Akihiro Jono, Yuta Yanagihara, Hiroshi Sakai, Noritaka Saeki, Tatsuhiko Kutsuna, Tomofumi Kinoshita, Akiyoshi Uezumi, Masaki Takao, Yuuki Imai
Osteophytes are a characteristic feature of osteoarthritis (OA), and clarifying their molecular regulation may contribute to preventive and therapeutic strategies. Uhrf1 (ubiquitin-like containing PHD and RING finger domains 1), a regulator of DNA methylation maintenance, is indispensable for chondrocyte proliferation and differentiation in the growth plate. Because osteophytes develop via endochondral ossification, we hypothesized that Uhrf1 is involved in osteophyte formation. platelet-derived growth factor receptor α (PDGFRα)-lineage cell-specific Uhrf1-knockout mice showed that Uhrf1 regulates the proliferation and chondrogenic potential of synovial PDGFR-α-lineage cells during osteophyte development, influencing osteophyte formation. Furthermore, experiments using human synovial cells revealed that UHRF1 maintains DNA methylation and identified NLK (nemo-like kinase) as a candidate gene that may be regulated by UHRF1-mediated DNA methylation. These findings suggest that UHRF1 may modulate Wnt signaling and chondrogenic differentiation through the regulation of NLK. Together, these results highlight the role of Uhrf1 in osteophyte formation and provide insight into the mechanisms underlying OA progression, suggesting Uhrf1-mediated pathways as targets for OA.