The mutation or loss of function of the gap junction protein connexin43 leads to skeletal abnormalities, delayed ossification and a generalized osteoblast dysfunction, characterized by diminished osteoblast gene transcription and decreased mineralization potential. We have previously characterized that the down regulation of gene transcription caused by loss of intercellular communication through gap junctions is a result of altered cell signaling leading to regulation of the recruitment of transcription factors to the promoter of affected genes. The overall HYPOTHESIS to be evaluated is that gap junctional communication is required to elicit the optimal response of cells to extracellular cues to modulate gene transcription. These issues will be addressed in three SPECIFIC AIMS that will: (1) Analyze the role of gap junction in regulating signal transduction in response to extracellular signals to regulate osteoblast function. (2) Determine the molecular basis of interactions which permit signal transduction from the gap junction signaling nexus. (3) Examine the role of Ca2+-dependent signaling in Cx43-mediated gene transcription. By triangulating on the gap junction channel, the messenger propagated by the gap junction, and the signal cascades activated by these signals, we will greatly elaborate on our knowledge and understanding of gap junction function in the context of regulating osteoblast function.
These aims will be carried out using well characterized osteoblastic cell lines and primary osteoblasts derived from Cx43 deficient mice. SIGNIFICANCE: The studies will provide insight into the molecular function of gap junction proteins in the coordination and propagation of extracellular signals and how these signals regulate cellular function at the level of the nucleus. Our long term goal is to develop methods for the prevention and treatment of skeletal pathologies by modulating gap junctional communication to potentiate the anabolic response of growth factors on bone formation.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-J (02))
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Chen, Faye H
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University of Maryland Baltimore
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Stains, Joseph P; Civitelli, Roberto (2016) Connexins in the skeleton. Semin Cell Dev Biol 50:31-9
Liu, Shuo; Niger, Corinne; Koh, Eugene Y et al. (2015) Connexin43 Mediated Delivery of ADAMTS5 Targeting siRNAs from Mesenchymal Stem Cells to Synovial Fibroblasts. PLoS One 10:e0129999
Casagrande, Danielle; Stains, Joseph P; Murthi, Anand M (2015) Identification of shoulder osteoarthritis biomarkers: comparison between shoulders with and without osteoarthritis. J Shoulder Elbow Surg 24:382-90
Gupta, Rishi R; Kim, Hyunchul; Chan, Yu-Kwan et al. (2015) Axial strain enhances osteotomy repair with a concomitant increase in connexin43 expression. Bone Res 3:15007
Gupta, Aditi; Niger, Corinne; Buo, Atum M et al. (2014) Connexin43 enhances the expression of osteoarthritis-associated genes in synovial fibroblasts in culture. BMC Musculoskelet Disord 15:425
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
Nanjundaiah, S M; Stains, J P; Moudgil, K D (2013) Kinetics and interplay of mediators of inflammation-induced bone damage in the course of adjuvant arthritis. Int J Immunopathol Pharmacol 26:37-48
Niger, Corinne; Luciotti, Maria A; Buo, Atum M et al. (2013) The regulation of runt-related transcription factor 2 by fibroblast growth factor-2 and connexin43 requires the inositol polyphosphate/protein kinase C? cascade. J Bone Miner Res 28:1468-77
Hebert, Carla; Stains, Joseph P (2013) An intact connexin43 is required to enhance signaling and gene expression in osteoblast-like cells. J Cell Biochem 114:2542-50
Pratt, Stephen J P; Shah, Sameer B; Ward, Christopher W et al. (2013) Effects of in vivo injury on the neuromuscular junction in healthy and dystrophic muscles. J Physiol 591:559-70

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