Heterotopic ossification (HO), true bone formation in soft tissue, is closely associated with abnormal injury/immune responses. We hypothesized that a key underlying mechanism of HO might be injury-induced dysregulation of immune checkpoint proteins (ICs). We found that the earliest stages of HO are characterized by enhanced infiltration of polarized macrophages into sites of minor injuries in an animal model of HO. The non-specific immune suppressants, Rapamycin and Ebselen, prevented HO providing evidence of the central role of the immune responses. We examined the expression pattern of ICs and found that they are dysregulated in HO lesions. More importantly, loss of function of inhibitory ICs (including PD1, PD-L1, and CD152) markedly inhibited HO, whereas loss of function of stimulatory ICs (including CD40L and OX-40L) facilitated HO. These findings suggest that IC inhibitors may provide a therapeutic approach to prevent or limit the extent of HO.

异位骨化（HO）是软组织中的真正骨形成，与异常的损伤/免疫反应密切相关。我们假设HO的一个关键潜在机制可能是损伤引起的免疫检查点蛋白（ICs）失调。我们发现HO的早期阶段的特征是在HO动物模型中极化巨噬细胞向轻伤部位的浸润增强。非特异性免疫抑制剂雷帕霉素和依贝硒仑可以预防HO，从而提供了免疫反应的核心作用的证据。我们检查了IC的表达模式，发现它们在HO病变中失调。更重要的是，抑制性IC（包括PD1，PD-L1和CD152）的功能丧失显着抑制了HO，而刺激性IC（包括CD40L和OX-40L）的功能丧失促进了HO。