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

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.