Connexin 43 in osteogenesis

REVIEW ARTICLE

Connexin 43 in osteogenesis

Krzysztof Łukowicz 1 , Karolina Fijał 1 , Aleksandra Nowak 1 , Anna M. Osyczka 1

1. Zakład Biologii i Obrazowania Komórki, Instytut Zoologii i Badań Biomedycznych, Wydział Biologii, Uniwersytet Jagielloński w Krakowie,

Published: 2020-09-25
DOI: 10.5604/01.3001.0014.4153
GICID: 01.3001.0014.4153
Available language versions: en pl
Issue: Postepy Hig Med Dosw 2020; 74 : 406-415

 

Abstract

Skeleton formation and its proper functioning is possible thanks to specialized bone tissue cells: bone forming osteoblasts, bone resorbing osteoclasts and osteocytes located in bone cavities. Gap junctions are transmembrane channels connecting neighboring cell. Thanks to gap junctions it is possible for signals to be directly transmitted by cells. Gap junction type channels, and more specifically the connexin proteins that build them, have a key impacton the bone turnover process, and thus on both bone building and remodeling. A particularly important connexin in bone tissue is connexin43 (Cx43), which is necessary in the proper course of the bone formation process and in maintaining bone homeostasis. The importance of the presence of Cx43 in bones is showed by skeletal defects in diseases such as ODD syndrome and craniometaphyseal dysplasia caused by mutations in GJA1, the gene encoding Cx43. The role of Cx43 in the differentiation of stem cells into bone cells, anti-apoptotic action of bisphosphonates and bone responses to hormonal and mechanical stimuli have also been demonstrated. In addition to connexin43, the presence of other connexins such as connexin45, 46 and 37 was also noted in bone tissue.

References

  • 1. Andrzejewska A., Lukomska B., Janowski M.: Concise review:Mesenchymal stem cells: From roots to boost. Stem Cells, 2019;37: 855–864
    Google Scholar
  • 2. Batra N., Kar R., Jiang J.X.: Gap junctions and hemichannels insignal transmission, function and development of bone. Biochim.Biophys. Acta, 2012; 1818: 1909–1918
    Google Scholar
  • 3. Bellido T., Plotkin L.I.: Novel actions of bisphosphonates inbone: preservation of osteoblast and osteocyte viability. Bone,2011; 49: 50–55
    Google Scholar
  • 4. Bivi N., PachecoCosta R., Brun L.R., Murphy T.R., Farlow, N.R.,Robling A.G., Bellido T., Plotkin L.I.: Absence of Cx43 selectivelyfrom osteocytes enhances responsiveness to mechanical force inmice. J. Orthop. Res., 2013; 31 1075–1081
    Google Scholar
  • 5. Bonewald L.F.: The role of the osteocyte in bone and non-bonedisease. Endocrinol. Metab. Clin. North Am., 2017; 46: 1–18
    Google Scholar
  • 6. Bonewald L.F.: The amazing osteocyte. J. Bone. Miner. Res.,2011; 26: 229–238
    Google Scholar
  • 7. Boyden L.M., Craiglow B.G., Zhou J., Hu R., Loring E.C., MorelK.D., Lauren C.T., Lifton R.P., Bilguvar K., Paller A.S., Choate K.A.:Dominant de novo mutations in GJA1 cause erythrokeratodermiavariabilis et progressiva, without features of oculodentodigitaldysplasia. J. Invest. Dermatol., 2015; 135: 1540–1547
    Google Scholar
  • 8. Briot K., Roux C.: Glucocorticoid-induced osteoporosis. RMDOpen, 2015: 1–8
    Google Scholar
  • 9. Brodzikowska A., Wojtowicz A., Galus R., Włodarski K.: Czynnikitranskrypcyjne w regulacji osteoblastogenezy i udział osteoblastóww regulacji osteoklastogenezy. Chir. Narzadow Ruchu Ortop. Pol.,2016; 81: 1–5
    Google Scholar
  • 10. Bruderer M., Richards R.G., Alini M., Stoddart M.J.: Role andregulation of RUNX2 in osteogenesis. Eur. Cell. Mater., 2014; 28:269–286
    Google Scholar
  • 11. Chaible L.M., Sanches D.S., Cogliati B., Mennecier G., Dagli M.L.:Delayed osteoblastic differentiation and bone development in Cx43knockout mice. Toxicol. Pathol., 2011; 39: 1046–1055
    Google Scholar
  • 12. Chen I.P., Wang, L., Jiang X., Aguila H.L., Reichenberger E.J.: APhe377del mutation in ANK leads to impaired osteoblastogenesisand osteoclastogenesis in a mouse model for craniometaphysealdysplasia (CMD). Hum. Mol. Genet., 2011; 20: 948–961
    Google Scholar
  • 13. Chen Y., Xu J., Liao H., Ma Z., Zhang Y., Chen H., Huang Z.,Hu J.: Prostaglandin E2 and Connexin 43 crosstalk in the osteogenesisinduced by extracorporeal shockwave. Med. Hypotheses,2016; 94: 123–125
    Google Scholar
  • 14. Chung D.J., Castro C. H., Watkins M., Stains J. P., Chung M.Y.,Szejnfeld V.L., Willecke K., Theis M., Civitelli R.: Low peak bonemass and attenuated anabolic response to parathyroid hormonein mice with an osteoblast-specific deletion of connexin 43. J. Cell.Sci., 2006, 119: 4187–4198
    Google Scholar
  • 15. Ellison D., Mugler A., Brennan M.D., Lee S.H., Huebner R.J.,Shamir E.R., Woo L.A., Kim J., Amar P., Nemenman I., Ewald A.J.,Levchenko A.: Cell-cell communication enhances the capacity ofcell ensembles to sense shallow gradients during morphogenesis.Proc. Natl. Acad. Sci. USA, 2016; 113: 679–688
    Google Scholar
  • 16. Fakhry M., Hamade E., Badran B., Buchet R., Magne D.: Molecularmechanisms of mesenchymal stem cell differentiation towardsosteoblasts. World J. Stem. Cells., 2013; 5: 136–148
    Google Scholar
  • 17. Florencio-Silva R., Sasso G.R., Sasso-Cerri E., Simões M.J., CerriP.S.: Biology of bone tissue: structure, function, and factors thatinfluence bone cells. Biomed. Res. Int., 2015; 2015: 421746
    Google Scholar
  • 18. Ghayor C., Rey A., Caverzasio J.: Prostaglandin-dependent activationof ERK mediates cell proliferation induced by transforminggrowth factor β in mouse osteoblastic cells. Bone, 2005; 36: 93–100
    Google Scholar
  • 19. Giaume J.A. Sáez J.C.: Role of connexinhemichannels in neurodegeneration.W: Neurodegenerative Diseases-Processes. IntechOpen, red.: Chuen-Chung Chang R. London 2011, 235–254
    Google Scholar
  • 20. Gradowski M., Jankiewicz U., Kowalczyk P.: Human diseasescaused by mutations in genes encoding connexin. Nowa Medycyna.2013; 4: 168–173
    Google Scholar
  • 21. Hu Y., Chen I.P., de Almeida S., Tiziani V., Do Amaral C.M.,Gowrishankar K., Passos-Bueno M.R., Reichenberger E.J.: A novelautosomal recessive GJA1 missense mutation linked to Craniometaphysealdysplasia. PLoS One, 2013; 8: e73576
    Google Scholar
  • 22. Ishikawa M., Williams G. L., Ikeuchi T., Sakai K., Fukumoto S.,Yamada, Y.: Pannexin 3 and connexin 43 modulate skeletal developmentthrough their distinct functions and expression patterns.J. Cell Sci., 2016; 129: 1018–1030
    Google Scholar
  • 23. Katoh M., Katoh M.: Molecular genetics and targeted therapyof WNT-related human diseases. Int. J. Mol. Med., 2017; 40: 587–606
    Google Scholar
  • 24. Kim J.H., Liu J.H., Wang J., Chen X., Zhang H., Kim S.H., Cui J.,Li R., Zhang W., Kong Y., Zhang J., Shui W., Lamplot J., Rogers M.R.,Zhao C. i wsp.: Wnt signaling in bone formation and its therapeuticpotential for bone diseases. Ther. Adv. Musculoskelet Dis.,2013; 5: 13–31
    Google Scholar
  • 25. Koziński K., Dobrzyń, A.: Szlak sygnałowy Wnt i jego rola wregulacji metabolizmu komórki. Postępy Hig. Med. Dośw., 2013;67: 1098–1108
    Google Scholar
  • 26. Kuo S.W., Rimando M.G., Liu Y.S., Lee O.K.: Intermittent administrationof parathyroid hormone 1-34 enhances osteogenesis ofhuman mesenchymal stem cells by regulating protein kinase Cδ.Int. J. Mol. Sci., 2017; 18: 2221
    Google Scholar
  • 27. Laird D.W.: Syndromic and non-syndromic disease-linked Cx43mutations. FEBS Lett., 2014; 588: 1339–1348
    Google Scholar
  • 28. Leithe E., Sirnes S., Fykerud T., Kjenseth A., Rivedal E.: Endocytosisand post-endocytic sorting of connexins. Biochim. Biophys.Acta, 2012; 1818: 1870–1879
    Google Scholar
  • 29. Lin F.X., Zheng G.Z., Chang B., Chen R.C., Zhang Q.H., Xie P., XieD., Yu G.Y., Hu Q.X., Liu D.Z., Du S.X., Li X.D.: Connexin 43 modulatesosteogenic differentiation of bone marrow stromal cells throughGSK-3beta/beta-catenin signaling pathways. Cell. Physiol. Biochem.,2018; 47: 161–175
    Google Scholar
  • 30. Lisowska B., Kosson D., Domaracka K.: Lights and shadows ofNSAIDs in bone healing: the role of prostaglandins in bone metabolism.Drug Des. Devel. Ther., 2018; 12: 1753–1758
    Google Scholar
  • 31. Liu W., Cui Y., Sun J., Cai L., Xie J.N., Zhou, X.: Transforminggrowth factor-β1 up-regulates connexin43 expression in osteocytesvia canonical Smad-dependent signaling pathway. Biosci.Rep., 2018; 38: BSR20181678
    Google Scholar
  • 32. Liu W., Zhang D., Li X., Zheng L., Cui C., Cui Y., Sun J., Xie J., ZhouX.: TGF-β1 facilitates cell-cell communication in osteocytes viaconnexin43-and pannexin1-dependent gap junctions. Cell DeathDiscov., 2019, 5: 141
    Google Scholar
  • 33. Lloyd S.A., Loiselle A.E., Zhang Y., Donahue H.J.: Shifting paradigmson the role of connexin43 in the skeletal response to mechanicalload. J. Bone Miner. Res., 2014; 29: 275–286
    Google Scholar
  • 34. Lohman A.W., Isakson B.E.: Differentiating connexin hemichannelsand pannexin channels in cellular ATP release. FEBS Lett.,2014; 588: 1379–1388
    Google Scholar
  • 35. Loiselle A.E., Jiang J.X., Donahue H.J.: Gap junction andhemichannel functions in osteocytes. Bone, 2013; 54: 205–212
    Google Scholar
  • 36. Loiselle A.E., Paul E.M., Lewis G.S., Donahue H.J.: Osteoblastand osteocyte‐specific loss of Connexin43 results in delayed boneformation and healing during murine fracture healing. J. Orthop.Res., 2013; 31: 147–154
    Google Scholar
  • 37. Long F.: Building strong bones: molecular regulation of theosteoblast lineage. Nat. Rev. Mol. Cell. Biol., 2012; 13: 27–38
    Google Scholar
  • 38. Martin K., Nathwani S., Bunyan R.: Craniometaphyseal dysplasia:A review and novel oral manifestation. J. Oral. Biol. Craniofac.Res., 2017; 2: 134–136
    Google Scholar
  • 39. Maxhimer J.B., Bradley J.P., Lee J.C.: Signaling pathways in osteogenesisand osteoclastogenesis: Lessons from cranial sutures andapplications to regenerative medicine. Genes Dis., 2015; 2: 57–68
    Google Scholar
  • 40. Moorer M.C., Stains J.P.: Connexin43 and the intercellular signalingnetwork regulating skeletal remodeling. Curr. Osteoporos.Rep., 2017; 15: 24–31
    Google Scholar
  • 41. Mu C., Lv T, Wang Z., Ma S., Ma J., Liu J., Yu J., Mu J.: Mechanicalstress stimulates the osteo/odontoblastic differentiation ofhuman stem cells from apical papilla via erk 1/2 and JNK MAPKpathways. Biomed. Res. Int., 2014; 2014: 494376
    Google Scholar
  • 42. Oshima A.: Structure and closure of connexin gap junctionchannels. FEBS Lett., 2014; 588: 1230–1237 43 Pace N.P., Benoit V., Agius D., Grima M.A., Parascandalo R.,Hilbert P., Borg I.: Two novel GJA1 variants in oculodentodigitaldysplasia. Mol. Genet. Genomic Med., 2019; 7: 882
    Google Scholar
  • 43. Calcif Tissue Int., 2014; 94: 55–67
    Google Scholar
  • 44. Pacheco-Costa R., Davis H.M., Sorenson C., Hon M.C., HassanI., Reginato R.D., Allen M.R.,, Bellido T., Plotkin L.I.: Defective cancellousbone structure and abnormal response to PTH in corticalbone of mice lacking Cx43 cytoplasmic C-terminus domain. Bone,2015; 81: 632–643
    Google Scholar
  • 45. Pacheco-Costa R., Hassan I., Reginato R.D., Davis H.M., BruzzanitiA., Allen M.R., Plotkin L.I.: High bone mass in mice lackingCx37 because of defective osteoclast differentiation. J. Biol. Chem.,2014; 289: 8508–8520
    Google Scholar
  • 46. Pazianas M., van der Geest S., Miller P.: Bisphosphonates andbone quality. Bonekey Rep., 2014; 3: 529
    Google Scholar
  • 47. Plotkin L.I.: Connexin 43 hemichannels and intracellular signalingin bone cells. Front. Physiol., 2014, 5: 131
    Google Scholar
  • 48. Plotkin L.I., Laird D.W., Amedee J.: Role of connexins and pannexinsduring ontogeny, regeneration, and pathologies of bone.BMC Cell Biol., 2016; 17: 19
    Google Scholar
  • 49. Plotkin L.I., Manolagas S.C., Bellido T.: Transduction of cellsurvival signals by connexin-43 hemichannels. J. Biol. Chem., 2002;277: 8648–8657
    Google Scholar
  • 50. Plotkin L.I., Speacht T.L., Donahue H.J.: Cx43 and mechanotransductionin bone. Curr. Osteoporos. Rep., 2015; 13: 67–72
    Google Scholar
  • 51. Rahman M.S., Akhtar N., Jamil H.M., Banik R.S., AsaduzzamanS.M.: TGF-β/BMP signaling and other molecular events: regulationof osteoblastogenesis and bone formation. Bone Res., 2015; 3: 15005
    Google Scholar
  • 52. Ribeiro-Rodrigues T.M., Martins-Marques T., Morel S., KwakB.R., Girão H.: Role of connexin 43 in different forms of intercellularcommunication–gap junctions, extracellular vesicles and tunnellingnanotubes. J. Cell. Sci., 2017; 130: 3619–3630
    Google Scholar
  • 53. Rodríguez-Carballo E., Gámez B., Ventura, F.: p38 MAPK signalingin osteoblast differentiation. Front. Cell. Dev. Biol., 2016, 4: 40
    Google Scholar
  • 54. Rutkowski R., Kosztyła-Hojna B., Kańczuga-Koda L., SulkowskaM., Sulkowski S., Rutkowski K., Bronchoskopii S.P.: Struktura ifizjologiczna funkcja białek koneksynowychStructure and physiologicalfunctionof connexinproteins. Postępy Hig. Med. Dośw.,2008; 62: 632–641
    Google Scholar
  • 55. Sadr-Eshkevari P., Ashnagar S., Rashad A., Dietz M., JackowskiJ., Abdulazim A., Prochnow N.: Bisphosphonates and connexin 43: acritical review of evidence. Cell Commun. Adhes., 2014; 21: 241–247
    Google Scholar
  • 56. Savopoulos C., Dokos C., Kaiafa G., Hatzitolios A.: Adipogenesisand osteoblastogenesis: trans-differentiation in the pathophysiologyof bone disorders. Hippokratia, 2011; 15: 18–21
    Google Scholar
  • 57. Singh S., Qin C., Medarametla S., Hegde S.V.: Craniometaphysealdysplasia in a 14-month old: a case report and review of imagingdifferential diagnosis. Radiol. Case Rep., 2016; 11: 260–265
    Google Scholar
  • 58. Sinha K.M., Zhou X.: Genetic and molecular control of osterixin skeletal formation. J. Cell. Biochem., 2013; 114: 975–984
    Google Scholar
  • 59. Stains J.P., Civitelli R.: Connexins in the skeleton. Semin. Cell.Dev. Biol., 2016; 50: 31–39
    Google Scholar
  • 60. Stains J.P., Watkins M.P., Grimston S.K., Hebert C., Civitelli R.Molecular mechanisms of osteoblast/osteocyte regulation by connexin
    Google Scholar
  • 61. Ton Q.V., Iovine M.K.: Determining how defects in connexin43cause skeletal disease. Genesis, 2013; 51: 75–82
    Google Scholar
  • 62. Tu X., Rhee Y., Condon K., Bivi N., Allen M.R., Dwyer D., StolinaM., Turner C.H., Robling A.G., Plotkin L.I., Bellido T.: Sost downregulationand local Wnt signaling are required for the osteogenicresponse to mechanical loading. Bone, 2012; 50: 209–217
    Google Scholar
  • 63. Vazquez M., Evans B.A., Riccardi D., Evans S.L., Ralphs J.R.,Dillingham C.M., Mason D.J.: A new method to investigate howmechanical loading of osteocytes controls osteoblasts. Front. Endocrinol.,2014; 5: 208
    Google Scholar
  • 64. Verheule S., Kaese S.: Connexin diversity in the heart: insightsfrom transgenic mouse models. Front. Pharmacol., 2013; 4: 81
    Google Scholar
  • 65. Watkins M., Grimston S.K., Norris J.Y., Guillotin B., Shaw A.,Beniash E., Civitelli R.: Osteoblast connexin43 modulates skeletalarchitecture by regulating both arms of bone remodeling. Mol.Biol. Cell., 2011; 22: 1240–1251
    Google Scholar
  • 66. Wheater G., Elshahaly M., Tuck S.P., Datta H.K., van Laar J.M.:The clinical utility of bone marker measurements in osteoporosis.J. Transl. Med., 2013; 11: 201
    Google Scholar
  • 67. Witkowska-Zimny M., Wróbel E., Przybylski J.: Najważniejszeczynniki transkrypcyjne procesu osteoblastogenezy. Postępy Biol.Kom., 2009; 36: 695–705
    Google Scholar
  • 68. Wróbel E., Leszczynska J., Przybylski J.: Rola połączeń typuGap w komórkach tkanki kostnej. Postępy Biochem., 2011; 57: 4
    Google Scholar
  • 69. Wu J., Zhang W., Ran Q., Xiang Y., Zhong J.F., Li S.C., Li Z.: Thedifferentiation balance of bone marrow mesenchymal stem cellsis crucial to hematopoiesis. Stem Cells Int., 2018; 2018: 1540148
    Google Scholar
  • 70. Wu M., Chen G., Li Y.P.: TGF-β and BMP signaling in osteoblast,skeletal development, and bone formation, homeostasis and disease.Bone Res., 2016; 4: 16009
    Google Scholar
  • 71. Xu X.L., Gou W.L., Wang A.Y., Wang Y., Guo Q.Y., Lu Q., Lu S.B.,Peng J.: Basic research and clinical applications of bisphosphonatesin bone disease: what have we learned over the last 40 years? J.Transl. Med., 2013, 11: 303
    Google Scholar
  • 72. Zhang Y., Paul E.M., Sathyendra V., Davison A., Sharkey N.,Bronson S., Srinivasan S., Gross T.S., Donahue H.J.: Enhanced osteoclasticresorption and responsiveness to mechanical load in gapjunction deficient bone. PLoS One, 2011; 6: 23516
    Google Scholar
  • 73. Zhang Y.D., Zhao S.C., Zhu Z.S., Wang Y.F., Liu J.X., Zhang Z.C.,Xue F.: Cx43-and smad-mediated TGF-β/BMP signaling pathwaypromotes cartilage differentiation of bone marrow mesenchymalstem cells and inhibits osteoblast differentiation. Cell. Physiol.Biochem., 2017; 42: 1277–1293
    Google Scholar

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