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<p>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<sub>R239Q</sub> mutation. <i>Cx43</i><sup><i>KI/KI</i></sup> mice replicate typical features of AR CMD, including thickening of craniofacial bones, club-shaped femurs, and widened diaphyseal cortical bones. Female <i>Cx43</i><sup><i>KI/KI</i></sup> mice display remarkably more bone overgrowth than male <i>Cx43</i><sup><i>KI/KI</i></sup> mice as they age. In contrast to <i>Cx43</i><sup><i>+/+</i></sup> littermates, <i>Cx43</i><sup><i>KI/KI</i></sup> mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones. Although formation of resting OCs in <i>Cx43</i><sup><i>+/+</i></sup> and <i>Cx43</i><sup><i>KI/KI</i></sup> mice is comparable, the actively resorbing <i>Cx43</i><sup><i>KI/KI</i></sup> OCs have reduced resorption on bone chips. <i>Cx43</i><sup><i>KI/KI</i></sup> mice display reduced osteocyte dendrites. RNA from <i>Cx43</i><sup><i>KI/KI</i></sup> femoral cortical bones show reduced expression levels of <i>Sost</i>, <i>Tnf-α</i>, <i>IL-1β</i>, <i>Esr1, Esr2</i>, and a lower <i>Rankl/Opg</i> ratio. Moreover, the Cx43<sub>R239Q</sub> mutation results in altered spatial expression of Cx43 protein and mild reduction of gap junction and hemichannel activity. The distinct phenotype seen in <i>Cx43</i><sup><i>KI/KI</i></sup> 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.</p>

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Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia

  • 期刊论文

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  • 发表日期：

    2025年1月23日

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  • Yasuyuki Fujii,
  • Iichiro Okabe,
  • Ayano Hatori,
  • Shyam Kishor Sah,
  • Jitendra Kanaujiya,
  • Melanie Fisher,
  • Rachael Norris,
  • Mark Terasaki,
  • Ernst J. Reichenberger,
  • I-Ping Chen

摘要

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 Cx43R239Q mutation. Cx43KI/KI mice replicate typical features of AR CMD, including thickening of craniofacial bones, club-shaped femurs, and widened diaphyseal cortical bones. Female Cx43KI/KI mice display remarkably more bone overgrowth than male Cx43KI/KI mice as they age. In contrast to Cx43+/+ littermates, Cx43KI/KI mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones. Although formation of resting OCs in Cx43+/+ and Cx43KI/KI mice is comparable, the actively resorbing Cx43KI/KI OCs have reduced resorption on bone chips. Cx43KI/KI mice display reduced osteocyte dendrites. RNA from Cx43KI/KI femoral cortical bones show reduced expression levels of Sost, Tnf-α, IL-1β, Esr1, Esr2, and a lower Rankl/Opg ratio. Moreover, the Cx43R239Q mutation results in altered spatial expression of Cx43 protein and mild reduction of gap junction and hemichannel activity. The distinct phenotype seen in Cx43KI/KI 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.