Wang Jie, Sun Lin, Zhang Yi, Chen Shuo, He Yang
Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, P. R. China.
BMC Musculoskelet Disord. 2025 May 30;26(1):533. doi: 10.1186/s12891-025-08765-y.
Gli1 has been identified as a marker of osteogenic progenitors in the condylar subchondral bone. The Wnt/β-catenin signaling pathway is known to regulate stem cell proliferation and differentiation in bone. Whether Wnt/β-catenin signaling pathway could influence Gli1 + osteogenic progenitors remains unclear. Here, we aimed to investigate the role and related mechanisms of Wnt/β-catenin signaling in the regulation of Gli1 + osteogenic progenitors in condylar development and temporomandibular joint osteoarthritis (TMJOA).
We generated Gli1-Cre;tdTomato mice to perform lineage tracing; We generated Gli1-Cre; β-catenin mice, in which β-catenin was lost in the Gli1 + lineage to examine the role of Wnt/β-catenin signaling pathway in regulating the proliferation and differentiation of Gli1 + cells. The β-catenin CKO mice and their wild-type (WT) littermates were induced at 3 days and were euthanized 1, 2 or 4 weeks after induction; We induced a TMJOA model through a unilateral partial discectomy (UPD) of the temporomandibular joint disc in 6-week-old tamoxifen-treated Gli1-Cre;β-catenin;tdTomato mice and control group (Gli1-Cre;tdTomato mice). We harvested the mandibles at 4 weeks post-surgery.
Conditional knockout of β-catenin inhibited the osteogenic activity of Gli1 + progenitor cells during condylar subchondral bone development. In discectomy-induced TMJOA, the overactivation of Gli1 in subchondral bone drove pathological osteogenesis and aberrant subchondral bone remodeling. Deletion of β-catenin in Gli1 + cells mitigated excessive Gli1 + cells activation and ectopic mineralization.
Our findings establish Wnt/β-catenin signaling as a key regulator of Gli1 + progenitor cell fate determination in both bone development and TMJOA pathogenesis.
Gli1已被确定为髁突软骨下骨中成骨祖细胞的标志物。已知Wnt/β-连环蛋白信号通路可调节骨中干细胞的增殖和分化。Wnt/β-连环蛋白信号通路是否会影响Gli1+成骨祖细胞仍不清楚。在此，我们旨在研究Wnt/β-连环蛋白信号在髁突发育和颞下颌关节骨关节炎（TMJOA）中对Gli1+成骨祖细胞调控的作用及相关机制。
我们构建了Gli1-Cre;tdTomato小鼠用于谱系追踪；构建了Gli1-Cre;β-连环蛋白小鼠，其中β-连环蛋白在Gli1+谱系中缺失，以研究Wnt/β-连环蛋白信号通路在调节Gli1+细胞增殖和分化中的作用。β-连环蛋白条件性敲除（CKO）小鼠及其野生型（WT）同窝小鼠在3日龄时被诱导，并在诱导后1、2或4周处死；我们通过对6周龄经他莫昔芬处理的Gli1-Cre;β-连环蛋白;tdTomato小鼠和对照组（Gli1-Cre;tdTomato小鼠）的颞下颌关节盘进行单侧部分切除术（UPD）诱导TMJOA模型。我们在术后4周收获下颌骨。
β-连环蛋白的条件性敲除在髁突软骨下骨发育过程中抑制了Gli1+祖细胞的成骨活性。在椎间盘切除诱导的TMJOA中，软骨下骨中Gli1的过度激活驱动了病理性骨生成和异常的软骨下骨重塑。Gli1+细胞中β-连环蛋白的缺失减轻了Gli1+细胞的过度激活和异位矿化。
我们的研究结果表明，Wnt/β-连环蛋白信号在骨发育和TMJOA发病机制中都是Gli1+祖细胞命运决定的关键调节因子。
