PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis

Author:

Chu Wenxiang1,Peng Weilin1,Lu Yingying2,Liu Yishan1,Li Qisheng1,Wang Haibin1,Wang Liang1,Zhang Bangke1,Liu Zhixiao3,Han Lin4,Ma Hongdao1,Yang Haisong1,Han Chaofeng35,Lu Xuhua1ORCID

Affiliation:

1. Department of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 China

2. Obstetrics and Gynecology Hospital Fudan University Shanghai 200011 China

3. Histology and Embryology Department and Shanghai Key Laboratory of Cell Engineering Naval Medical University Shanghai 200433 China

4. Department of Orthopaedics Third Affiliated Hospital of Naval Medical University Shanghai 201805 China

5. National Key Laboratory of Immunity and Inflammation, Institute of Immunology Naval Medical University Shanghai 200433 China

Abstract

AbstractEpigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By transcriptional sequence and ATAC analysis, this study identifies that activation of RANK signaling upregulates PRMT6 by epigenetic modification, triggering a metabolic switching from fatty acids oxidation toward glycolysis. Conversely, Prmt6 deficiency reverses this shift, markedly reducing HIF‐1α‐mediated glycolysis and enhancing fatty acid oxidation. Consequently, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss in ovariectomized (OVX) mice. At the molecular level, Prmt6 deficiency reduces asymmetric dimethylation of H3R2 at the promoters of genes including Ppard, Acox3, and Cpt1a, enhancing genomic accessibility for fatty acid oxidation. PRMT6 thus emerges as a metabolic checkpoint, mediating metabolic switch from fatty acid oxidation to glycolysis, thereby supporting osteoclastogenesis. Unveiling PRMT6's critical role in epigenetically orchestrating metabolic shifts in osteoclastogenesis offers a promising target for anti‐resorptive therapy.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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