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<p>Osteoporosis is a multifactorial skeletal disorder characterized by increased bone resorption and impaired remodeling balance. Osteoclast differentiation is accompanied by metabolic reprogramming toward enhanced glycolysis, yet whether nutritional factors modulate osteoclast metabolism remains incompletely understood. Vitamin B5 (VB5), a precursor of coenzyme A (CoA), has been implicated in metabolic regulation, but its role in osteoclast biology is unclear. An ovariectomy (OVX)-induced osteoporosis mouse model was established and fed VB5-deficient, normal, or VB5-supplemented diets. Bone microarchitecture was assessed by micro-computed tomography and histomorphometry. Osteoclast differentiation was evaluated in RAW264.7 cells and bone marrow–derived macrophages (BMDMs). Metabolic flux analysis, molecular docking, co-immunoprecipitation, and Western blotting were performed to investigate the involvement of the PANK–CoA–PKM2 axis. VB5 supplementation attenuated OVX-induced bone loss and reduced osteoclast numbers in vivo, whereas VB5 deficiency exacerbated bone deterioration. In vitro, VB5 and its metabolic derivative CoA suppressed osteoclast differentiation without inducing significant cytotoxicity. Mechanistically, VB5 increased intracellular CoA levels in a PANK-dependent manner. CoA interacted with PKM2, reduced Y105 phosphorylation, and decreased nuclear translocation, accompanied by suppression of glycolytic and oxidative phosphorylation activity. Pharmacological stabilization of PKM2 partially reversed molecular alterations associated with VB5 deficiency. VB5 is associated with inhibition of osteoclast differentiation and attenuation of estrogen deficiency–induced bone loss, potentially through modulation of metabolic reprogramming involving the PANK–CoA–PKM2 axis. These findings provide preliminary insight into a link between vitamin-dependent metabolic pathways and skeletal remodeling.</p>

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VB5 modulates osteoclast metabolic reprogramming and suppresses differentiation by blocking PKM2 nuclear translocation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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  • Hongming Zhou,
  • Hengren Li,
  • Ming Fu,
  • Heng Yang,
  • Xingang Cui

摘要

Osteoporosis is a multifactorial skeletal disorder characterized by increased bone resorption and impaired remodeling balance. Osteoclast differentiation is accompanied by metabolic reprogramming toward enhanced glycolysis, yet whether nutritional factors modulate osteoclast metabolism remains incompletely understood. Vitamin B5 (VB5), a precursor of coenzyme A (CoA), has been implicated in metabolic regulation, but its role in osteoclast biology is unclear. An ovariectomy (OVX)-induced osteoporosis mouse model was established and fed VB5-deficient, normal, or VB5-supplemented diets. Bone microarchitecture was assessed by micro-computed tomography and histomorphometry. Osteoclast differentiation was evaluated in RAW264.7 cells and bone marrow–derived macrophages (BMDMs). Metabolic flux analysis, molecular docking, co-immunoprecipitation, and Western blotting were performed to investigate the involvement of the PANK–CoA–PKM2 axis. VB5 supplementation attenuated OVX-induced bone loss and reduced osteoclast numbers in vivo, whereas VB5 deficiency exacerbated bone deterioration. In vitro, VB5 and its metabolic derivative CoA suppressed osteoclast differentiation without inducing significant cytotoxicity. Mechanistically, VB5 increased intracellular CoA levels in a PANK-dependent manner. CoA interacted with PKM2, reduced Y105 phosphorylation, and decreased nuclear translocation, accompanied by suppression of glycolytic and oxidative phosphorylation activity. Pharmacological stabilization of PKM2 partially reversed molecular alterations associated with VB5 deficiency. VB5 is associated with inhibition of osteoclast differentiation and attenuation of estrogen deficiency–induced bone loss, potentially through modulation of metabolic reprogramming involving the PANK–CoA–PKM2 axis. These findings provide preliminary insight into a link between vitamin-dependent metabolic pathways and skeletal remodeling.