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Delayed eruption of permanent teeth is a common symptom of cleidocranial dysplasia (CCD). Previous studies have focused on the anomaly of osteogenesis resulting from mutations in the Runt-related transcription factor-2 gene (RUNX2). However, deficiencies in osteoclastogenesis and bone resorption, and the epigenetic regulation mediated by long non-coding (lnc)RNAs in CCD remain to be elucidated. Here, a novel osteoclast-specific lncRNA (OC-lncRNA) was identified during the osteoclast differentiation of RAW 264.7 cells transfected with a RUNX2 mutation expression cassette. We further confirmed that OC-lncRNA positively regulated osteoclastogenesis and bone resorption. The OC-lncRNA promoted the expression of CXC chemokine receptor type 3 (CXCR3) by competitively binding to microRNA (miR)-221-5p. The CXCR3–CXC-motif chemokine ligand 10 (CXCL10) interaction and nuclear factor-κB constituted a positive feedback that positively regulated osteoclastogenesis and bone resorption. These results demonstrate that OC-lncRNA-mediated osteoclast dysfunction via the OC-lncRNA–miR-221-5p–CXCR3 axis, which is involved in the process of delayed tooth eruption of CCD. [ABSTRACT FROM AUTHOR]

Cleidocranial dysplasia is an autosomal dominant skeletal disorder resulting from RUNX2 mutations. The influence of RUNX2 mutations on osteoclastogenesis and bone resorption have not been reported. To investigate the role of RUNX2 in osteoclast, RUNX2 expression in macrophages (RAW 264.7 cells) was detected. Stable RAW 264.7 cell lines expressing wild-type RUNX2 or mutated RUNX2 (c.514delT, p.172 fs) were established, and their functions in osteoclasts were investigated. Wild-type RUNX2 promoted osteoclast differentiation, formation of F-actin ring, and bone resorption, while mutant RUNX2 attenuated the positive differentiation effect. Wild-type RUNX2 increased the expression and activity of mTORC2. Subsequently, mTORC2 specifically promoted phosphorylation of AKT at the serine 473 residue. Activated AKT improved the nuclear translocation of NFATc1 and increased the expression of downstream genes, including CTSK. Inhibition of AKT phosphorylation abrogated the osteoclast formation of wild-type macrophages, whereas constitutively activated AKT rescued the osteoclast formation of mutant macrophages. The present study suggested that RUNX2 promotes osteoclastogenesis and bone resorption through the AKT/NFATc1/CTSK axis. Mutant RUNX2 lost the function of regulating osteoclast differentiation and bone remodeling, resulting in the defective formation of the tooth eruption pathway and impaction of permanent teeth in cleidocranial dysplasia. This study, for the first time, verifies the effect of RUNX2 on osteoclast differentiation and bone resorption and provides new insight for the explanation of cleidocranial dysplasia. [ABSTRACT FROM AUTHOR]

The aim was to provide a comprehensive review of the current knowledge of the multiple roles of Runt-related transcription factor-2 (RUNX2) in regulating tooth eruption, focusing on the molecular mechanisms regarding tooth eruption mediated by RUNX2. Relevant literatures in PubMed, Medline, and Scopus database were searched, and a narrative review was performed. The multiple roles of RUNX2 in regulating tooth eruption was reviewed and discussed. Aberrant RUNX2 expression leads to disturbed or failed tooth eruption. Tooth eruption involves both the process of bone formation and bone resorption. RUNX2 promotes osteogenesis around the radicular portion of the dental follicle that provides the biological force for tooth eruption through inducing the expression of osteogenesis-related genes in dental follicle cells/osteoblasts. On the other hand, through indirect and direct pathways, RUNX2 regulates osteoclastogenesis and the formation of the eruption pathway. RUNX2 exerts a pivotal and complex influence in regulating tooth eruption. This review provides a better understanding of the function of RUNX2 in tooth eruption, which is beneficial to illuminate the precise molecular mechanism of osteogenesis and bone resorption, aiding the development of effective therapy for the failure of tooth eruption. • Tooth eruption involves both bone formation and bone resorption. • Tooth eruption is a valuable model to study bone remodeling. • Runt-related transcription factor-2 (RUNX2) plays a critical role in tooth eruption. • RUNX2 directly regulates osteoclastogenesis and bone resorption. • Function of RUNX2 will benefit the precision therapy for bone remodeling disorders. [ABSTRACT FROM AUTHOR]