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

先天免疫对进行性骨化性纤维发育不良异位骨化的贡献

• 批准号: 10150273
• 负责人: Daniel S Perrien
• 金额: $ 40.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10150273
• 关键词: contribution; innate; immunity; heterotopic; ossification

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.

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，其中 骨骼肌修复转向软骨内骨形成（异位骨化，HO）。这些 病理引起疼痛、肌肉破坏和关节融合，导致逐渐固定和 最终过早死亡。 FOP 是由 Alk2（最常见的是 R206H）突变引起的，该突变导致 对激活素 A (ActA) 异常激活敏感的受体。然而，导致 HO 的“耀斑”似乎是 由炎症损伤引发，并且 FOP 小鼠中的 H2O 可以通过先天炎症的消耗而减少 免疫细胞包括巨噬细胞。存在于肌肉间质中的纤维脂肪祖细胞 (FAP) 出现 是 FOP 中软骨细胞的关键前体细胞。在健康的肌肉修复中，巨噬细胞分泌 TNFα 在修复过程中的精确关键时刻触发 FAP 凋亡。然而，在受伤的FOP中 在肌肉中，FAP 存活并分化为软骨细胞，这表明它们与巨噬细胞的相互作用是 扰乱了。因此，本提案将探讨促炎和抗炎的假设 巨噬细胞是细胞因子的重要来源，使软骨细胞能够存活和扩张 FOP 中的纤维脂肪祖细胞。具体来说，它旨在确定 ActA 的关键来源以及什么 FAPS 中的信号通路被破坏，从而阻止其正常的凋亡命运。这些研究将首先 探索巨噬细胞与软骨形成 FAP 相互作用以支持软骨形成的机制 和 HO，它们将为 FOP 耀斑的早期阶段提供重要见解。