Fujii Yasuyuki, Okabe Iichiro, Hatori Ayano, Sah Shyam Kishor, Kanaujiya Jitendra, Fisher Melanie, Norris Rachael, Terasaki Mark, Reichenberger Ernst J, Chen I-Ping
Department of Endodontology, School of Dental Medicine, University of Connecticut Health, Farmington, CT, USA.
Department of Cell Biology, University of Connecticut Health, Farmington, CT, USA.
Bone Res. 2025 Jan 23;13(1):14. doi: 10.1038/s41413-024-00383-z.
Craniometaphyseal dysplasia (CMD), a rare craniotubular disorder, occurs in an autosomal dominant (AD) or autosomal recessive (AR) form. CMD is characterized by hyperostosis of craniofacial bones and metaphyseal flaring of long bones. Many patients with CMD suffer from neurological symptoms. The pathogenesis of CMD is not fully understood. Treatment is limited to craniofacial surgery. Here, we report a knock in (KI) mouse model for AR CMD carrying a Cx43 mutation. Cx43 mice replicate typical features of AR CMD, including thickening of craniofacial bones, club-shaped femurs, and widened diaphyseal cortical bones. Female Cx43 mice display remarkably more bone overgrowth than male Cx43 mice as they age. In contrast to Cx43 littermates, Cx43 mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones. Although formation of resting OCs in Cx43 and Cx43 mice is comparable, the actively resorbing Cx43 OCs have reduced resorption on bone chips. Cx43 mice display reduced osteocyte dendrites. RNA from Cx43 femoral cortical bones show reduced expression levels of Sost, Tnf-α, IL-1β, Esr1, Esr2, and a lower Rankl/Opg ratio. Moreover, the Cx43 mutation results in altered spatial expression of Cx43 protein and mild reduction of gap junction and hemichannel activity. The distinct phenotype seen in Cx43 mice but not in Cx43 ablation models suggests that Cx43 loss-of-function is unlikely the main cause of AR CMD. Additional studies are required to investigate new roles of CMD-mutant Cx43.
颅骨骨干发育异常（CMD）是一种罕见的颅管状疾病，以常染色体显性（AD）或常染色体隐性（AR）形式出现。CMD的特征是颅面骨骨质增生和长骨干骺端增宽。许多CMD患者伴有神经症状。CMD的发病机制尚未完全明确。治疗方法仅限于颅面外科手术。在此，我们报告了一种携带Cx43突变的AR CMD基因敲入（KI）小鼠模型。Cx43小鼠复制了AR CMD的典型特征，包括颅面骨增厚、杵状股骨和骨干皮质骨增宽。随着年龄增长，雌性Cx43小鼠的骨过度生长比雄性Cx43小鼠明显更多。与Cx43同窝小鼠相比，Cx43小鼠在长骨内膜出现骨膜骨沉积且破骨细胞（OC）数量增加。尽管Cx43和Cx43小鼠中静止OC的形成相当，但活跃吸收的Cx43 OC对骨片的吸收减少。Cx43小鼠的骨细胞树突减少。来自Cx43股骨干皮质骨的RNA显示Sost、Tnf-α、IL-1β、Esr1、Esr2的表达水平降低，且Rankl/Opg比值较低。此外，Cx43突变导致Cx43蛋白的空间表达改变以及缝隙连接和半通道活性轻度降低。在Cx43小鼠而非Cx43基因敲除模型中观察到的独特表型表明，Cx43功能丧失不太可能是AR CMD的主要原因。需要进一步研究来探究CMD突变型Cx43的新作用。
