Aging of craniofacial skeleton significantly impairs the repair and regeneration of trauma-induced bony defects, and complicates dental treatment outcomes. Age-related alveolar bone loss could be attributed to decreased progenitor pool through senescence, imbalance in bone metabolism and bone-fat ratio. Mesenchymal stem cells isolated from oral bones (OMSCs) have distinct lineage propensities and characteristics compared to MSCs from long bones, and are more suited for craniofacial regeneration. However, the effect of epigenetic modifications regulating OMSC differentiation and senescence in aging has not yet been investigated. In this study, we found that the histone demethylase KDM4B plays an essential role in regulating the osteogenesis of OMSCs and oral bone aging. Loss of KDM4B in OMSCs leads to inhibition of osteogenesis. Moreover, KDM4B loss promoted adipogenesis and OMSC senescence which further impairs bone-fat balance in the mandible. Together, our data suggest that KDM4B may underpin the molecular mechanisms of OMSC fate determination and alveolar bone homeostasis in skeletal aging, and present as a promising therapeutic target for addressing craniofacial skeletal defects associated with age-related deteriorations.

颅面骨骼的老化显着损害创伤引起的骨缺损的修复和再生，并使牙科治疗结果复杂化。与年龄相关的牙槽骨丢失可能是由于衰老导致祖细胞池减少、骨代谢和骨脂肪比失衡所致。与长骨中的 MSC 相比，从口腔骨中分离的间充质干细胞 (OMSC) 具有独特的谱系倾向和特征，并且更适合颅面再生。然而，表观遗传修饰在衰老过程中调节 OMSC 分化和衰老的作用尚未得到研究。在这项研究中，我们发现组蛋白去甲基化酶KDM4B在调节OMSCs的成骨和口腔骨老化中发挥着重要作用。OMSC 中 KDM4B 的缺失会导致成骨抑制。此外，KDM4B 缺失促进脂肪生成和 OMSC 衰老，进一步损害下颌骨的骨脂肪平衡。总之，我们的数据表明，KDM4B 可能支持骨骼衰老过程中 OMSC 命运决定和牙槽骨稳态的分子机制，并成为解决与年龄相关恶化相关的颅面骨骼缺陷的有前景的治疗靶点。