Major vault protein (MVP) negatively regulates osteoclastogenesis via calcineurin-NFATc1 pathway inhibition

Abstract

Rationale: Bone homeostasis is maintained by a balanced interplay of osteoblasts and osteoclasts. Osteoclasts are derived from monocyte/macrophage lineage. Major vault protein (MVP) is known to promote apoptosis and prevent metabolic diseases in macrophage. However, whether MVP is involved in osteoclastogenesis is unknown. Here, we identified an important function of MVP as a negative regulator of osteoclastogenesis and its therapeutic potential in preventing bone loss. Methods: Expression of MVP in osteoclasts was investigated in human tumor tissues with immunohistochemical staining. Next, we generated total body ( Mvp -/- ) and monocyte-specific ( Mvp f/f Lyz2-Cre ) MVP gene knockout mice to observe bone phenotype and osteoclastogenesis using micro-CT and bone histomorphometry. Moreover, we examined the effects of MVP on osteoclast differentiation, bone resorption, NFATc1 activation and calcium oscillations in vitro . Finally, we explored the clinical potential of targeting MVP in two osteoporosis mouse models and used an adeno-associated virus (AAV) gene to overexpress MVP locally in mice. Results: We found that Mvp -/- and Mvp f/f Lyz2-Cre mice both exhibited osteoporosis-like phenotypes. MVP-deficiency also enhanced calcineurin-NFATc1 signaling and promoted NFATc1 activity, which led to enhanced osteoclastogenesis and bone resorption. Calcineurin inhibition using the small molecule inhibitor FK506 corrected the enhanced osteoclastogenesis in Mvp f/f Lyz2-Cre group. Additionally, MVP reexpression in Mvp f/f Lyz2-Cre group rescued calcineurin expression. MVP overexpression in wild-type mice prevented pathologic bone loss in mouse models of ovariectomized (OVX) and calvaria-adjacent lipopolysaccharide (LPS)-injected. Conclusions: Our data suggested that MVP negatively regulates osteoclast differentiation and bone resorption via inhibition of calcineurin-NFATc1 signaling. In osteoclast-related bone diseases such as osteoporosis, manipulation of MVP activity may be an attractive therapeutic target.

Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis

“…The induction of MVP expression by viral infection upregulates type-I interferon production by enhancing the expression of IRF7 (interferon regulatory factor 7), but not IRF3 (interferon regulatory factor 3) [ 105 ]. Moreover, MVP inhibits the calcineurin-NFATc1 signaling pathway, which regulates genes involved in intracellular calcium concentrations, negatively regulating osteoclast differentiation and bone resorption [ 140 ]. MVP is also closely connected to signaling pathways in cancer cells, and upregulation most often results in chemotherapy resistance of the cells.…”

Recent Advances in Osteoclast Biological Behavior

“…Vaults are highly conserved across species and most mammalian cell vaults are in the cytoplasm ( Esfandiary et al, 2009 ). Research suggested that MVP negatively regulates osteoclast differentiation and bone resorption via inhibition of calcineurin-NFATc1 signaling and Mvp−/− and Mvp f/f Lyz2-Cre mice both exhibited osteoporosis-like phenotypes ( Yuan L. et al, 2021 ). MVP-deficiency also enhanced calcineurin-NFATc1 signaling and promoted NFATc1 activity, which led to enhanced osteoclastogenesis and bone resorption ( Yuan L. et al, 2021 ).…”

“…Research suggested that MVP negatively regulates osteoclast differentiation and bone resorption via inhibition of calcineurin-NFATc1 signaling and Mvp−/− and Mvp f/f Lyz2-Cre mice both exhibited osteoporosis-like phenotypes ( Yuan L. et al, 2021 ). MVP-deficiency also enhanced calcineurin-NFATc1 signaling and promoted NFATc1 activity, which led to enhanced osteoclastogenesis and bone resorption ( Yuan L. et al, 2021 ). Hh pathway, an evolutionarily conserved signaling pathway, plays critical roles in skeletal development and homeostasis, and is regarded as a promising anabolic pathway for treating osteoporosis and promoting bone regeneration.…”

Role of Lipid Rafts in Pathogen-Host Interaction - A Mini Review

“…MVP has also been implicated in suppression of metabolic diseases, such as obesity and atherosclerosis, through IKK-NF-κB signaling-mediated inflammation ( 158 ). MVP negatively regulates osteoclast differentiation by inhibiting the calcineurin-NFATc1 signaling pathway ( 159 ). Moreover, it interacts with Src in an epidermal growth factor (EGFR)-dependent manner and downregulates Src tyrosine kinase activity in stomach tissue, with this latter being necessary for activation of extracellular signal-regulated kinase (ERK) signaling ( 160 ).…”