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)。这些 病理导致疼痛、肌肉破坏和关节融合，导致渐进性制动和 最终过早死亡。FOP是由Alk2(最常见的是R206H)的突变引起的 对激活素A(Activin A，Acta)异常激活敏感的受体。然而，导致HO的“耀斑”似乎是 由炎性损伤启动，通过耗尽炎性固有物质可减少FOP小鼠的HO 免疫细胞，包括巨噬细胞。存在于肌肉间质的纤维脂肪前体细胞(FAP)出现 是FOP中软骨细胞的关键前体。在健康的肌肉修复中，巨噬细胞分泌肿瘤坏死因子α以 在修复过程中的精确和关键时间触发FAP的凋亡。然而，在受伤的FOP中 肌肉，FAP存活并分化为软骨细胞，表明它们与巨噬细胞的相互作用 打乱了。因此，这一提议将探索促炎和抗炎的假设 巨噬细胞是细胞因子的重要来源，使软骨细胞得以存活和扩张 FOP中的纤维脂肪前体细胞。具体地说，它试图确定ACTA的临界来源(S)以及 FAPS中的信号通路被扰乱，以阻止其正常的凋亡命运。这些研究将是第一次 探讨巨噬细胞与软骨源性FAPs相互作用支持软骨形成的机制 和Ho，他们将为FOP耀斑的早期阶段提供关键的见解。

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). These pathologies cause 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. In healthy muscle repair, macrophages secrete TNFα to trigger apoptosis of FAPs at a precise and critical time in the repair process. However, in injured FOP muscles, FAPs survive and differentiate into chondrocytes, suggesting their interaction with macrophages is disrupted. Therefore, this proposal will explore the hypothesis that pro-inflammatory and anti-inflammatory macrophages are critical sources of cytokines that enable survival and expansion of the chondrogenic fibroadipoprogenitors in FOP. Specifically, it seeks to determine the critical source(s) 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.