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We previously isolated a low bone mass mouse, Gja1(Jrt) / + , with a mutation in the gap junction protein, alpha 1 gene (Gja1), encoding for a dominant negative G60S Connexin 43 (Cx43) mutant protein. Similar to other Cx43 mutant mouse models described, including a global Cx43 deletion, four skeletal cell conditional-deletion mutants, and a Cx43 missense mutant (G138R/ +), a reduction in Cx43 gap junction formation and/or function resulted in mice with early onset osteopenia. In contrast to other Cx43 mutants, however, we found that Gja1(Jrt) /+ mice have both higher bone marrow stromal osteoprogenitor numbers and increased appendicular skeleton osteoblast activity, leading to cell autonomous upregulation of both matrix bone sialoprotein (BSP) and membrane-bound receptor activator of nuclear factor-κB ligand (mbRANKL). In younger Gja1(Jrt) /+ mice, these contributed to increased osteoclast number and activity resulting in early onset osteopenia. In older animals, however, this effect was abrogated by increased osteoprotegerin (OPG) levels and serum alkaline phosphatase (ALP) so that differences in mutant and wild-type (WT) bone parameters and mechanical properties lessened or disappeared with age. Our study is the first to describe a Cx43 mutation in which osteopenia is caused by increased rather than decreased osteoblast function and where activation of osteoclasts occurs not only through increased mbRANKL but an increase in a matrix protein that affects bone resorption, which together abrogate age-related bone loss in older animals.
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http://dx.doi.org/10.1002/jbmr.1965 | DOI Listing |
Dev Dyn
July 2023
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
Background: We previously determined a nonlinear relationship between connexin 43 (Cx43) function and craniofacial phenotypic variation in the mutant mouse model G60S/+, and that this variation was driven by nasal bone deviation. While nonlinearities in the genotype-phenotype map appear to be common, few studies have looked at the developmental processes that underlie this nonlinearity. Here, we investigated the potential tissue-level developmental determinants of the variation in nasal bone phenotype in G60S/+ mice through postnatal development.
View Article and Find Full Text PDFDev Dyn
December 2021
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
Background: We compared skull shape and variation among genetically modified mice that exhibit different levels of connexin43 (Cx43) channel function, to determine whether Cx43 contributes to craniofacial phenotypic robustness. Specifically, we used two heterozygous mutant mouse models (G60S/+ and I130T/+) that, when compared to their wildtype counterparts, have an ~80% and ~50% reduction in Cx43 function, respectively.
Results: Both mutant strains showed significant differences in skull shape compared to wildtype littermates and while these differences were more severe in the G60S/+ mouse, shape differences were localized to similar regions of the skull in both mutants.
Calcif Tissue Int
December 2020
Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.
Mutations in the gene encoding the gap-junctional protein connexin43 (Cx43) are the cause of the human disease oculodentodigital dysplasia (ODDD). The mandible is often affected in this disease, with clinical reports describing both mandibular overgrowth and conversely, retrognathia. These seemingly opposing observations underscore our relative lack of understanding of how ODDD affects mandibular morphology.
View Article and Find Full Text PDFCell Death Dis
May 2020
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada.
Cisplatin is a very effective chemotherapeutic, but severe and permanent hearing loss remains a prevalent side effect. The processes underpinning cisplatin-induced ototoxicity are not well understood. Gap junction channels composed of connexin (Cx) subunits allow for the passage of small molecules and ions between contacting neighboring cells.
View Article and Find Full Text PDFJ Cell Sci
May 2018
University of Western Ontario, Department of Anatomy and Cell Biology, London, Ontario, Canada, N6A 5C1
Given the importance of connexin43 (Cx43, encoded by ) function in the central nervous system and sensory organ processing, we proposed that it would also be crucial in auditory function. To that end, hearing was examined in two mouse models of oculodentodigital dysplasia that globally express mutations resulting in mild or severe loss of Cx43 function. Although Cx43 mutant mice, with ∼50% Cx43 channel function, did not have any hearing loss, Cx43 mutant mice, with ∼20% Cx43 channel function, had severe hearing loss.
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