Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Road, Hefei 230022, Anhui, China; Anhui Province Key Laboratory of Zoonoses, Anhui Medical University, Anhui, China.
Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Road, Hefei 230022, Anhui, China.
Cell Signal. 2024 Dec;124:111463. doi: 10.1016/j.cellsig.2024.111463. Epub 2024 Oct 11.
Subchondral bone sclerosis is a key characteristic of osteoarthritis (OA). Prior research has shown that Forkhead box C1 (FoxC1) plays a role in the synovial inflammation of OA, but its specific role in the subchondral bone of OA has not been explored. Our research revealed elevated expression levels of FoxC1 and Piezo1 in OA subchondral bone tissues. Further experiments on OA subchondral bone osteoblasts with FoxC1 or Piezo1 overexpression showed increased cell proliferation activity, expression of Yes-associated Protein 1 (YAP) and osteogenic markers, and secretion of proinflammatory factors. Mechanistically, the overexpression of FoxC1 through Piezo1 activation, in combination with downstream YAP signaling, led to increased levels of alkaline phosphatase (ALP), collagen type 1 (COL1) A1, RUNX2, Osteocalcin, matrix metalloproteinase (MMP) 3, and MMP9 expression. Notably, inhibition of Piezo1 reversed the regulatory function of FoxC1. The binding of FoxC1 to the targeted area (ATATTTATTTA, residues +612 to +622) and the activation of Piezo1 transcription were verified by the dual luciferase assays. Additionally, Reduced subchondral osteosclerosis and microangiogenesis were observed in knee joints from FoxC1-conditional knockout (CKO) and Piezo1-CKO mice, indicating reduced lesions. Collectively, our study reveals the significant involvement of FoxC1 in the pathologic process of OA subchondral bone via the Piezo1/YAP signaling pathway, potentially establishing a novel therapeutic target.
软骨下骨硬化是骨关节炎（OA）的一个关键特征。先前的研究表明，叉头框 C1（FoxC1）在 OA 的滑膜炎症中发挥作用，但它在 OA 软骨下骨中的具体作用尚未得到探索。我们的研究揭示了 FoxC1 和 Piezo1 在 OA 软骨下骨组织中的表达水平升高。对 OA 软骨下骨成骨细胞中 FoxC1 或 Piezo1 的过表达进行的进一步实验表明，细胞增殖活性增加，Yes 相关蛋白 1（YAP）和成骨标志物的表达以及促炎因子的分泌增加。在机制上，通过 Piezo1 激活过表达 FoxC1，与下游 YAP 信号通路结合，导致碱性磷酸酶（ALP）、胶原类型 1（COL1）A1、RUNX2、骨钙素、基质金属蛋白酶（MMP）3 和 MMP9 的表达水平增加。值得注意的是，Piezo1 的抑制作用逆转了 FoxC1 的调节功能。通过双荧光素酶测定验证了 FoxC1 与靶区（+612 到+622 位的 ATATTTATTTA 残基）的结合以及 Piezo1 转录的激活。此外，FoxC1 条件性敲除（CKO）和 Piezo1-CKO 小鼠膝关节中的软骨下骨硬化和微血管生成减少，表明病变减少。总之，我们的研究表明，FoxC1 通过 Piezo1/YAP 信号通路显著参与 OA 软骨下骨的病理过程，可能为该疾病提供新的治疗靶点。
