Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J Bone Miner Res. 2018 Feb;33(2):269-282. doi: 10.1002/jbmr.3304. Epub 2018 Jan 3.
Heterotopic ossification (HO) is a clinical condition that often reduces mobility and diminishes quality of life for affected individuals. The most severe form of progressive HO occurs in those with fibrodysplasia ossificans progressiva (FOP; OMIM #135100), a genetic disorder caused by a recurrent heterozygous gain-of-function mutation (R206H) in the bone morphogenetic protein (BMP) type I receptor ACVR1/ALK2. In individuals with FOP, episodes of HO frequently follow injury. The first sign of active disease is commonly an inflammatory "flare-up" that precedes connective tissue degradation, progenitor cell recruitment, and endochondral HO. We used a conditional-on global knock-in mouse model expressing Acvr1 (referred to as Acvr1 ) to investigate the cellular and molecular inflammatory response in FOP lesions following injury. We found that the Acvr1 R206H mutation caused increased BMP signaling in posttraumatic FOP lesions and early divergence from the normal skeletal muscle repair program with elevated and prolonged immune cell infiltration. The proinflammatory cytokine response of TNFα, IL-1β, and IL-6 was elevated and prolonged in Acvr1 lesions and in Acvr1 mast cells. Importantly, depletion of mast cells and macrophages significantly impaired injury-induced HO in Acvr1 mice, reducing injury-induced HO volume by ∼50% with depletion of each cell population independently, and ∼75% with combined depletion of both cell populations. Together, our data show that the immune system contributes to the initiation and development of HO in FOP. Further, the expression of Acvr1 in immune cells alters cytokine expression and cellular response to injury and unveils novel therapeutic targets for treatment of FOP and nongenetic forms of HO. © 2017 American Society for Bone and Mineral Research.
异位骨化（HO）是一种临床病症，常导致受影响个体的活动能力降低和生活质量下降。在纤维发育不良性骨化症进展型（FOP；OMIM #135100）患者中，会出现最严重形式的进行性 HO，这是一种由骨形态发生蛋白（BMP）I 型受体 ACVR1/ALK2 中的重复杂合功能获得性突变（R206H）引起的遗传性疾病。在 FOP 患者中，HO 发作常继发于损伤。疾病活动的最初迹象通常是炎症“爆发”，随后是结缔组织降解、祖细胞募集和软骨内 HO。我们使用了一个条件性全局敲入小鼠模型来表达 Acvr1（称为 Acvr1 ），以研究损伤后 FOP 病变中的细胞和分子炎症反应。我们发现，Acvr1 R206H 突变导致创伤后 FOP 病变中的 BMP 信号增加，并与正常的骨骼肌修复程序早期分离，免疫细胞浸润增加且持续时间延长。Acvr1 病变和 Acvr1 肥大细胞中的促炎细胞因子 TNFα、IL-1β 和 IL-6 反应升高且持续时间延长。重要的是，肥大细胞和巨噬细胞耗竭可显著抑制 Acvr1 小鼠的损伤诱导性 HO，独立耗竭每种细胞群可使损伤诱导性 HO 体积减少约 50%，联合耗竭两种细胞群则可减少约 75%。总之，我们的数据表明免疫系统参与了 FOP 中 HO 的起始和发展。此外，免疫细胞中 Acvr1 的表达改变了细胞因子表达和对损伤的细胞反应，并为治疗 FOP 和非遗传性 HO 揭示了新的治疗靶点。2017 年美国骨骼与矿物质研究协会。
