RUNX2 promotes osteoclast differentiation and bone resorption via the newly identified LncRNA-ROD: implications for alveolar remodeling

Abstract

Abstract Delayed tooth eruption is a hallmark of cleidocranial dysplasia (CCD) caused by RUNX2 haploinsufficiency, yet the underlying molecular mechanism remains undefined. Here, we show that RUNX2 regulates osteoclast-mediated alveolar bone remodeling, a process closely associated with tooth eruption. Runx2 +/− mice exhibit impaired osteoclast differentiation and reduced alveolar bone resorption, resulting in delayed mandibular molar eruption—a phenotype that recapitulates human CCD. Mechanistically, RUNX2 transcriptionally activates LncRNA-ROD ( Regulator of Osteoclast Differentiation ), which promotes osteoclastogenesis by sequestering QKI to stabilize Csf1r mRNA. LncRNA-ROD −/− mice phenocopy the eruption defects and reduced alveolar bone resorption observed in Runx2 +/− mice. Critically, both Runx2 +/− and LncRNA-ROD −/− mice show reduced osteoclast differentiation in alveolar bone, consistent with in vitro data from bone marrow-derived monocytes/macrophages demonstrating impaired osteoclast differentiation. Notably, rescue experiments in ovariectomy-induced osteoporosis models demonstrate that QKI knockdown restores osteoclast differentiation in Runx2 +/− and LncRNA-ROD −/− mice, highlighting the critical role of the RUNX2/ LncRNA-ROD /QKI axis in osteoclastogenesis. The axis supports alveolar bone remodeling associated with tooth eruption. These results provide mechanistic insights into cleidocranial dysplasia-related alveolar bone remodeling defects and delayed tooth eruption, and identify LncRNA-ROD as a potential therapeutic target for alveolar bone remodeling disorders. Furthermore, this axis is implicated in broader bone metabolic disorders, as demonstrated by its impact on osteoporosis progression in Runx2 +/− and LncRNA-ROD −/− mice.