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

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.

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Funding

National Natural Science Foundation of China (National Science Foundation of China)(82370911)

National Key R&D Program of China (grant number: 2022YFA1206102; project number: 2022YFA1206100)

Peking University School and Hospital of Stomatology Science Foundation for Young Scientists (PKUSS20230115)

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