脊柱异位成骨是强直性脊柱炎（AS）致残的重要原因，目前无有效治疗方法。机械应力刺激是异位新骨形成的关键因素，但机制尚不清楚。机械应力敏感离子通道Piezo1在多种炎症性疾病中起重要作用。我们预实验发现，Piezo1在AS韧带标本中高表达；炎症因子可以上调成骨细胞Piezo1的表达；抑制Piezo1可以抑制应力刺激下的成骨分化，且需要Rap1-PI3K/AKT的参与；动物模型中，抑制Piezo1可以显著减轻异位新骨新成。由此我们提出科学假设：在附着点区域，炎症因子通过上调Piezo1表达与其介导的Rap1-PI3K/AKT信号活性，增强成骨前体细胞对应力刺激的应答，促进异位新骨形成。本课题拟在细胞模型中探讨炎症因子上调Piezo1及其促进成骨分化的分子机制，并在动物模型中验证Piezo1在异位新骨形成过程中的作用。本研究有望揭示AS异位成骨的新机制，为其防治提供新的靶点。

Axial skeleton ankylosis resulted from ectopic bone formation is a major cause of disability in patients with Ankylosing Spondylitis (AS). No targeted and effective therapy is available to prevent ankylosis progression in clinical practice so far. Previous studies have shown that mechanical force plays a critical role in ectopic new bone formation at the entheses. However, the detailed mechanism is not clear. Piezo1 is a newly identified mechanically activated ion channel with significant function in inflammatory diseases, but its effects on ectopic bone formation are not clarified. In our preliminary study, we discovered that Piezo1 was highly expressed in the bone forming sites of ligament tissues collected from AS patients. In a cell culture system, piezo1 was up-regulated by inflammatory cytokines in osteoprogenitor cells. Inhibition of piezo1 suppressed osteogenesis under mechanical stimulation in vitro and in vivo, which possibly through Rap1-PI3K/AKT pathway. Hence, we hypothesize that during ectopic new bone formation, inflammatory cytokines enhance the response of osteoprogenitor cells to mechanical force by up-regulation of Piezo1, therefore enhance bone formation via Rap1-PI3K/AKT signaling pathway. To prove this hypothesis, we propose the current study, including in vitro study for investigating the molecular mechanism of Piezo1- Rap1-PI3K/AKT axis enhancing new bone formation, as well in vivo study for validating its role in ankylosis. The potential findings would provide more insight of AS and help with identification of novel treatment strategies.