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， 骨骼肌修复重定向至软骨内骨形成（异位骨化，HO）， 疼痛，肌肉破坏和关节融合，导致进行性固定，最终过早 死亡FOP是由Alk2（最常见的是R206 H）突变引起的，该突变使受体对 激活素A（Activin A，ActA）。然而，导致HO的“耀斑”似乎是由 在FOP小鼠中，HO可以通过消耗炎性先天免疫细胞来减少 包括巨噬细胞。纤维脂肪祖细胞（FAP），居住在肌肉软骨似乎是 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TNFα， FAPs凋亡的临界时间。FAP存活并分化为软骨细胞的事实 表明它们与巨噬细胞的相互作用在FOP中被破坏。因此，本提案将探讨 假设促炎性M1样和抗炎性M2样巨噬细胞是 能够使FOP中软骨形成纤维脂肪祖细胞存活和扩增的细胞因子。具体地说， 它试图确定巨噬细胞是否是ActA的关键来源以及FAPS中的信号通路 被破坏以阻止其正常的凋亡命运。这些研究将是第一个探索机制， 巨噬细胞与软骨形成FAP相互作用，以支持软骨形成和HO，它们将提供 对FOP耀斑早期阶段的重要见解。

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.