Muscle injury promotes heterotopic ossification by stimulating local bone morphogenetic protein-7 production

Abstract

Background: Heterotopic ossification (HO) is a pathological condition of abnormal bone formation in soft tissue, which causes pain and restricted range of motion in patients. There are two broad categories of HO, hereditary and acquired. Although different types of HO do not use identical mechanistic pathways of pathogenesis, muscle injury appears to be a unifying feature for all types of HO. However, little is known about the mechanisms by which muscle injury facilitates HO formation. Objective and method: This study aimed to explore the cellular and molecular mechanisms linking muscle injury to HO by using cardiotoxin to induce muscle injury in a bone morphogenetic protein-2 (BMP-2)–induced HO mouse model. Results: We found that muscle injury augmented HO formation and that this effect was correlated with BMP signalling activation and upregulation of BMP-7 expression at the early phase of HO progression. We further demonstrated that inhibition of BMP-7 activity in vitro suppressed the osteogenesis-promoting effect of conditioned medium derived from injured muscle tissue and in vivo reduced the volume of HO formation. We also showed that antiinflammatory drug treatment reduced the volume of HO with concomitant reduction in BMP-7 production. Conclusion: In summary, our study has identified BMP-7 as a key osteoinductive factor in injured muscle that facilitates HO formation. The translational potential of this article: Our results provide a candidate mechanistic rationale for the use of antiinflammatory drugs in the prevention of HO. Keywords: Bone morphogenetic protein, Heterotopic ossification, Inflammation, Macrophages, Muscle injury, Stromal/stem cells