Diseases of low bone mass, like age-dependent osteoporosis, have a profound impact on society. Current therapies for the restoration or maintenance of bone mass are limited and focus primarily on the attenuation of osteoclast activity. The gap junction protein connexin 43, which permits the direct cell-to-cell communication of signals between osteoblasts and osteocytes, has been shown to play an important role in osteoblast/osteocyte function and the acquisition of peak bone mass. Despite the clear importance of connexin 43 in skeletal function, key molecular details of how connexin 43 regulates bone mass acquisition, osteoblast differentiation and osteoblast/osteocyte function are unknown. Rational therapies to impact skeletal diseases, like osteoporosis, cannot be designed without understanding the underlying molecular mechanisms affecting bone mass acquisition. Indeed, any intervention intended to impact the entire bone forming unit to reverse or slow down skeletal diseases will require an understanding of the intricate methods of intercellular exchange of information, such as those afforded by connexin 43, among osteoblasts and osteocytes for optimal efficacy. In this grant application, we hypothesize that connexin 43 regulates osteogenic differentiation and function, and ultimately bone quality, by regulating the recruitment and activation of signal transduction cascades that converge upon the master regulators of osteoblastogenesis, Runx2 and Osterix. This grant has two specific aims to address this hypothesis. (Specific Aim 1) To determine the contribution of Cx43 and Cx43-dependent signaling to osteogenic differentiation at the level of Runx2 and/or Osterix; (Specific Aim 2) To determine the requirements for both signal complex recruitment to connexin 43 and second messenger permeability by connexin 43 for downstream modulation of osteogenic differentiation and signaling. We will use cell and molecular biology, as well as in vivo genetic models to resolve key knowledge gaps, regarding how connexin 43 regulates bone. By defining these mechanisms, we will gain critical understanding of how connexin 43 ultimately affects osteoblast function and bone mass acquisition. Indeed our long-term goal is to apply the knowledge gleaned from these studies to modulate connexin 43 expression or connexin 43-dependent signaling cascades, either physiologically or pharmacologically, to increase bone mass acquisition to prevent or treat diseases of skeletal fragility. Indeed, understanding the coordination of osteoblast, osteocyte and osteoclasts networks is vital to the understanding nearly all diseases of skeletal metabolism.
The proposed research will illuminate critical details of how bone is formed and how the skeleton responds to the demands placed upon it. This knowledge will assist in the development of strategies and interventions to combat devastating skeletal diseases, such as age-dependent and post-menopausal osteoporosis, as well as genetic disorders like oculodentodigital dysplasia.
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|Buo, Atum M; Tomlinson, Ryan E; Eidelman, Eric R et al. (2017) Connexin43 and Runx2 Interact to Affect Cortical Bone Geometry, Skeletal Development, and Osteoblast and Osteoclast Function. J Bone Miner Res 32:1727-1738|
|Lyons, James S; Joca, Humberto C; Law, Robert A et al. (2017) Microtubules tune mechanotransduction through NOX2 and TRPV4 to decrease sclerostin abundance in osteocytes. Sci Signal 10:|
|Moorer, Megan C; Hebert, Carla; Tomlinson, Ryan E et al. (2017) Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation. J Cell Sci 130:531-540|
|Lyons, James S; Iyer, Shama R; Lovering, Richard M et al. (2016) Novel multi-functional fluid flow device for studying cellular mechanotransduction. J Biomech 49:4173-4179|
|Buo, Atum M; Williams, Mark S; Kerr, Jaclyn P et al. (2016) A cost-effective method to enhance adenoviral transduction of primary murine osteoblasts and bone marrow stromal cells. Bone Res 4:16021|
|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|
|Gupta, Aditi; Anderson, Hidayah; Buo, Atum M et al. (2016) Communication of cAMP by connexin43 gap junctions regulates osteoblast signaling and gene expression. Cell Signal 28:1048-57|
|Stains, Joseph P; Civitelli, Roberto (2016) Connexins in the skeleton. Semin Cell Dev Biol 50:31-9|
|Lindberg, Iris; Pang, Hong Weng; Stains, Joseph P et al. (2015) FGF23 is endogenously phosphorylated in bone cells. J Bone Miner Res 30:449-54|
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