Macrophage MVP regulates fracture repair by promoting M2 polarization via JAK2-STAT6 pathway

Yan Yang; Na Zhao; Ruobing Wang; Zhuorong Zhan; Shuyu Guo; Haiyang Song; Erik A C Wiemer; Jingjing Ben; Junqing Ma

doi:10.1016/j.intimp.2023.110313

Macrophage MVP regulates fracture repair by promoting M2 polarization via JAK2-STAT6 pathway

Int Immunopharmacol. 2023 Jul:120:110313. doi: 10.1016/j.intimp.2023.110313. Epub 2023 May 31.

Authors

Yan Yang¹, Na Zhao¹, Ruobing Wang¹, Zhuorong Zhan¹, Shuyu Guo¹, Haiyang Song², Erik A C Wiemer³, Jingjing Ben⁴, Junqing Ma⁵

Affiliations

¹ Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
² Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.
³ Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands.
⁴ Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, China.
⁵ Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China. Electronic address: jma@njmu.edu.cn.

PMID: 37267856
DOI: 10.1016/j.intimp.2023.110313

Abstract

Objective: Major vault protein (MVP) is vital in various macrophage-related inflammatory diseases. However, the effects of MVP on macrophage polarization during fracture repair are still unknown.

Methods: We used Mvp^flox/floxLyz2-Cre mice (myeloid-specific MVP gene knockout, abbreviated as MacKO) and Mvp^flox/flox (abbreviated as MacWT) mice to compare their fracture healing phenotype. Next, we traced the changes in macrophage immune status in vivo and in vitro. We further explored the effects of MVP on osteogenesis and osteoclastogenesis. Finally, we re-expressed MVP in MacKO mice to confirm the role of MVP in fracture healing.

Results: The lack of MVP in macrophages impaired their transition from a pro-inflammatory to an anti-inflammatory phenotype during fracture repair. The increased secretion of pro-inflammatory cytokines by macrophages promoted their osteoclastic differentiation and impaired BMSC osteogenic differentiation, ultimately leading to impaired fracture repair in MacKO mice. Last, adeno-associated virus (AAV)-Mvp tibial injection significantly promoted fracture repair in MacKO mice.

Conclusions: Our findings showed MVP has a previously unknown immunomodulatory role in macrophages during fracture repair. Targeting macrophage MVP may represent a novel therapeutic method for fracture treatment.

Keywords: Fracture repair; Immunomodulation; MVP; Macrophages; Polarization.

MeSH terms

Animals
Cytokines / metabolism
Macrophages*
Mice
Osteogenesis*
Vault Ribonucleoprotein Particles / metabolism
Vault Ribonucleoprotein Particles / pharmacology

Substances

major vault protein
Vault Ribonucleoprotein Particles
Cytokines