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Connexin43 modulates post-natal cortical bone modeling and mechano-responsiveness.

ABSTRACT: Recent advances have established connexin43 (Cx43) as a key regulator of osteoblast function and of bone response to mechanical stimuli. Work by independent laboratories has consistently demonstrated postnatal development of larger than normal cross-section of long bones after conditional ablation of the Cx43 gene, Gja1, selectively in osteoblasts and/or osteocytes. This phenotype is caused by excessive endocortical bone resorption associated with periosteal expansion and cortical thinning. Review of published data suggests that the earlier in the osteogenic lineage is Gja1 deleted, the more severe is the cortical phenotype, implying functional roles of Cx43 at different stages of the osteoblast differentiation program. Such cortical modeling abnormalities resemble the changes occurring in the cortex upon disuse or aging. Indeed, Cx43 deficiency desensitizes endocortical osteoclasts from activation induced by removal of mechanical load, thus preventing medullary area expansion. The action of Cx43 on cancellous bone is controversial. Furthermore, the absence of Cx43 in osteoblasts and osteocytes results in activation of periosteal bone formation at lower strains than in wild-type bones, suggesting that Cx43 deficiency increased cortical sensitivity to mechanical load. Thus, Cx43 modulates cortical bone modeling in homeostatic conditions and in response to mechanical load by restraining both endocortical bone resorption and periosteal bone formation. Cx43 may represent a novel pharmacologic target for improving cortical bone strength through modulation of mechano-responsiveness.

SUBMITTER: Grimston SK

PROVIDER: S-EPMC3844976 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other

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Project description:The coupling of osteoblasts and osteocytes by connexin43 (Cx43) gap junctions permits the sharing of second messengers that coordinate bone cell function and cortical bone acquisition. However, details of how Cx43 converts shared second messengers into signals that converge onto essential osteogenic processes are incomplete. Here, we use in vitro and in vivo methods to show that Cx43 and Runx2 functionally interact to regulate osteoblast gene expression and proliferation, ultimately affecting cortical bone properties. Using compound hemizygous mice for the Gja1 (Cx43) and Runx2 genes, we observed a skeletal phenotype not visible in wild-type or singly hemizygous animals. Cortical bone analysis by micro-computed tomography (μCT) revealed that 8-week-old male, compound Gja1+/- Runx2+/- mice have a marked increase in cross-sectional area, endosteal and periosteal bone perimeter, and an increase in porosity compared to controls. These compound Gja1+/- Runx2+/- mice closely approximate the cortical bone phenotypes seen in osteoblast-specific Gja1-conditional knockout models. Furthermore, μCT analysis of skulls revealed an altered interparietal bone geometry in compound hemizygotes. Consistent with this finding, Alizarin red/Alcian blue staining of 2-day-old Gja1+/- Runx2+/- neonates showed a hypomorphic interparietal bone, an exacerbation of the open fontanelles, and a further reduction in the hypoplastic clavicles compared to Runx2+/- neonates. Expression of osteoblast genes, including osteocalcin, osterix, periostin, and Hsp47, was markedly reduced in tibial RNA extracts from compound hemizygous mice, and osteoblasts from compound hemizygous mice exhibited increased proliferative capacity. Further, the reduced osteocalcin expression and hyperproliferative nature of osteoblasts from Cx43 deficient mice was rescued by Runx2 expression. In summary, these findings provide evidence that Cx43 and Runx2 functionally intersect in vivo to regulate cortical bone properties and affect osteoblast differentiation and proliferation, and likely contributes to aspects of the skeletal phenotype of Cx43 conditional knockout mice. © 2017 American Society for Bone and Mineral Research.

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Connexin43 modulates post-natal cortical bone modeling and mechano-responsiveness.

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