Abstract：
Energy metabolism, through pathways such as oxidative phosphorylation (OxPhos) and glycolysis, plays a pivotal role in cellular differentiation and function. Our study investigates the impact of OxPhos disruption in cortical bone development by deleting Mitochondrial Transcription Factor A (TFAM). TFAM controls OxPhos by regulating the transcription of mitochondrial genes. The cortical bone, constituting the long bones\' rigid shell, is sheathed by the periosteum, a connective tissue layer populated with skeletal progenitors that spawn osteoblasts, the bone-forming cells. TFAM-deficient mice presented with thinner cortical bone, spontaneous midshaft fractures, and compromised periosteal cell bioenergetics, characterized by reduced ATP levels. Additionally, they exhibited an enlarged periosteal progenitor cell pool with impaired osteoblast differentiation. Increasing Hypoxia-Inducible Factor 1a (HIF1) activity within periosteal cells significantly mitigated the detrimental effects induced by TFAM deletion. HIF1 is known to promote glycolysis in all cell types. Our findings underscore the indispensability of OxPhos for the proper accrual of cortical bone mass and indicate a compensatory mechanism between OxPhos and glycolysis in periosteal cells. The study opens new avenues for understanding the relationship between energy metabolism and skeletal health and suggests that modulating bioenergetic pathways may provide a therapeutic avenue for conditions characterized by bone fragility.
摘要：
能量代谢，通过氧化磷酸化（OxPhos）和糖酵解等途径，在细胞分化和功能中起着关键作用。我们的研究通过删除线粒体转录因子A（TFAM）来调查OxPhos破坏对皮质骨发育的影响。TFAM通过调节线粒体基因的转录来控制OxPhos。皮质骨，构成长骨的刚性外壳，被骨膜包裹着，一个由骨骼祖细胞组成的结缔组织层可以产生成骨细胞，骨形成细胞。TFAM缺陷小鼠呈现较薄的皮质骨，自发性中段骨折,受损的骨膜细胞生物能学，以降低的ATP水平为特征。此外,他们表现出一个增大的骨膜祖细胞池，成骨细胞分化受损。骨膜细胞内缺氧诱导因子1a(HIF1)活性的增加显著减轻了TFAM缺失诱导的有害作用。已知HIF1在所有细胞类型中促进糖酵解。我们的发现强调了OxPhos对于皮质骨量的适当积累是不可或缺的，并表明了OxPhos与骨膜细胞糖酵解之间的代偿机制。该研究为理解能量代谢与骨骼健康之间的关系开辟了新途径，并表明调节生物能量途径可能为以骨脆性为特征的疾病提供治疗途径。
