Abstract：
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 Acvr1Q207D, Sox2-Cre; Acvr1R206H/+ 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.
摘要：
异位骨化（HO），定义为肌肉和软组织中骨骼外骨的形成，是由基因突变或煽动创伤引起的多种病理过程。纤维化骨化性增生（FOP）是由骨形态发生蛋白（BMP）I型受体基因激活素A受体1型（ACVR1）突变引起的HO的遗传形式。这些突变使ACVR1对BMP过敏并对激活素A起反应。Hedgehog（Hh）信号传导也有助于HO发育。然而,在FOP中,成骨细胞如何促进软骨内骨化的确切病理生理学仍不清楚.这里,我们表明，野生型或FOP突变体ACVR1位于人类脱落乳牙干细胞的纤毛中，具有关键的FOP信号传导成分，包括激活素A受体2A/2B，SMAD家族成员1/5和FK506结合蛋白12kD。通过缺失绒毛内转运88或ADP核糖基化因子如GTP酶3抑制纤毛，有效抑制病理性BMP和Hh信号，在原代小鼠或人FOP细胞中抑制异常软骨成骨分化，Acvr1Q207D体内骨化减少，Sox2-Cre;Acvr1R206H/+FOP小鼠和烧伤肌腱切开术治疗的野生型小鼠。我们的结果为损伤后早期和局部抑制受影响组织中的纤毛提供了理论依据，作为针对遗传或获得性HO的治疗策略。
