Heterotopic ossification (HO), defined as the formation of extraskeletal bone in muscle and soft tissues, is a diverse pathological process caused by either genetic mutations or inciting trauma. Fibrodysplasia ossificans progressiva (FOP) is a genetic form of HO caused by mutations in the bone morphogenetic protein (BMP) type I receptor gene activin A receptor type 1 ( ACVR1 ). These mutations make ACVR1 hypersensitive to BMP and responsive to activin A. Hedgehog (Hh) signaling also contributes to HO development. However, the exact pathophysiology of how skeletogenic cells contribute to endochondral ossification in FOP remains unknown. Here, we showed that the wild-type or FOP-mutant ACVR1 localized in the cilia of stem cells from human exfoliated deciduous teeth with key FOP signaling components, including activin A receptor type 2A/2B, SMAD family member 1/5, and FK506-binding protein 12kD. Cilia suppression by deletion of intraflagellar transport 88 or ADP ribosylation factor like GTPase 3 effectively inhibited pathological BMP and Hh signaling, subdued aberrant chondro-osteogenic differentiation in primary mouse or human FOP cells, and diminished in vivo extraskeletal ossification in Acvr1 Q207D , Sox2-Cre ; Acvr1 R206H/+ FOP mice and in burn tenotomy–treated wild-type mice. Our results provide a rationale for early and localized suppression of cilia in affected tissues after injury as a therapeutic strategy against either genetic or acquired HO.

中文翻译：

---

原发纤毛介导异位骨化中的成骨 BMP 和 Hedgehog 信号传导


异位骨化（HO）被定义为肌肉和软组织中骨骼外骨的形成，是由基因突变或诱发创伤引起的多种病理过程。进行性骨化性纤维发育不良 (FOP) 是一种由骨形态发生蛋白 (BMP) I 型受体基因突变引起的 HO 遗传形式激活素 A 受体 1 型（交流电压调节器1 ）。这些突变使 ACVR1 对 BMP 高度敏感并对激活素 A 敏感。Hedgehog (Hh) 信号传导也有助于 HO 的形成。然而，成骨细胞如何促进 FOP 软骨内骨化的确切病理生理学仍不清楚。在这里，我们发现野生型或 FOP 突变型 ACVR1 位于人脱落乳牙干细胞的纤毛中，具有关键的 FOP 信号成分，包括激活素 A 受体 2A/2B 型、SMAD 家族成员 1/5 和 FK506 -结合蛋白12kD。通过删除抑制纤毛鞭毛内运输 88或者ADP 核糖基化因子，如 GTPase 3有效抑制病理性 BMP 和 Hh 信号传导，抑制原代小鼠或人 FOP 细胞中的异常软骨成骨分化，并减少体内骨骼外骨化加速器1 Q207D , Sox2-Cre ;加速器1 R206H/+ FOP 小鼠和烧伤腱切断术治疗的野生型小鼠。我们的研究结果为损伤后受影响组织中的纤毛的早期和局部抑制提供了理论基础，作为针对遗传性或获得性 HO 的治疗策略。