FENDRR-mediated regulation of osteoclast differentiation through the miRNA-129-5p/P2X7R axis

OBJECTIVE: Osteoclast differentiation is a pivotal driver in the pathogenesis of bone-related disorders. This study aimed to elucidate the functional role of long non-coding RNA FENDRR. METHODOLOGY: Functional validation was performed through both overexpression and knockdown of FENDRR. Osteoclast development and functionality were assessed using TRAP staining, ALP activity assays, and quantification of intracellular calcium levels. Inflammatory responses were evaluated by measuring cytokine production and examining key inflammasome components. Molecular interactions were further investigated via dual-luciferase reporter assays. RESULTS: Overexpression of FENDRR promoted osteoclast development and activation, enhanced inflammatory cytokine release, and activated the NF-κB signaling pathway along with the NLRP3 inflammasome. Conversely, FENDRR knockdown attenuated these effects. Mechanistically, miRNA-129-5p was identified as a downstream target of FENDRR, and its overexpression counteracted the pro-osteoclastogenic and pro-inflammatory effects of FENDRR. Furthermore, P2X7R, regulated by miRNA-129-5p, was demonstrated to be critically involved in mediating inflammatory responses in osteoclasts. CONCLUSION: These findings suggest that FENDRR plays a significant role in the pathophysiology of osteoarthritis by promoting osteoclast development and activation, thereby exacerbating inflammatory cascades.