Connexin43 and the Intercellular Signaling Network Regulating Skeletal Remodeling
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Purpose of the Review
This review highlights recent developments into how intercellular communication through connexin43 facilitates bone modeling and remodeling.
Connexin43 is required for both skeletal development and maintenance, particularly in cortical bone, where it carries out multiple functions, including preventing osteoclastogenesis, restraining osteoprogenitor proliferation, promoting osteoblast differentiation, coordinating organized collagen matrix deposition, and maintaining osteocyte survival. Emerging data shows that connexin43 regulates both the exchange of small molecules among osteoblast lineage cells and the docking of signaling proteins to the gap junction, affecting the efficiency of signal transduction.
Understanding how and what connexin43 communicates to coordinate tissue remodeling has therapeutic implications in bone. Altering the information shared by intercellular communication and/or targeting the recruitment of signaling machinery to the gap junction could be used to impact the skeletal homeostatic set point, either driving osteogenesis or inhibiting resorption.
KeywordsConnexin Intercellular communication Signal transduction Osteoblast Osteocyte
This work was supported by a grant, R01-AR063631 (JPS) from the National Institutes of Health/National Institute for Arthritis, Musculoskeletal and Skin Diseases. We thank Lynda Bonewald (Indiana University-Purdue University Indianapolis) for providing the EM image of the osteocyte lacunae-canalicular network.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 9.• Hebert C, Stains JP. An intact connexin43 is required to enhance signaling and gene expression in osteoblast-like cells. J Cell Biochem. 2013;114(11):2542–50. Demonstrates the necessary, but insufficient role for the connexin43 C-terminus in regulating the downstream effects of ERK1/2 and PKCδ In vitro, setting the stage for the notion of Cx43 as a docking platform for signaling CrossRefPubMedPubMedCentralGoogle Scholar
- 33.• Watkins M, Grimston SK, Norris JY, Guillotin B, Shaw A, Beniash E, et al. Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling. Mol Biol Cell. 2011;22(8):1240–51. Using osteoblast-lineage conditional knockout models, this paper established the major role of connexin43 as a controller of osteoblast progenitor proliferation, osteoblast differentiation, and as a regulator of osteoclastogenesis, impacting cortical bone CrossRefPubMedPubMedCentralGoogle Scholar
- 37.• Bivi N, Condon KW, Allen MR, Farlow N, Passeri G, Brun LR, et al. Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Miner Res. 2012;27(2):374–89. Established the fundamental importance of connexin43 in the survival of osteocytes in vivo and the contribution to cortical bone CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Pacheco-Costa R, Davis HM, Atkinson EG, Katchburian E, Plotkin LI, Reginato RD. Osteocytic connexin 43 is not required for the increase in bone mass induced by intermittent PTH administration in male mice. Journal of musculoskeletal & neuronal interactions. 2016;16(1):45–57.Google Scholar
- 58.• Gupta A, Anderson H, Buo AM, Moorer MC, Ren M, Stains JP. Communication of cAMP by connexin43 gap junctions regulates osteoblast signaling and gene expression. Cell Signal. 2016;28(8):1048–57. Demonstrates that cAMP is a biologically relevant second messenger passed by connexin43 channels with a biological consequence on osteoblasts CrossRefPubMedGoogle Scholar
- 59.• Niger C, Luciotti MA, Buo AM, Hebert C, Ma V, Stains JP. The regulation of runt-related transcription factor 2 by fibroblast growth factor-2 and connexin43 requires the inositol polyphosphate/protein kinase Cdelta cascade. J Bone Miner Res. 2013;28(6):1468–77. Shows that inostiol polyphosphates might be novel second messengers communicated by gap junctions in bone CrossRefPubMedPubMedCentralGoogle Scholar
- 64.• Xu H, Gu S, Riquelme MA, Burra S, Callaway D, Cheng H, et al. Connexin 43 channels are essential for normal bone structure and osteocyte viability. J Bone Miner Res. 2015;30(3):436–48. Using transgenic mice expressing mutant connexin43, this paper addressed the role of Cx43 gap junctions versus connexin43 hemichannels in vivo Google Scholar
- 75.• Batra N, Burra S, Siller-Jackson AJ, Gu S, Xia X, Weber GF, et al. Mechanical stress-activated integrin alpha5beta1 induces opening of connexin 43 hemichannels. Proc Natl Acad Sci U S A. 2012;109(9):3359–64. Systematically demonstrated the role of Cx43 in the mechano-activation of osteocytes by the direct physical interaction of the Cx43 C-terminus with integrins CrossRefPubMedPubMedCentralGoogle Scholar
- 76.• Pacheco-Costa R, Davis HM, Sorenson C, Hon MC, Hassan I, Reginato RD, et al. Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain. Bone. 2015;81:632–43. Revealed an important role of the Cx43 C-terminus in the trabecular compartment of female mice CrossRefPubMedPubMedCentralGoogle Scholar