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

Lichan Yuan; Na Zhao; Junyi Wang; Yuying Liu; Li Meng; Shuyu Guo; Erik A C Wiemer; Qi Chen; Yelin Mao; Jingjing Ben; Junqing Ma

doi:10.7150/thno.58468

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

Theranostics. 2021 May 24;11(15):7247-7261. doi: 10.7150/thno.58468. eCollection 2021.

Authors

Lichan Yuan¹, Na Zhao¹, Junyi Wang¹, Yuying Liu², Li Meng¹, Shuyu Guo¹, Erik A C Wiemer³, Qi Chen², Yelin Mao⁴, Jingjing Ben², Junqing Ma¹

Affiliations

¹ Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China.
² Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing 211166, China.
³ Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherland.
⁴ Suzhou Huaxia Stomatology Hospital affiliated to Suzhou Vocational Health College, Suzhou 215009, China.

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/fLyz2-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/fLyz2-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/fLyz2-Cre group. Additionally, MVP reexpression in Mvp^f/fLyz2-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.

Keywords: MVP; NFATc1; calcineurin; osteoclast; osteoporosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Resorption / genetics
Bone Resorption / metabolism
Bone Resorption / pathology
Calcineurin / genetics
Calcineurin / metabolism*
Cell Differentiation*
Humans
Mice
Mice, Knockout
NFATC Transcription Factors / genetics
NFATC Transcription Factors / metabolism*
Osteoclasts / metabolism*
Signal Transduction*
Vault Ribonucleoprotein Particles / genetics
Vault Ribonucleoprotein Particles / metabolism*

Substances

NFATC Transcription Factors
Nfatc1 protein, mouse
Vault Ribonucleoprotein Particles
major vault protein
Calcineurin