1. Academic Validation
  2. HIF-1α mediates osteoclast-induced disuse osteoporosis via cytoophidia in the femur of mice

HIF-1α mediates osteoclast-induced disuse osteoporosis via cytoophidia in the femur of mice

  • Bone. 2022 Dec 21;168:116648. doi: 10.1016/j.bone.2022.116648.
Miaomiao Bie 1 Yi Tang 2 Yuxing Xia 1 Qian Zhang 1 Yuanye Tian 1 Chunan Cheng 1 Xinzhao Li 1 Xin Qi 1 Feiwu Kang 3
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial Surgery, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China.
  • 2 Department of Periodontology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China.
  • 3 Department of Oral and Maxillofacial Surgery, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China. Electronic address: kfw@tongji.edu.cn.
Abstract

Osteoporosis induced by disuse because of bed rest or the aerospace industry has become one of the most common skeletal disorders. However, mechanisms underlying the disuse osteoporosis remain largely unknown. We validated the tail-suspended model in mice and demonstrated that there is bone loss in the trabecular and cortical bones of the femur. Importantly, we showed that genetical deletion of hypoxia-inducible factor-1α (HIF-1α) in osteoclasts ameliorated osteoclastic bone resorption in the trabecular bone whereas pharmacological treatment with HIF-1α Inhibitor protected the hindlimb-unloaded mice from disuse-induced osteoporosis in the trabecular and cortical bones. The HIF-1α knockout RAW264.7 cells and RNA-sequencing proved that HIF-1α is vital for osteoclastogenesis and bone resorption because it regulated the level of inosine monophosphate dehydrogenase (IMPDH) and cytidine triphosphate synthetase (CTPS) via cellular myelocytomatosis (c-Myc) oncogene. The IMPDH and CTPS are vital nucleotide metabolic Enzymes which have an important functional role in cell metabolism, and they can assemble into intracellular linear or ring-shaped structures to cope with cell stress. Interestingly, both in vitro and in vivo, the IMPDH and CTPS cytoophidia were found in osteoclasts, and the level of HIF-1α correlated with osteoclastogenesis and bone-resorbing activity. Our data revealed that HIF-1α/c-Myc/cytoophidia signalling might be required for osteoclasts to mediate cell metabolism in disuse-induced osteoporosis. Overall, our results revealed a new role of HIF-1α/c-Myc/cytoophidia in supporting osteoclastogenesis and bone resorption and exposed evidence for its role in the pathogenesis of disuse osteoporosis, which might provide promising therapeutic targets.

Keywords

Cytoophidia; Disuse osteoporosis; HIF-1α; Osteoclasts; c-Myc.

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