Defective bone remodeling is the pathophysiologic basis of most metabolic bone diseases, including post-menopausal and age-dependent osteoporosis. During the tenure of this project, we have demonstrated hat osteoblasts are coupled through functional gap junctions, formed primarily by the gap junction protein, connexin43 (Cx43), and also by connexin45 (Cx45) [new gene designations: Gja1 and G/a7, respectively]. The finding that Gja1 mutations cause the human disease oculodentodigital dysplasia (ODDD), characterized primarily by skeletal abnormalities, further demonstrates that the skeleton represents one of :he main sites of action of Cx43. Indeed, we find that conditional G/a1 deletion in osteoblasts results in significant osteopenia and reduced bone formation rates, and that Cx43 is required for a full response to anabolic signals. The central hypothesis of this renewal application is that osteoblast connexins, Cx43 and Cx45, are essential modulators of skeletal growth and osteoblast function, and are involved in homeostatic responses to hormonal and physical stimuli in the post-natal skeleton. To test this hypothesis, we propose to determine;1: the relative contribution of Cx43 and Cx45 to postnatal skeletal growth and maintenance;2: the cellular and molecular mechanisms of connexin regulation of osteoblast differentiation and function: 3: the role of connexins in the homeostatic response to mechanical load in the postnatal skeleton. The proposed studies will take advantage of novel models of conditional Gja1 and G/a7 deletion, as well as of a new Gja1 ODDD mutant, building upon experimental methods and expertise we have accumulated during the tenure of this grant, and take the experimentation on gap junction biology in bone to a more translational level. This research will study two molecules that allow bone cells to directly communicate with each other thus influencing each others'function and ability to manufacture new bone. Results will allow us to better understand how the skeleton grows and becomes denser after birth, and how these molecules influence the skeletal response to disuse and mechanical load. The results will disclose new mechanisms by which bone is maintained in post-natal life, thus helping devise new therapeutic approaches to prevent bone loss and reduce fracture risk.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Chen, Faye H
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Stains, Joseph P; Civitelli, Roberto (2016) A Functional Assay to Assess Connexin 43-Mediated Cell-to-Cell Communication of Second Messengers in Cultured Bone Cells. Methods Mol Biol 1437:193-201
Stains, Joseph P; Civitelli, Roberto (2016) Connexins in the skeleton. Semin Cell Dev Biol 50:31-9
Shen, Hua; Grimston, Susan; Civitelli, Roberto et al. (2015) Deletion of connexin43 in osteoblasts/osteocytes leads to impaired muscle formation in mice. J Bone Miner Res 30:596-605
Chang, Kyung Hee; Sengupta, Amitava; Nayak, Ramesh C et al. (2014) p62 is required for stem cell/progenitor retention through inhibition of IKK/NF-?B/Ccl4 signaling at the bone marrow macrophage-osteoblast niche. Cell Rep 9:2084-97
Stains, Joseph P; Watkins, Marcus P; Grimston, Susan K et al. (2014) Molecular mechanisms of osteoblast/osteocyte regulation by connexin43. Calcif Tissue Int 94:55-67
Grimston, Susan K; Watkins, Marcus P; Stains, Joseph P et al. (2013) Connexin43 modulates post-natal cortical bone modeling and mechano-responsiveness. Bonekey Rep 2:446
Watkins, Marcus P; Norris, Jin Yi; Grimston, Susan K et al. (2012) Bisphosphonates improve trabecular bone mass and normalize cortical thickness in ovariectomized, osteoblast connexin43 deficient mice. Bone 51:787-94
Gonzalez-Nieto, Daniel; Li, Lina; Kohler, Anja et al. (2012) Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood 119:5144-54
Grimston, Susan K; Watkins, Marcus P; Brodt, Michael D et al. (2012) Enhanced periosteal and endocortical responses to axial tibial compression loading in conditional connexin43 deficient mice. PLoS One 7:e44222
Watkins, Marcus; Grimston, Susan K; Norris, Jin Yi et al. (2011) Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling. Mol Biol Cell 22:1240-51

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