Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Stem Cell Institute, Boston, MA 02115, USA.
Biomolecules. 2024 Mar 14;14(3):347. doi: 10.3390/biom14030347.
Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by abnormal bone formation due to ACVR1 gene mutations. The identification of the molecular mechanisms underlying the ectopic bone formation and expansion in FOP is critical for the effective treatment or prevention of HO. Here we find that Hh signaling activation is required for the aberrant ectopic bone formation in FOP. We show that the expression of (), a Hh ligand, as well as downstream Hh signaling, was increased in ectopic bone lesions in ; mice. Pharmacological treatment with an Ihh-neutralizing monoclonal antibody dramatically reduced chondrogenesis and ectopic bone formation. Moreover, we find that the activation of Yap in the FOP mouse model and the genetic deletion of halted ectopic bone formation and decreased expression. Our mechanistic studies showed that Yap and Smad1 directly bind to the Ihh promoter and coordinate to induce chondrogenesis by promoting expression. Therefore, the Yap activation in FOP lesions promoted ectopic bone formation and expansion in both cell-autonomous and non-cell-autonomous manners. These results uncovered the crucial role of the Yap-Ihh axis in FOP pathogenesis, suggesting the inhibition of Ihh or Yap as a potential therapeutic strategy to prevent and reduce HO.
进行性骨化性纤维发育不良（FOP）是一种罕见的先天性疾病，其特征是由于 ACVR1 基因突变导致异常骨形成。明确 FOP 中异位骨形成和扩张的分子机制对于 HO 的有效治疗或预防至关重要。在这里，我们发现 Hh 信号激活对于 FOP 中的异常异位骨形成是必需的。我们表明，Hh 配体 ()的表达以及下游 Hh 信号在 ; 小鼠的异位骨病变中增加。用 Ihh 中和单克隆抗体进行药物治疗可显著减少软骨生成和异位骨形成。此外，我们发现 FOP 小鼠模型中 Yap 的激活和 的遗传缺失阻止了异位骨形成并降低了 表达。我们的机制研究表明， Yap 和 Smad1 直接结合到 Ihh 启动子上，并通过促进 表达来协调诱导软骨生成。因此，FOP 病变中的 Yap 激活以细胞自主和非细胞自主的方式促进异位骨形成和扩张。这些结果揭示了 yap-Ihh 轴在 FOP 发病机制中的关键作用，表明抑制 Ihh 或 yap 可能是预防和减少 HO 的潜在治疗策略。
