Skeletal abnormalities caused by a Connexin43_R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia.

Abstract

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_R239Q mutation. Cx43^KI/KI mice replicate typical features of AR CMD, including thickening of craniofacial bones, club-shaped femurs, and widened diaphyseal cortical bones. Female Cx43^KI/KI mice display remarkably more bone overgrowth than male Cx43^KI/KI mice as they age. In contrast to Cx43^+/+ littermates, Cx43^KI/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 Cx43^KI/KI mice is comparable, the actively resorbing Cx43^KI/KI OCs have reduced resorption on bone chips. Cx43^KI/KI mice display reduced osteocyte dendrites. RNA from Cx43^KI/KI femoral cortical bones show reduced expression levels of Sost, Tnf-α, IL-1β, Esr1, Esr2, and a lower Rankl/Opg ratio. Moreover, the Cx43_R239Q mutation results in altered spatial expression of Cx43 protein and mild reduction of gap junction and hemichannel activity. The distinct phenotype seen in Cx43^KI/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.