Researchers uncover molecular pathway controlling bone resorption and tooth eruption

RUNX2 is best known as a master transcription factor of osteoblast differentiation. Mutations in, or haploinsufficiency of RUNX2 cause CCD, a skeletal disorder characterized by delayed permanent tooth eruption, supernumerary teeth and clavicular defects. Analyses of alveolar bone from patients with CCD reveal increased bone density and reduced numbers of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, suggesting that impaired bone resorption, in addition to altered bone formation, contributes to the pathogenesis of CCD. Although emerging evidence indicates that RUNX2 can indirectly regulate osteoclasts, the mechanisms by which RUNX2 directly controls osteoclast differentiation and the potential contribution of lncRNAs to this process remain poorly defined. Several lncRNAs have been shown to regulate osteoclast differentiation, but their roles in RUNX2-driven osteoclastogenesis are largely unknown. Therefore, elucidating how RUNX2 and lncRNAs directly govern osteoclast differentiation and alveolar bone remodeling is essential.

Researchers at Peking University School and Hospital of Stomatology (Beijing, China) reported the findings (DOI: 10.1038/s41368-026-00466-z) on 28 September 2026 in International Journal of Oral Science. In this open-access study, the researchers integrated analyses of a sample from a patient with CCD, Runx2^⁺/⁻ and LncRNA-ROD^⁻/⁻ mouse models, gene-edited cells, RNA pull-down and RNA immunoprecipitation assays, micro-computed tomography (micro-CT), TRAP staining, and ovariectomy (OVX) experiments. They investigated whether the RUNX2–LncRNA-ROD–QKI axis regulates osteoclast differentiation and bone resorption in cultured precursor cells and in vivo. Rescue experiments further linked this axis to alveolar bone remodeling and OVX-induced bone loss.

The patient carried a RUNX2 missense mutation (c.557G>C; R186T). Compared with controls, her alveolar bone exhibited greater density and contained no detectable TRAP-positive osteoclasts. Runx2^⁺/⁻ mice recapitulated CCD-like skeletal abnormalities and exhibited delayed eruption of the mandibular first molars at postnatal days 11 and 13, together with reduced numbers of TRAP-positive osteoclasts at postnatal day 5. In both RAW 264.7 cells and bone marrow-derived monocytes/macrophages (BMMs), RUNX2 loss reduced osteoclast marker expression, the number of TRAP-positive cells, and resorption-pit formation. RNA sequencing identified LncRNA-ROD as a 1147-bp, three-exon transcript enriched in bone and directly activated by RUNX2. Chromatin immunoprecipitation and luciferase reporter assays confirmed RUNX2 binding to the LncRNA-ROD promoter. Overexpression of LncRNA-ROD rescued defective osteoclastogenesis in BMMs derived from Runx2^⁺/⁻ mice, whereas LncRNA-ROD^⁻/⁻ mice phenocopied the eruption and bone-resorption defects. In isolated osteoclast precursors, LncRNA-ROD deletion increased the expression of the fusion markers CD44 (cluster of differentiation 44) and ITGB3 (integrin subunit beta 3), as well as the number of TRAP-positive cells, but decreased the expression of CTSK (cathepsin K) and MMP9 (matrix metalloproteinase 9) and reduced resorption-pit area. In vivo, however, osteoclast numbers were reduced. Mechanistically, LncRNA-ROD bound QKI, an RNA-binding protein that promotes Csf1r mRNA degradation. By sequestering nuclear QKI-5 and cytoplasmic QKI-6, LncRNA-ROD stabilized Csf1r mRNA and increased CSF1R protein levels. QKI knockdown restored osteoclast differentiation in cells derived from Runx2^⁺/⁻ and LncRNA-ROD^⁻/⁻ mice, and both mutant strains exhibited resistance to OVX-induced bone loss.

The authors noted that these findings position LncRNA-ROD as a central component of a CCD-associated osteoclast regulatory network and suggest that the RUNX2–LncRNA-ROD–QKI axis is pharmacologically targetable. They also emphasized that the current data do not demonstrate that restoration of this axis can reverse tooth-eruption defects, because the existing mouse models involve global gene modification and alveolar-targeted rescue has not been tested. Osteoclast-specific conditional knockout models and localized alveolar rescue experiments are therefore needed. In addition, direct assays of bone formation are required to fully interpret the OVX findings. The authors cautioned that, although these results support the development of RNA-directed therapies, cell-type specificity must be carefully addressed.

These findings may inform therapeutic strategies for delayed tooth eruption in CCD and for other skeletal disorders characterized by excessive or impaired osteoclast activity. Given its bone-enriched expression and position upstream of CSF1R, the LncRNA-ROD–CSF1R axis may be amenable to modulation by antisense oligonucleotides or small molecules. However, its functional RNA motifs and methods for targeted delivery to alveolar bone remain to be validated. This axis may also provide a mechanistic framework for distinguishing osteoclast fusion from resorptive capacity, an important consideration in bone diseases in which osteoclast number and function are uncoupled. More broadly, this work supports RNA-directed approaches for treating disorders of alveolar bone remodeling and systemic bone metabolism.