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Current Osteoporosis Reports

, Volume 15, Issue 1, pp 24–31 | Cite as

Connexin43 and the Intercellular Signaling Network Regulating Skeletal Remodeling

  • Megan C. Moorer
  • Joseph P. StainsEmail author
Skeletal Development (P Trainor and K Svoboda, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Skeletal Development

Abstract

Purpose of the Review

This review highlights recent developments into how intercellular communication through connexin43 facilitates bone modeling and remodeling.

Recent Findings

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.

Summary

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.

Keywords

Connexin Intercellular communication Signal transduction Osteoblast Osteocyte 

Notes

Acknowledgements

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.

References

Papers of Particular Interest, Published recently, Have Been Highlighted as: • Of Importance •• Of Major Importance

  1. 1.
    Plotkin LI, Bellido T. Osteocytic signalling pathways as therapeutic targets for bone fragility. Nat Rev Endocrinol. 2016;12(10):593–605.CrossRefPubMedGoogle Scholar
  2. 2.
    Prideaux M, Findlay DM, Atkins GJ. Osteocytes: the master cells in bone remodelling. Curr Opin Pharmacol. 2016;28:24–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229–38.CrossRefPubMedGoogle Scholar
  4. 4.
    McNutt NS, Weinstein RS. The ultrastructure of the nexus. A correlated thin-section and freeze-cleave study. J Cell Biol. 1970;47(3):666–88.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Gaietta G, Deerinck TJ, Adams SR, Bouwer J, Tour O, Laird DW, et al. Multicolor and electron microscopic imaging of connexin trafficking. Science. 2002;296(5567):503–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Sohl G, Willecke K. Gap junctions and the connexin protein family. Cardiovasc Res. 2004;62(2):228–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Solan JL, Lampe PD. Specific Cx43 phosphorylation events regulate gap junction turnover in vivo. FEBS Lett. 2014;588(8):1423–9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Koval M, Molina SA, Burt JM. Mix and match: investigating heteromeric and heterotypic gap junction channels in model systems and native tissues. FEBS Lett. 2014;588(8):1193–204.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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
  10. 10.
    Herve JC, Derangeon M. Gap-junction-mediated cell-to-cell communication. Cell Tissue Res. 2013;352(1):21–31.CrossRefPubMedGoogle Scholar
  11. 11.
    Herve JC, Derangeon M, Sarrouilhe D, Giepmans BN, Bourmeyster N. Gap junctional channels are parts of multiprotein complexes. Biochim Biophys Acta. 2012;1818(8):1844–65.CrossRefPubMedGoogle Scholar
  12. 12.
    Palatinus JA, Rhett JM, Gourdie RG. The connexin43 carboxyl terminus and cardiac gap junction organization. Biochim Biophys Acta. 2012;1818(8):1831–43.CrossRefPubMedGoogle Scholar
  13. 13.
    Civitelli R, Beyer EC, Warlow PM, Robertson AJ, Geist ST, Steinberg TH. Connexin43 mediates direct intercellular communication in human osteoblastic cell networks. J Clin Invest. 1993;91(5):1888–96.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Schirrmacher K, Schmitz I, Winterhager E, Traub O, Brummer F, Jones D, et al. Characterization of gap junctions between osteoblast-like cells in culture. Calcif Tissue Int. 1992;51(4):285–90.CrossRefPubMedGoogle Scholar
  15. 15.
    Elfgang C, Eckert R, Lichtenberg-Frate H, Butterweck A, Traub O, Klein RA, et al. Specific permeability and selective formation of gap junction channels in connexin-transfected HeLa cells. J Cell Biol. 1995;129(3):805–17.CrossRefPubMedGoogle Scholar
  16. 16.
    Jones SJ, Gray C, Sakamaki H, Arora M, Boyde A, Gourdie R, et al. The incidence and size of gap junctions between the bone cells in rat calvaria. Anat Embryol. 1993;187(4):343–52.CrossRefPubMedGoogle Scholar
  17. 17.
    Brink PR, Valiunas V, Gordon C, Rosen MR, Cohen IS. Can gap junctions deliver? Biochim Biophys Acta. 2012;1818(8):2076–81.CrossRefPubMedGoogle Scholar
  18. 18.
    Lemcke H, Steinhoff G, David R. Gap junctional shuttling of miRNA—A novel pathway of intercellular gene regulation and its prospects in clinical application. Cell Signal. 2015;27(12):2506–14.CrossRefPubMedGoogle Scholar
  19. 19.
    Kruger O, Plum A, Kim JS, Winterhager E, Maxeiner S, Hallas G, et al. Defective vascular development in connexin 45-deficient mice. Development. 2000;127(19):4179–93.PubMedGoogle Scholar
  20. 20.
    Steinberg TH, Civitelli R, Geist ST, Robertson AJ, Hick E, Veenstra RD, et al. Connexin43 and connexin45 form gap junctions with different molecular permeabilities in osteoblastic cells. EMBO J. 1994;13(4):744–50.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Koval M, Harley JE, Hick E, Steinberg TH. Connexin46 is retained as monomers in a trans-Golgi compartment of osteoblastic cells. J Cell Biol. 1997;137(4):847–57.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Pacheco-Costa R, Hassan I, Reginato RD, Davis HM, Bruzzaniti A, Allen MR, et al. High bone mass in mice lacking Cx37 because of defective osteoclast differentiation. J Biol Chem. 2014;289(12):8508–20.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Schilling AF, Filke S, Lange T, Gebauer M, Brink S, Baranowsky A, et al. Gap junctional communication in human osteoclasts in vitro and in vivo. J Cell Mol Med. 2008;12(6A):2497–504.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ilvesaro J, Vaananen K, Tuukkanen J. Bone-resorbing osteoclasts contain gap-junctional connexin-43. J Bone Miner Res. 2000;15(5):919–26.CrossRefPubMedGoogle Scholar
  25. 25.
    Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, et al. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet. 2003;72(2):408–18.CrossRefPubMedGoogle Scholar
  26. 26.
    Hu Y, Chen IP, de Almeida S, Tiziani V, Do Amaral CM, Gowrishankar K, et al. A novel autosomal recessive GJA1 missense mutation linked to craniometaphyseal dysplasia. PLoS One. 2013;8(8):e73576.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lecanda F, Warlow PM, Sheikh S, Furlan F, Steinberg TH, Civitelli R. Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J Cell Biol. 2000;151(4):931–44.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Reaume AG, de Sousa PA, Kulkarni S, Langille BL, Zhu D, Davies TC, et al. Cardiac malformation in neonatal mice lacking connexin43. Science. 1995;267(5205):1831–4.CrossRefPubMedGoogle Scholar
  29. 29.
    Misu A, Yamanaka H, Aramaki T, Kondo S, Skerrett IM, Iovine MK, et al. Two different functions of Connexin43 confer two different bone phenotypes in zebrafish. J Biol Chem. 2016;291(24):12601–11.CrossRefPubMedGoogle Scholar
  30. 30.
    Hoptak-Solga AD, Klein KA, DeRosa AM, White TW, Iovine MK. Zebrafish short fin mutations in connexin43 lead to aberrant gap junctional intercellular communication. FEBS Lett. 2007;581(17):3297–302.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Iovine MK, Higgins EP, Hindes A, Coblitz B, Johnson SL. Mutations in connexin43 (GJA1) perturb bone growth in zebrafish fins. Dev Biol. 2005;278(1):208–19.CrossRefPubMedGoogle Scholar
  32. 32.
    Sims Jr K, Eble DM, Iovine MK. Connexin43 regulates joint location in zebrafish fins. Dev Biol. 2009;327(2):410–8.CrossRefPubMedGoogle Scholar
  33. 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
  34. 34.
    Chung DJ, Castro CH, Watkins M, Stains JP, Chung MY, Szejnfeld VL, et al. Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43. J Cell Sci. 2006;119(Pt 20):4187–98.CrossRefPubMedGoogle Scholar
  35. 35.
    Grimston SK, Brodt MD, Silva MJ, Civitelli R. Attenuated response to in vivo mechanical loading in mice with conditional osteoblast ablation of the connexin43 gene (Gja1). J Bone Miner Res. 2008;23(6):879–86.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Watkins MP, Norris JY, Grimston SK, Zhang X, Phipps RJ, Ebetino FH, et al. Bisphosphonates improve trabecular bone mass and normalize cortical thickness in ovariectomized, osteoblast connexin43 deficient mice. Bone. 2012;51(4):787–94.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 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
  38. 38.
    Bivi N, Nelson MT, Faillace ME, Li J, Miller LM, Plotkin LI. Deletion of Cx43 from osteocytes results in defective bone material properties but does not decrease extrinsic strength in cortical bone. Calcif Tissue Int. 2012;91(3):215–24.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 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
  40. 40.
    Flenniken AM, Osborne LR, Anderson N, Ciliberti N, Fleming C, Gittens JE, et al. A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia. Development. 2005;132(19):4375–86.CrossRefPubMedGoogle Scholar
  41. 41.
    Roscoe W, Veitch GI, Gong XQ, Pellegrino E, Bai D, McLachlan E, et al. Oculodentodigital dysplasia-causing connexin43 mutants are non-functional and exhibit dominant effects on wild-type connexin43. J Biol Chem. 2005;280(12):11458–66.CrossRefPubMedGoogle Scholar
  42. 42.
    Dobrowolski R, Sasse P, Schrickel JW, Watkins M, Kim JS, Rackauskas M, et al. The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans. Hum Mol Genet. 2008;17(4):539–54.CrossRefPubMedGoogle Scholar
  43. 43.
    Lloyd SA, Loiselle AE, Zhang Y, Donahue HJ. Connexin 43 deficiency desensitizes bone to the effects of mechanical unloading through modulation of both arms of bone remodeling. Bone. 2013;57(1):76–83.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lloyd SA, Loiselle AE, Zhang Y, Donahue HJ. Evidence for the role of connexin 43-mediated intercellular communication in the process of intracortical bone resorption via osteocytic osteolysis. BMC Musculoskelet Disord. 2014;15:122.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Komori T. Mouse models for the evaluation of osteocyte functions. J Bone Metab. 2014;21(1):55–60.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab. 2007;5(6):464–75.CrossRefPubMedGoogle Scholar
  47. 47.
    Li M, Hasegawa T, Hogo H, Tatsumi S, Liu Z, Guo Y, et al. Histological examination on osteoblastic activities in the alveolar bone of transgenic mice with induced ablation of osteocytes. Histol Histopathol. 2013;28(3):327–35.PubMedGoogle Scholar
  48. 48.
    Moriishi T, Maruyama Z, Fukuyama R, Ito M, Miyazaki T, Kitaura H, et al. Overexpression of Bcl2 in osteoblasts inhibits osteoblast differentiation and induces osteocyte apoptosis. PLoS One. 2011;6(11):e27487.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Jahani M, Genever PG, Patton RJ, Ahwal F, Fagan MJ. The effect of osteocyte apoptosis on signalling in the osteocyte and bone lining cell network: a computer simulation. J Biomech. 2012;45(16):2876–83.CrossRefPubMedGoogle Scholar
  50. 50.
    Stains JP, Civitelli R. Connexins in the skeleton. Semin Cell Dev Biol. 2016;50:31–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Grimston SK, Watkins MP, Stains JP, Civitelli R. Connexin43 modulates post-natal cortical bone modeling and mechano-responsiveness. BoneKEy reports. 2013;2:446.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Lloyd SA, Loiselle AE, Zhang Y, Donahue HJ. Shifting paradigms on the role of connexin43 in the skeletal response to mechanical load. J Bone Miner Res. 2014;29(2):275–86.CrossRefPubMedGoogle Scholar
  53. 53.
    Ellison D, Mugler A, Brennan MD, Lee SH, Huebner RJ, Shamir ER, et al. Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis. Proc Natl Acad Sci U S A. 2016;113(6):E679–88.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Henriksen Z, Hiken JF, Steinberg TH, Jorgensen NR. The predominant mechanism of intercellular calcium wave propagation changes during long-term culture of human osteoblast-like cells. Cell Calcium. 2006;39(5):435–44.CrossRefPubMedGoogle Scholar
  55. 55.
    Geneau G, Defamie N, Mesnil M, Cronier L. Endothelin1-induced Ca(2+) mobilization is altered in calvarial osteoblastic cells of Cx43(+/−) mice. J Membr Biol. 2007;217(1–3):71–81.CrossRefPubMedGoogle Scholar
  56. 56.
    Jorgensen NR, Geist ST, Civitelli R, Steinberg TH. ATP- and gap junction-dependent intercellular calcium signaling in osteoblastic cells. J Cell Biol. 1997;139(2):497–506.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Ishihara Y, Kamioka H, Honjo T, Ueda H, Takano-Yamamoto T, Yamashiro T. Hormonal, pH, and calcium regulation of connexin 43-mediated dye transfer in osteocytes in chick calvaria. J Bone Miner Res. 2008;23(3):350–60.CrossRefPubMedGoogle Scholar
  58. 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. 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
  60. 60.
    Genetos DC, Kephart CJ, Zhang Y, Yellowley CE, Donahue HJ. Oscillating fluid flow activation of gap junction hemichannels induces ATP release from MLO-Y4 osteocytes. J Cell Physiol. 2007;212(1):207–14.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Romanello M, Pani B, Bicego M, D'Andrea P. Mechanically induced ATP release from human osteoblastic cells. Biochem Biophys Res Commun. 2001;289(5):1275–81.CrossRefPubMedGoogle Scholar
  62. 62.
    Cherian PP, Siller-Jackson AJ, Gu S, Wang X, Bonewald LF, Sprague E, et al. Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. Mol Biol Cell. 2005;16(7):3100–6.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Siller-Jackson AJ, Burra S, Gu S, Xia X, Bonewald LF, Sprague E, et al. Adaptation of connexin 43-hemichannel prostaglandin release to mechanical loading. J Biol Chem. 2008;283(39):26374–82.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 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
  65. 65.
    Thi MM, Islam S, Suadicani SO, Spray DC. Connexin43 and pannexin1 channels in osteoblasts: who is the “hemichannel”? J Membr Biol. 2012;245(7):401–9.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Lima F, Niger C, Hebert C, Stains JP. Connexin43 potentiates osteoblast responsiveness to fibroblast growth factor 2 via a protein kinase C-delta/Runx2-dependent mechanism. Mol Biol Cell. 2009;20(11):2697–708.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Niger C, Buo AM, Hebert C, Duggan BT, Williams MS, Stains JP. ERK acts in parallel to PKCdelta to mediate the connexin43-dependent potentiation of Runx2 activity by FGF2 in MC3T3 osteoblasts. Am J Physiol Cell Physiol. 2012;302(7):C1035–44.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Stains JP, Civitelli R. Gap junctions regulate extracellular signal-regulated kinase signaling to affect gene transcription. Mol Biol Cell. 2005;16(1):64–72.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Bivi N, Lezcano V, Romanello M, Bellido T, Plotkin LI. Connexin43 interacts with betaarrestin: a pre-requisite for osteoblast survival induced by parathyroid hormone. J Cell Biochem. 2011;112(10):2920–30.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Bivi N, Pacheco-Costa R, Brun LR, Murphy TR, Farlow NR, Robling AG, et al. Absence of Cx43 selectively from osteocytes enhances responsiveness to mechanical force in mice. J Orthop Res. 2013;31(7):1075–81.CrossRefPubMedGoogle Scholar
  71. 71.
    Niger C, Lima F, Yoo DJ, Gupta RR, Buo AM, Hebert C, et al. The transcriptional activity of osterix requires the recruitment of Sp1 to the osteocalcin proximal promoter. Bone. 2011;49(4):683–92.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Stains JP, Lecanda F, Screen J, Towler DA, Civitelli R. Gap junctional communication modulates gene transcription by altering the recruitment of Sp1 and Sp3 to connexin-response elements in osteoblast promoters. J Biol Chem. 2003;278(27):24377–87.CrossRefPubMedGoogle Scholar
  73. 73.
    Plotkin LI, Manolagas SC, Bellido T. Transduction of cell survival signals by connexin-43 hemichannels. J Biol Chem. 2002;277(10):8648–57.CrossRefPubMedGoogle Scholar
  74. 74.
    Plotkin LI, Aguirre JI, Kousteni S, Manolagas SC, Bellido T. Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation. J Biol Chem. 2005;280(8):7317–25.CrossRefPubMedGoogle Scholar
  75. 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. 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
  77. 77.
    Hammond MA, Berman AG, Pacheco-Costa R, Davis HM, Plotkin LI, Wallace JM. Removing or truncating connexin 43 in murine osteocytes alters cortical geometry, nanoscale morphology, and tissue mechanics in the tibia. Bone. 2016;88:85–91.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of OrthopaedicsUniversity of Maryland School of MedicineBaltimoreUSA

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