Skip to main content

Advertisement

SpringerLink
Log in

Molecular Mechanisms of Osteoblast/Osteocyte Regulation by Connexin43

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Osteoblasts, osteocytes, and osteoprogenitor cells are interconnected into a functional network by gap junctions formed primarily by connexin43 (Cx43). Over the past two decades, it has become clear that Cx43 is important for the function of osteoblasts and osteocytes. This connexin contributes to the acquisition of peak bone mass and is a major modulator of cortical modeling. We review key data from human and mouse genetics on the skeletal consequences of ablation or mutation of the Cx43 gene (Gja1) and the molecular mechanisms by which Cx43 regulates the differentiation, function, and survival of osteogenic lineage cells. We also discuss putative second messengers that are communicated by Cx43 gap junctions, the role of hemichannels, and the function of Cx43 as a scaffold for signaling molecules. Current knowledge demonstrates that Cx43 is more than a passive channel; rather, it actively participates in the generation and modulation of cellular signals that drive skeletal development and homeostasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Segretain D, Falk MM (2004) Regulation of connexin biosynthesis, assembly, gap junction formation, and removal. Biochim Biophys Acta 1662:3–21

    Article  CAS  PubMed  Google Scholar 

  2. Goodenough DA, Paul DL (2003) Beyond the gap: functions of unpaired connexon channels. Nat Rev Mol Cell Biol 4:285–294

    Article  CAS  PubMed  Google Scholar 

  3. Civitelli R (2008) Cell–cell communication in the osteoblast/osteocyte lineage. Arch Biochem Biophys 473:188–192

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Civitelli R, Stains JP, Shin CS, Jørgensen N (2008) Intercellular junctions and cell–cell communication in the skeletal system. In: Bilezikian JP, Raisz LG, Martin TJ (eds) Principles of bone biology. Academic Press, San Diego, pp 425–444

    Chapter  Google Scholar 

  5. Paic F, Igwe JC, Nori R, Kronenberg MS, Franceschetti T, Harrington P, Kuo L, Shin DG, Rowe DW, Harris SE, Kalajzic I (2009) Identification of differentially expressed genes between osteoblasts and osteocytes. Bone 45:682–692

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, Innis JW, Dinulos MB, Christian C, Hannibal MC, Jabs EW (2003) Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 72:408–418

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Paznekas WA, Karczeski B, Vermeer S, Lowry RB, Delatycki M, Laurence F, Koivisto PA, Van Maldergem L, Boyadjiev SA, Bodurtha JN, Jabs EW (2009) GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype. Hum Mutat 30:724–733

    Article  CAS  PubMed  Google Scholar 

  8. Flenniken AM, Osborne LR, Anderson N, Ciliberti N, Fleming C, Gittens JE, Gong XQ, Kelsey LB, Lounsbury C, Moreno L, Nieman BJ, Peterson K, Qu D, Roscoe W, Shao Q, Tong D, Veitch GI, Voronina I, Vukobradovic I, Wood GA, Zhu Y, Zirngibl RA, Aubin JE, Bai D, Bruneau BG, Grynpas M, Henderson JE, Henkelman RM, McKerlie C, Sled JG, Stanford WL, Laird DW, Kidder GM, Adamson SL, Rossant J (2005) A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia. Development 132:4375–4386

    Article  CAS  PubMed  Google Scholar 

  9. Gong XQ, Shao Q, Langlois S, Bai D, Laird DW (2007) Differential potency of dominant negative connexin43 mutants in oculodentodigital dysplasia. J Biol Chem 282:19190–19202

    Article  CAS  PubMed  Google Scholar 

  10. McLachlan E, Plante I, Shao Q, Tong D, Kidder GM, Bernier SM, Laird DW (2008) ODDD-linked Cx43 mutants reduce endogenous Cx43 expression and function in osteoblasts and inhibit late stage differentiation. J Bone Miner Res 23:928–938

    Article  CAS  PubMed  Google Scholar 

  11. Dobrowolski R, Sasse P, Schrickel JW, Watkins M, Kim JS, Rackauskas M, Troatz C, Ghanem A, Tiemann K, Degen J, Bukauskas FF, Civitelli R, Lewalter T, Fleischmann BK, Willecke K (2008) The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans. Hum Mol Genet 17:539–554

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Roscoe W, Veitch GI, Gong XQ, Pellegrino E, Bai D, McLachlan E, Shao Q, Kidder GM, Laird DW (2005) Oculodentodigital dysplasia-causing connexin43 mutants are non-functional and exhibit dominant effects on wild-type connexin43. J Biol Chem 280:11458–11466

    Article  CAS  PubMed  Google Scholar 

  13. Watkins M, Grimston SK, Norris JY, Guillotin B, Shaw A, Beniash E, Civitelli R (2011) Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling. Mol Biol Cell 22:1240–1251

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Becker DL, McGonnell I, Makarenkova HP, Patel K, Tickle C, Lorimer J, Green CR (1999) Roles for alpha 1 connexin in morphogenesis of chick embryos revealed using a novel antisense approach. Dev Genet 24:33–42

    Article  CAS  PubMed  Google Scholar 

  15. Lecanda F, Warlow PM, Sheikh S, Furlan F, Steinberg TH, Civitelli R (2000) Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J Cell Biol 151:931–944

    Article  CAS  PubMed  Google Scholar 

  16. Reaume AG, de Sousa PA, Kulkarni S, Langille BL, Zhu D, Davies TC, Juneja SC, Kidder GM, Rossant J (1995) Cardiac malformation in neonatal mice lacking connexin43. Science 267:1831–1834

    Article  CAS  PubMed  Google Scholar 

  17. Rodda SJ, McMahon AP (2006) Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133:3231–3244

    Article  CAS  PubMed  Google Scholar 

  18. Chung DJ, Castro CH, Watkins M, Stains JP, Chung MY, Szejnfeld VL, Willecke K, Theis M, Civitelli R (2006) Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43. J Cell Sci 119:4187–4198

    Article  CAS  PubMed  Google Scholar 

  19. Grimston SK, Brodt MD, Silva MJ, Civitelli R (2008) Attenuated response to in vivo mechanical loading in mice with conditional osteoblast ablation of the connexin43 gene (Gja1). J Bone Miner Res 23:879–886

    Article  PubMed  Google Scholar 

  20. Gonzalez-Nieto D, Li L, Kohler A, Ghiaur G, Ishikawa E, Sengupta A, Madhu M, Arnett JL, Santho RA, Dunn SK, Fishman GI, Gutstein DE, Civitelli R, Barrio LC, Gunzer M, Cancelas JA (2012) Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood 119:5144–5154

    Article  CAS  PubMed  Google Scholar 

  21. Schajnovitz A, Itkin T, D’Uva G, Kalinkovich A, Golan K, Ludin A, Cohen D, Shulman Z, Avigdor A, Nagler A, Kollet O, Seger R, Lapidot T (2011) CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions. Nat Immunol 12:391–398

    Article  CAS  PubMed  Google Scholar 

  22. Zhang Y, Paul EM, Sathyendra V, Davison A, Sharkey N, Bronson S, Srinivasan S, Gross TS, Donahue HJ (2011) Enhanced osteoclastic resorption and responsiveness to mechanical load in gap junction deficient bone. PLoS ONE 6:e23516

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Bivi N, Condon KW, Allen MR, Farlow N, Passeri G, Brun LR, Rhee Y, Bellido T, Plotkin LI (2012) Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. J Bone Miner Res 27:374–389

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Bivi N, Nelson MT, Faillace ME, Li J, Miller LM, Plotkin LI (2012) Deletion of Cx43 from osteocytes results in defective bone material properties but does not decrease extrinsic strength in cortical bone. Calcif Tissue Int 91:215–224

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA (2011) Matrix-embedded cells control osteoclast formation. Nat Med 17:1235–1241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Kalajzic I, Matthews BG, Torreggiani E, Harris MA, Pajevic PD, Harris SE (2012) In vitro and in vivo approaches to study osteocyte biology. Bone 54:296–306

    Article  PubMed  Google Scholar 

  27. Plotkin LI, Bellido T (2013) Beyond gap junctions: connexin43 and bone cell signaling. Bone 52:157–166

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Grimston SK, Watkins MP, Brodt MD, Silva MJ, Civitelli R (2012) Enhanced periosteal and endocortical responses to axial tibial compression loading in conditional connexin43 deficient mice. PLoS ONE 7:e44222

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Grimston SK, Goldberg DB, Watkins M, Brodt MD, Silva MJ, Civitelli R (2011) Connexin43 deficiency reduces the sensitivity of cortical bone to the effects of muscle paralysis. J Bone Miner Res 26:2151–2160

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Grimston SK, Silva MJ, Civitelli R (2007) Bone loss after temporarily induced muscle paralysis by Botox is not fully recovered after 12 weeks. Ann N Y Acad Sci 1116:444–460

    Article  CAS  PubMed  Google Scholar 

  31. Grimston SK, Screen J, Haskell JH, Chung DJ, Brodt MD, Silva MJ, Civitelli R (2006) Role of connexin43 in osteoblast response to physical load. Ann N Y Acad Sci 1068:214–224

    Article  CAS  PubMed  Google Scholar 

  32. Lloyd SA, Lewis GS, Zhang Y, Paul EM, Donahue HJ (2012) Connexin 43 deficiency attenuates loss of trabecular bone and prevents suppression of cortical bone formation during unloading. J Bone Miner Res 27:2359–2372

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Lecanda F, Towler DA, Ziambaras K, Cheng SL, Koval M, Steinberg TH, Civitelli R (1998) Gap junctional communication modulates gene expression in osteoblastic cells. Mol Biol Cell 9:2249–2258

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Li Z, Zhou Z, Saunders MM, Donahue HJ (2006) Modulation of connexin43 alters expression of osteoblastic differentiation markers. Am J Physiol Cell Physiol 290:C1248–C1255

    Article  CAS  PubMed  Google Scholar 

  35. Li Z, Zhou Z, Yellowley CE, Donahue HJ (1999) Inhibiting gap junctional intercellular communication alters expression of differentiation markers in osteoblastic cells. Bone 25:661–666

    Article  CAS  PubMed  Google Scholar 

  36. Donahue HJ, Li Z, Zhou Z, Yellowley CE (2000) Differentiation of human fetal osteoblastic cells and gap junctional intercellular communication. Am J Physiol Cell Physiol 278:C315–C322

    CAS  PubMed  Google Scholar 

  37. Schiller PC, D’Ippolito G, Balkan W, Roos BA, Howard GA (2001) Gap-junctional communication is required for the maturation process of osteoblastic cells in culture. Bone 28:362–369

    Article  CAS  PubMed  Google Scholar 

  38. Schiller PC, D’Ippolito G, Balkan W, Roos BA, Howard GA (2001) Gap-junctional communication mediates parathyroid hormone stimulation of mineralization in osteoblastic cultures. Bone 28:38–44

    Article  CAS  PubMed  Google Scholar 

  39. Lima F, Niger C, Hebert C, Stains JP (2009) Connexin43 potentiates osteoblast responsiveness to fibroblast growth factor 2 via a protein kinase C-delta/Runx2-dependent mechanism. Mol Biol Cell 20:2697–2708

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Niger C, Buo AM, Hebert C, Duggan BT, Williams MS, Stains JP (2012) 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 302:C1035–C1044

    Article  CAS  PubMed  Google Scholar 

  41. Xiao G, Jiang D, Gopalakrishnan R, Franceschi RT (2002) Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. J Biol Chem 277:36181–36187

    Article  CAS  PubMed  Google Scholar 

  42. Kim HJ, Kim JH, Bae SC, Choi JY, Kim HJ, Ryoo HM (2003) The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. J Biol Chem 278:319–326

    Article  CAS  PubMed  Google Scholar 

  43. Park OJ, Kim HJ, Woo KM, Baek JH, Ryoo HM (2010) FGF2-activated ERK mitogen-activated protein kinase enhances Runx2 acetylation and stabilization. J Biol Chem 285:3568–3574

    Article  CAS  PubMed  Google Scholar 

  44. Stains JP, Lecanda F, Screen J, Towler DA, Civitelli R (2003) Gap junctional communication modulates gene transcription by altering the recruitment of Sp1 and Sp3 to connexin-response elements in osteoblast promoters. J Biol Chem 278:24377–24387

    Article  CAS  PubMed  Google Scholar 

  45. Stains JP, Civitelli R (2005) Gap junctions regulate extracellular signal-regulated kinase signaling to affect gene transcription. Mol Biol Cell 16:64–72

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29

    Article  CAS  PubMed  Google Scholar 

  47. Niger C, Lima F, Yoo DJ, Gupta RR, Buo AM, Hebert C, Stains JP (2011) The transcriptional activity of osterix requires the recruitment of Sp1 to the osteocalcin proximal promoter. Bone 49:683–692

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Hoptak-Solga AD, Nielsen S, Jain I, Thummel R, Hyde DR, Iovine MK (2008) Connexin43 (GJA1) is required in the population of dividing cells during fin regeneration. Dev Biol 317:541–548

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Iovine MK, Higgins EP, Hindes A, Coblitz B, Johnson SL (2005) Mutations in connexin43 (GJA1) perturb bone growth in zebrafish fins. Dev Biol 278:208–219

    Article  CAS  PubMed  Google Scholar 

  50. Sims K Jr, Eble DM, Iovine MK (2009) Connexin43 regulates joint location in zebrafish fins. Dev Biol 327:410–418

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Ton QV, Iovine MK (2012) Semaphorin3d mediates Cx43-dependent phenotypes during fin regeneration. Dev Biol 366:195–203

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Ton QV, Iovine MK (2013) Determining how defects in connexin43 cause skeletal disease. Genesis 51:75–82

    Article  CAS  PubMed  Google Scholar 

  53. Jilka RL, Noble B, Weinstein RS (2013) Osteocyte apoptosis. Bone 54:264–271

    Article  PubMed  Google Scholar 

  54. Tatsumi S, Ishii K, Amizuka N, Li M, Kobayashi T, Kohno K, Ito M, Takeshita S, Ikeda K (2007) Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab 5:464–475

    Article  CAS  PubMed  Google Scholar 

  55. Bivi N, Lezcano V, Romanello M, Bellido T, Plotkin LI (2011) Connexin43 interacts with betaarrestin: a pre-requisite for osteoblast survival induced by parathyroid hormone. J Cell Biochem 112:2920–2930

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Cherian PP, Siller-Jackson AJ, Gu S, Wang X, Bonewald LF, Sprague E, Jiang JX (2005) Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. Mol Biol Cell 16:3100–3106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Siller-Jackson AJ, Burra S, Gu S, Xia X, Bonewald LF, Sprague E, Jiang JX (2008) Adaptation of connexin 43-hemichannel prostaglandin release to mechanical loading. J Biol Chem 283:26374–26382

    Article  CAS  PubMed  Google Scholar 

  58. Genetos DC, Kephart CJ, Zhang Y, Yellowley CE, Donahue HJ (2007) Oscillating fluid flow activation of gap junction hemichannels induces ATP release from MLO-Y4 osteocytes. J Cell Physiol 212:207–214

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Batra N, Burra S, Siller-Jackson AJ, Gu S, Xia X, Weber GF, DeSimone D, Bonewald LF, Lafer EM, Sprague E, Schwartz MA, Jiang JX (2012) Mechanical stress-activated integrin alpha5beta1 induces opening of connexin 43 hemichannels. Proc Natl Acad Sci USA 109:3359–3364

    Article  CAS  PubMed  Google Scholar 

  60. Taylor AF, Saunders MM, Shingle DL, Cimbala JM, Zhou Z, Donahue HJ (2007) Mechanically stimulated osteocytes regulate osteoblastic activity via gap junctions. Am J Physiol Cell Physiol 292:C545–C552

    Article  CAS  PubMed  Google Scholar 

  61. Jiang J, Burra S, Harris S, Zhao H, Johnson M, Bonewald LF (2010) Inhibiting gap junction function in osteocytes, but not Cx43 hemichannel function results in defects in skeletal structure and bone mass. J Bone Miner Res. http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=b7a23bf22-371f-4146-4149eac-4190e4148ceee3856

  62. Thi MM, Islam S, Suadicani SO, Spray DC (2012) Connexin43 and pannexin1 channels in osteoblasts: who is the “hemichannel”? J Membr Biol 245:401–409

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Sosinsky GE, Boassa D, Dermietzel R, Duffy HS, Laird DW, MacVicar B, Naus CC, Penuela S, Scemes E, Spray DC, Thompson RJ, Zhao HB, Dahl G (2011) Pannexin channels are not gap junction hemichannels. Channels (Austin) 5:193–197

    Article  CAS  Google Scholar 

  64. D’Hondt C, Ponsaerts R, De Smedt H, Vinken M, De Vuyst E, De Bock M, Wang N, Rogiers V, Leybaert L, Himpens B, Bultynck G (2011) Pannexin channels in ATP release and beyond: an unexpected rendezvous at the endoplasmic reticulum. Cell Signal 23:305–316

    Article  PubMed  Google Scholar 

  65. D’Hondt C, Ponsaerts R, De Smedt H, Bultynck G, Himpens B (2009) Pannexins, distant relatives of the connexin family with specific cellular functions? BioEssays 31:953–974

    Article  PubMed  Google Scholar 

  66. Bond SR, Lau A, Penuela S, Sampaio AV, Underhill TM, Laird DW, Naus CC (2011) Pannexin 3 is a novel target for Runx2, expressed by osteoblasts and mature growth plate chondrocytes. J Bone Miner Res 26:2911–2922

    Article  CAS  PubMed  Google Scholar 

  67. Ishikawa M, Iwamoto T, Nakamura T, Doyle A, Fukumoto S, Yamada Y (2011) Pannexin 3 functions as an ER Ca2+ channel, hemichannel, and gap junction to promote osteoblast differentiation. J Cell Biol 193:1257–1274

    Article  CAS  PubMed  Google Scholar 

  68. Plotkin LI, Aguirre JI, Kousteni S, Manolagas SC, Bellido T (2005) Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation. J Biol Chem 280:7317–7325

    Article  CAS  PubMed  Google Scholar 

  69. Plotkin LI, Manolagas SC, Bellido T (2002) Transduction of cell survival signals by connexin-43 hemichannels. J Biol Chem 277:8648–8657

    Article  CAS  PubMed  Google Scholar 

  70. Rogers MJ, Frith JC, Luckman SP, Coxon FP, Benford HL, Monkkonen J, Auriola S, Chilton KM, Russell RG (1999) Molecular mechanisms of action of bisphosphonates. Bone 24:73S–79S

    Article  CAS  PubMed  Google Scholar 

  71. Bellido T, Plotkin LI (2011) Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability. Bone 49:50–55

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Plotkin LI, Lezcano V, Thostenson J, Weinstein RS, Manolagas SC, Bellido T (2008) Connexin 43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts in vivo. J Bone Miner Res 23:1712–1721

    Article  CAS  PubMed  Google Scholar 

  73. Watkins MP, Norris JY, Grimston SK, Zhang X, Phipps RJ, Ebetino FH, Civitelli R (2012) Bisphosphonates improve trabecular bone mass and normalize cortical thickness in ovariectomized, osteoblast connexin43 deficient mice. Bone 51:787–794

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Idris AI, Rojas J, Greig IR, Van’t Hof RJ, Ralston SH (2008) Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int 82:191–201

    Article  CAS  PubMed  Google Scholar 

  75. Lezcano V, Bellido T, Plotkin LI, Boland R, Morelli S (2012) Role of connexin 43 in the mechanism of action of alendronate: dissociation of anti-apoptotic and proliferative signaling pathways. Arch Biochem Biophys 518:95–102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Niessen H, Harz H, Bedner P, Kramer K, Willecke K (2000) Selective permeability of different connexin channels to the second messenger inositol 1,4,5-trisphosphate. J Cell Sci 113(pt 8):1365–1372

    CAS  PubMed  Google Scholar 

  77. Niger C, Luciotti MA, Buo AM, Hebert C, Ma V, Stains JP (2013) The regulation of Runx2 by FGF2 and connexin43 requires the inositol polyphosphate/protein kinase Cdelta cascade. J Bone Miner Res. doi:10.1002/jbmr.1867

    PubMed  Google Scholar 

  78. Jorgensen NR, Geist ST, Civitelli R, Steinberg TH (1997) ATP- and gap junction-dependent intercellular calcium signaling in osteoblastic cells. J Cell Biol 139:497–506

    Article  CAS  PubMed  Google Scholar 

  79. Jorgensen NR, Henriksen Z, Brot C, Eriksen EF, Sorensen OH, Civitelli R, Steinberg TH (2000) Human osteoblastic cells propagate intercellular calcium signals by two different mechanisms. J Bone Miner Res 15:1024–1032

    Article  CAS  PubMed  Google Scholar 

  80. Yellowley CE, Li Z, Zhou Z, Jacobs CR, Donahue HJ (2000) Functional gap junctions between osteocytic and osteoblastic cells. J Bone Miner Res 15:209–217

    Article  CAS  PubMed  Google Scholar 

  81. Jorgensen NR, Teilmann SC, Henriksen Z, Civitelli R, Sorensen OH, Steinberg TH (2003) Activation of L-type calcium channels is required for gap junction-mediated intercellular calcium signaling in osteoblastic cells. J Biol Chem 278:4082–4086

    Article  CAS  PubMed  Google Scholar 

  82. Huo B, Lu XL, Guo XE (2010) Intercellular calcium wave propagation in linear and circuit-like bone cell networks. Philos Trans A Math Phys Eng Sci 368:617–633

    Article  CAS  PubMed  Google Scholar 

  83. Huo B, Lu XL, Costa KD, Xu Q, Guo XE (2010) An ATP-dependent mechanism mediates intercellular calcium signaling in bone cell network under single cell nanoindentation. Cell Calcium 47:234–241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Ishihara Y, Sugawara Y, Kamioka H, Kawanabe N, Hayano S, Balam TA, Naruse K, Yamashiro T (2013) Ex vivo real-time observation of Ca2+ signaling in living bone in response to shear stress applied on the bone surface. Bone 53:204–215

    Article  CAS  PubMed  Google Scholar 

  85. Ishihara Y, Sugawara Y, Kamioka H, Kawanabe N, Kurosaka H, Naruse K, Yamashiro T (2012) In situ imaging of the autonomous intracellular Ca2+ oscillations of osteoblasts and osteocytes in bone. Bone 50:842–852

    Article  CAS  PubMed  Google Scholar 

  86. Jing D, Lu XL, Luo E, Sajda P, Leong PL, Guo XE (2013) Spatiotemporal properties of intracellular calcium signaling in osteocytic and osteoblastic cell networks under fluid flow. Bone 53:531–540

    Article  CAS  PubMed  Google Scholar 

  87. Molen MAV, Donahue HJ, Rubin CT, McLeod KJ (2000) Osteoblastic networks with deficient coupling: differential effects of magnetic and electric field exposure. Bone 27:227–231

    Article  Google Scholar 

  88. Herve JC, Derangeon M, Sarrouilhe D, Giepmans BN, Bourmeyster N (2012) Gap junctional channels are parts of multiprotein complexes. Biochim Biophys Acta 1818:1844–1865

    Article  CAS  PubMed  Google Scholar 

  89. Herve JC, Bourmeyster N, Sarrouilhe D (2004) Diversity in protein–protein interactions of connexins: emerging roles. Biochim Biophys Acta 1662:22–41

    Article  CAS  PubMed  Google Scholar 

  90. Niger C, Hebert C, Stains JP (2010) Interaction of connexin43 and protein kinase C-delta during FGF2 signaling. BMC Biochem 11:14

    Article  PubMed Central  PubMed  Google Scholar 

  91. Jorgensen NR, Teilmann SC, Henriksen Z, Meier E, Hansen SS, Jensen JE, Sorensen OH, Petersen JS (2005) The antiarrhythmic peptide analog rotigaptide (ZP123) stimulates gap junction intercellular communication in human osteoblasts and prevents decrease in femoral trabecular bone strength in ovariectomized rats. Endocrinology 146:4745–4754

    Article  PubMed  Google Scholar 

  92. Axelsen LN, Stahlhut M, Mohammed S, Larsen BD, Nielsen MS, Holstein-Rathlou NH, Andersen S, Jensen ON, Hennan JK, Kjolbye AL (2006) Identification of ischemia-regulated phosphorylation sites in connexin43: a possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123). J Mol Cell Cardiol 40:790–798

    Article  CAS  PubMed  Google Scholar 

  93. Haugan K, Marcussen N, Kjolbye AL, Nielsen MS, Hennan JK, Petersen JS (2006) Treatment with the gap junction modifier rotigaptide (ZP123) reduces infarct size in rats with chronic myocardial infarction. J Cardiovasc Pharmacol 47:236–242

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopaedics, University of Maryland, School of Medicine, 100 Penn Street, Allied Health Building, Room 540E, Baltimore, MD, 21201, USA

    Joseph P. Stains & Carla Hebert

  2. Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, USA

    Marcus P. Watkins, Susan K. Grimston & Roberto Civitelli

Authors
  1. Joseph P. Stains
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcus P. Watkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susan K. Grimston
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carla Hebert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roberto Civitelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph P. Stains.

Additional information

R. C. has a material transfer agreement with Zealand Pharma (Glostrup, Denmark) for the use of gap junction-modifying peptides but receives no honoraria or research funds from Zealand. He receives grant support from Amgen and Pfizer and owns stock in Eli-Lilly, Merck, and Amgen. All other authors state they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stains, J.P., Watkins, M.P., Grimston, S.K. et al. Molecular Mechanisms of Osteoblast/Osteocyte Regulation by Connexin43. Calcif Tissue Int 94, 55–67 (2014). https://doi.org/10.1007/s00223-013-9742-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-013-9742-6

Keywords

Search

Navigation