Abstract
ABSTRACTOsteoclast differentiation is a dynamic differentiation process, which is accompanied by dramatic changes in metabolic status as well as in gene expression. Recent findings have revealed an essential connection between metabolic reprogramming and dynamic gene expression changes during osteoclast differentiation. However, the upstream regulatory mechanisms that drive these metabolic changes in osteoclastogenesis remain to be elucidated. Here, we demonstrate that induced deletion of a tumor suppressor gene, Folliculin (Flcn), in mouse osteoclast precursors causes severe osteoporosis in 3 weeks through excess osteoclastogenesis. Flcn‐deficient osteoclast precursors reveal cell autonomous accelerated osteoclastogenesis with increased sensitivity to receptor activator of NF‐κB ligand (RANKL). We demonstrate that Flcn regulates oxidative phosphorylation and purine metabolism through suppression of nuclear localization of the transcription factor Tfe3, thereby inhibiting expression of its target gene Pgc1. Metabolome studies revealed that Flcn‐deficient osteoclast precursors exhibit significant augmentation of oxidative phosphorylation and nucleotide production, resulting in an enhanced purinergic signaling loop that is composed of controlled ATP release and autocrine/paracrine purinergic receptor stimulation. Inhibition of this purinergic signaling loop efficiently blocks accelerated osteoclastogenesis in Flcn‐deficient osteoclast precursors. Here, we demonstrate an essential and novel role of the Flcn‐Tfe3‐Pgc1 axis in osteoclastogenesis through the metabolic reprogramming of oxidative phosphorylation and purine metabolism. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
Highlights
Cellular metabolism regulates cell proliferation and differentiation
To investigate the significance of metabolic reprogramming in osteoclast differentiation, we conditionally deleted Flcn by utilizing Mx1 promoter-driven Cre transgenic mice.[17]. Flcn knockout mice (Flcnf/f, Mx1-cre) demonstrated severe osteoporosis with acute progression in 3 weeks after Flcn deletion induced by polyinosinic–polycytidylic acid solution (pIpC) injection. 3D reconstruction of femora by micro-CT analysis revealed severe osteoporosis of Flcn knockout mice
Pgc1b is known to have an essential role in osteoclastogenesis.[1]. We observed a significant increase in Pgc1b expression caused by forced nuclear localization of Tfe3-GR, suggesting possible transcriptional regulation of Pgc1b by Tfe3, as has been demonstrated for Pgc1a (Fig. 3L, M).(29) we confirmed the direct binding of Tfe3 to the M-box motifs in Pgc1b gene as well as Pgc1a gene by Chromatin immunoprecipitation (ChIP)-qPCR, which was observed in Tfe3 activated cells (Fig. 3J, K)
Summary
Recent emerging developments in the research field of metabolism are defining many novel molecular mechanisms involved in cell differentiation. Osteoclastogenesis is one of the most dramatic cell differentiation events, which is accompanied by dynamic changes in cellular metabolism and gene expression. The osteoclast differentiation process is one of the best physiological conditions in which to investigate novel mechanisms of metabolic regulation that drive cell differentiation. It is known that glucose metabolism shifts toward a more oxidative state when osteoclast precursors differentiate to preosteoclasts and osteoclasts upon receptor activator of NF-kB ligand (RANKL) stimulation. Induction of Pgc1b expression by RANKL stimulation causes the aforementioned metabolic reprogramming of osteoclast precursors, resulting in a dramatic change in cellular metabolite profiling, which in turn regulates gene expression that facilitates osteoclastogenesis.[1,2,3]
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