The contribution of innate immunity to heterotopic ossification in fibrodysplasia ossificans progressiva

进行性骨化性纤维发育不良(FOP)是一种罕见的、目前无法治疗的先天性疾病。 骨骼肌修复被重定向到软骨内骨形成(异位骨化，HO)导致 疼痛、肌肉破坏和关节融合，导致渐进性制动，最终导致过早 死亡。FOP是由Alk2(最常见的是R206H)的突变引起的，该突变使受体对 激活素A(Activin A，ActA)的异常激活。然而，导致HO的“耀斑”似乎是由 损毁炎性固有免疫细胞可减少FOP小鼠的炎性损伤和HO 包括巨噬细胞。位于肌肉间质中的纤维脂肪前体细胞(FAP)似乎是 FOP中软骨细胞的关键前体。然而，在健康的肌肉修复中，巨噬细胞分泌肿瘤坏死因子α 触发FAP细胞凋亡的关键时刻。FAP存活并分化为软骨细胞的事实 提示它们与巨噬细胞的相互作用在FOP中被破坏。因此，这项提案将探索 假设促炎的M1样和抗炎的M2样的巨噬细胞是 支持软骨成纤维脂肪前体细胞在FOP中存活和扩增的细胞因子。具体来说， 它试图确定巨噬细胞是否是ActA的关键来源，以及FAPS中的哪些信号通路 被破坏以阻止它们正常的凋亡命运。这些研究将通过以下方式第一次探索这种机制 哪些巨噬细胞与软骨源性FAP相互作用以支持软骨形成和HO，它们将提供 对FOP耀斑早期阶段的批判性见解。

Fibrodysplasia ossificans progressiva (FOP) is a rare, currently untreatable, congenital disease in which skeletal muscle repair is redirected to endochondral bone formation (heterotopic ossification, HO) causing pain, muscle destruction, and joint fusion, leading to progressive immobilization and eventually premature death. FOP is caused by a mutation in Alk2 (most commonly R206H) that renders the receptor sensitive to aberrant activation by Activin A (ActA). However, the “flares” that lead to HO appear to be initiated by inflammatory insults, and HO can be reduced in FOP mice by depletion of inflammatory innate immune cells including macrophages. Fibroadipoprogenitors (FAPs), residing in the muscle interstitium appear to be the critical precursors of chondrocytes in FOP. However, in healthy muscle repair, macrophages secrete TNFα at a critical time to trigger apoptosis of FAPs. The fact that FAPs survive and differentiate into chondrocytes suggests their interaction with macrophages is disrupted in FOP. Therefore, this proposal will explore the hypothesis that pro-inflammatory M1-like and anti-inflammatory M2-like macrophages are critical sources of cytokines that enable survival and expansion of the chondrogenic fibroadipoprogenitors in FOP. Specifically, it seeks to determine whether macrophages are a critical source of ActA and what signals pathways in FAPS are disrupted to block their normal apoptotic fate. These studies will be the first to explore the mechanisms by which macrophages interact with chondrogenic FAPs to support chondrogenesis and HO, and they will provide critical insights to the early stages of FOP flares.