaller osteophytes with reduced width, area, and maturity scores compared to controls.

Twelve weeks after DMM, despite similar maturity scores, osteophytes in cKO mice were still smaller, and articular cartilage degeneration was more severe in cKO. UHRF1 knockdown in human synovial cells led to decreased proliferation and chondrogenic differentiation with less methylated DNA. Integrated analyses with RNA-seq and MBD-seq revealed that UHRF1 deficiency upregulates genes that negatively affect cell development and growth including TORC1 and β-catenin-independent Wnt signaling.