Wang Shengnan, Zhang Shuai, Xu Huichong, Zhang Mingyue, Liu Xiu, Liu Sirui, Li Hongyu, Hu Ying
Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, No.9 Fanjiacun Road, Fengtai District, Beijing 100070, China.
Int J Mol Sci. 2025 May 30;26(11):5267. doi: 10.3390/ijms26115267.
Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant genetic disease, mainly characterized by enlargement of the mandible, osteosclerosis, and frequent fracture of tubular bone. GDD is caused by heterozygous mutations in (). We have previously generated an knockout (KO) mice model and validated the phenotypes consistent with GDD patients, including enhanced bone formation and alkaline phosphatase (ALP) activity. Experiments have identified that deficiency elevated the osteogenesis of calvaria-derived osteoblasts (mCOBs). In this study, we found that deficiency notably inhibited miR-34c-5p expression. Krüppel-Like Factor 4 (), a target gene of miR-34c-5p confirmed by dual luciferase reporter assay, was up-regulated in mCOBs, accompanied by activated downstream canonical Wnt/β-catenin signaling and increased expression of β-catenin. Overexpression of miR-34c-5p in mCOBs inhibited osteogenic capacity by suppressing proliferative capacity, osteoblast-related factor levels, ALP activity, and matrix calcification through regulating KLF4/β-catenin signaling axis. Furthermore, miR-34c-5p adeno-associated virus (AAV) treatment in vivo rescued the abnormally thickened cortical bone and enhanced biomechanical properties in mice. Importantly, the serum level of P1NP, a marker of bone formation, was also significantly declined. We conclude that dysregulation of miR-34c-5p contributes to the enhanced osteogenesis in GDD by excessive activation of KLF4/β-catenin signaling axis under Ano5-deficient conditions. This study elucidates the pathogenesis of GDD and provides novel insights into the therapeutic strategies.
颌骨干骺端发育异常（GDD）是一种罕见的常染色体显性遗传病，主要特征为下颌骨增大、骨硬化以及管状骨频繁骨折。GDD由（）中的杂合突变引起。我们之前构建了一种敲除（KO）小鼠模型，并验证了与GDD患者一致的表型，包括增强的骨形成和碱性磷酸酶（ALP）活性。实验已确定，缺乏（）会提高颅骨来源的成骨细胞（mCOB）的成骨能力。在本研究中，我们发现缺乏（）会显著抑制miR - 34c - 5p的表达。经双荧光素酶报告基因检测证实，miR - 34c - 5p的靶基因Krüppel样因子4（KLF4）在（）mCOB中上调，同时伴有下游经典Wnt/β - 连环蛋白信号通路的激活以及β - 连环蛋白表达增加。在（）mCOB中过表达miR - 34c - 5p通过调节KLF4/β - 连环蛋白信号轴，抑制增殖能力、成骨细胞相关因子水平、ALP活性和基质钙化，从而抑制成骨能力。此外，体内给予miR - 34c - 5p腺相关病毒（AAV）治疗可挽救（）小鼠异常增厚的皮质骨并增强生物力学性能。重要的是，骨形成标志物P1NP的血清水平也显著下降。我们得出结论，在缺乏Ano5的条件下，miR - 34c - 5p失调通过过度激活KLF4/β - 连环蛋白信号轴导致GDD中成骨增强。本研究阐明了GDD的发病机制，并为治疗策略提供了新的见解。
