Heterotopic ossification (HO) is the abnormal formation of bone in extraskeletal sites. However, the mechanisms linking HO pathogenesis with bone mass dysfunction remain unclear. Here, we showed that mice harboring injury-induced and BMP4-dependent HO exhibit bone mass loss similar to that presented by patients with HO. Moreover, we found that injury-induced hyperinflammatory responses at the injury site triggered HO initiation but did not result in bone mass loss at 1 day post-injury (dpi). In contrast, a suppressive immune response promoted HO propagation and bone mass loss by 7 dpi. Correcting immune dysregulation by PD1/PDL1 blockade dramatically alleviated HO propagation and bone mass loss. We further demonstrated that fetuin-A (FetA), which has been frequently detected in HO lesions but rarely observed in HO-adjacent normal bone, acts as an immunomodulator to promote PD1 expression and M2 macrophage polarization, leading to immunosuppression. Intervention with recombinant FetA inhibited hyperinflammation and prevented HO and associated bone mass loss. Collectively, our findings provide new insights into the osteoimmunological interactions that occur during HO formation and suggest that FetA is an immunosuppressor and a potential therapeutic option for the treatment of HO.

异位骨化 (HO) 是骨骼外部位骨骼的异常形成。然而，将 HO 发病机制与骨量功能障碍联系起来的机制仍不清楚。在这里，我们发现携带损伤诱导和 BMP4 依赖性 HO 的小鼠表现出与 HO 患者相似的骨量丢失。此外，我们发现损伤部位的损伤诱导的过度炎症反应触发了 HO 的启动，但并未导致损伤后 1 天 (dpi) 的骨量丢失。相反，抑制性免疫反应促进了 7 dpi 的 H2O 传播和骨质流失。通过 PD1/PDL1 阻断纠正免疫失调可显着缓解 HO 传播和骨量丢失。我们进一步证明了在 HO 病变中经常检测到但在 HO 相邻正常骨中很少观察到的胎球蛋白 A (FetA)，作为免疫调节剂促进 PD1 表达和 M2 巨噬细胞极化，导致免疫抑制。用重组 FetA 进行干预可抑制过度炎症并防止 HO 和相关的骨质流失。总的来说，我们的研究结果为 HO 形成过程中发生的骨免疫相互作用提供了新的见解，并表明 FetA 是一种免疫抑制剂和治疗 HO 的潜在治疗选择。