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Volume 51 Issue 6
Nov.  2020
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LIU Wen-jing, ZHANG De-mao, ZHOU Xue-dong, et al. The Role of Connexins and Pannexins in the Cell Communications of Bone Cells[J]. JOURNAL OF SICHUAN UNIVERSITY (MEDICAL SCIENCE EDITION), 2020, 51(6): 771-776. doi: 10.12182/20201160102
Citation: LIU Wen-jing, ZHANG De-mao, ZHOU Xue-dong, et al. The Role of Connexins and Pannexins in the Cell Communications of Bone Cells[J]. JOURNAL OF SICHUAN UNIVERSITY (MEDICAL SCIENCE EDITION), 2020, 51(6): 771-776. doi: 10.12182/20201160102

The Role of Connexins and Pannexins in the Cell Communications of Bone Cells

doi: 10.12182/20201160102
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  • Corresponding author: E-mail: xiejing@scu.edu.cn
  • Received Date: 2020-06-23
  • Rev Recd Date: 2020-10-30
  • Publish Date: 2020-11-20
  • Connexins and Pannexins play important roles in osteocytes and osteoblasts differentiation, intracellular signal transduction, maintenance of bone balance, and bone regeneration. This article reviews the progress and limitations of Connexins-mediated gap junctions and Pannexins mediated hemichannel in bone. Current research has shown that these molecules, in the form of gap junctions or separate hemichannels, deliver external stimuli to the skeletal system. However, little is known about the role of other cell types in bone development and homeostasis, such as pre-osteoblasts and bone marrow mesenchymal stem cells, in maintaining normality. In addition, at present, the most well-studied member of the Connexins family is Connexin43 (Cx43), while the roles and mechanisms of other members in bone development are still behind the veil. Gene-edited animal models provide basic information on the role of Connexins and Pannexins in the skeletal system, but the similarities and differences between Connexins and Pannexins remain to be discovered. Targeting a specific function of Connexins or Pannexins for bone stimulation and bone disease remains a challenge, with pharmacological selective overlap between channels, compensation of other subtypes, differences in methods for assessing channel function, and genetic changes associated with transgenic mouse models. Therefore, better tools and research pathways are needed to understand the role of these pathways in bone and cartilage. An essential task for future research will be to identify specific compounds that regulate Connexins or Pannexins subtypes to enable them to be used as pharmaceutical agents in the treatment of bone diseases, providing the possibility to develop new therapeutic strategies for improving bone health and treating diseases of the skeletal system.
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  • [1]
    PLOTKIN L I, STAINS J P. Connexins and pannexins in the skeleton: gap junctions, hemichannels and more. Cell Mol Life Sci,2015,72(15): 2853–2867. doi: 10.1007/s00018-015-1963-6
    [2]
    DONAHUE H J, QU R W, GENETOS D C. Joint diseases: from connexins to gap junctions. Nat Rev Rheumatol,2018,14(1): 42–51. doi: 10.1038/nrrheum.2017.204
    [3]
    PLOTKIN L I, DAVIS H M, CISTERNA B A, et al. Connexins and pannexins in bone and skeletal muscle. Curr Osteoporos Rep,2017,15(4): 326–334. doi: 10.1007/s11914-017-0374-z
    [4]
    BRÜCHER B L, JAMALL I S. Cell-cell communication in the tumor microenvironment, carcinogenesis, and anticancer treatment. Cell Physiol Biochem,2014,34(2): 213–243. doi: 10.1159/000362978
    [5]
    KUMAR V, COUSER N L, PANDYA A. Oculodentodigital dysplasia: a case report and major review of the eye and ocular adnexa features of 295 reported cases. Case Rep Ophthalmol Med, 2020, 4: 6535974[2020-05-25]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165356/. doi: 10.1155/2020/6535974.
    [6]
    黄卫民, 张小敏, 陶亮. 细胞缝隙连接与骨及相关疾病研究进展. 新疆医科大学学报,2016,39(11): 1474–1477. doi: 10.3969/j.issn.1009-5551.2016.11.032
    [7]
    ROY S, JIANG J X, LI A F, et al. Connexin channel and its role in diabetic retinopathy. Prog Retin Eye Res,2017,61: 35–59. doi: 10.1016/j.preteyeres.2017.06.001
    [8]
    BEYER E C, BERTHOUD V M. Gap junction gene and protein families: connexins, innexins, and pannexins. Biochim Biophys Acta Biomembr,2018,1860(1): 5–8. doi: 10.1016/j.bbamem.2017.05.016
    [9]
    RODRÍGUEZ-SINOVAS A, RUIZ-MEANA M, DENUC A, et al. Mitochondrial Cx43, an important component of cardiac preconditioning. Biochim Biophys Acta Biomembr,2018,1860(1): 174–181. doi: 10.1016/j.bbamem.2017.06.011
    [10]
    TOTLAND M Z, RASMUSSEN N L, KNUDSEN L M, et al. Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications. Cell Mol Life Sci,2020,77(4): 573–591. doi: 10.1007/s00018-019-03285-0
    [11]
    EPIFANTSEVA I, SHAW R M. Intracellular trafficking pathways of Cx43 gap junction channels. Biochim Biophys Acta Biomembr,2018,1860(1): 40–47. doi: 10.1016/j.bbamem.2017.05.018
    [12]
    HERVE J C, DERANGEON M. Gap-junction-mediated cell-to-cell communication. Cell Tissue Res,2013,352(1): 21–31. doi: 10.1007/s00441-012-1485-6
    [13]
    WILLEBRORDS J, MAES M, CRESPO YANGUAS S, et al. Inhibitors of Connexin and Pannexin channels as potential therapeutics. Pharmacol Ther,2017,180: 144–160. doi: 10.1016/j.pharmthera.2017.07.001
    [14]
    SCEMES E, VELÍŠKOVÁ J. Exciting and not so exciting roles of Pannexins. Neurosci Lett,2019,695: 25–31. doi: 10.1016/j.neulet.2017.03.010
    [15]
    CARPINTERO-FERNANDEZ P, GAGO-FUENTES R, WANG H Z, et al. Intercellular communication via gap junction channels between chondrocytes and bone cells. Biochim Biophysica Acta Biomembr,2018,1860(12): 2499–2505. doi: 10.1016/j.bbamem.2018.09.009
    [16]
    LIU W, ZHANG D, LI X, et al. TGF-β1 facilitates cell-cell communication in osteocytes via Connexin43- and Pannexin1-dependent gap junctions. Cell Death Discov, 2019, 5: 141[2020-05-25]. https://www.nature.com/articles/s41420-019-0221-3. doi: 10.1038/s41420-019-0221-3.
    [17]
    PLOTKIN L I, LAIRD D W, AMEDEE J. Role of Connexins and Pannexins during ontogeny, regeneration, and pathologies of bone. BMC Cell Biol, 2016, 17 (Suppl 1): 19[2020-05-25]. https://bmcmolcellbiol.biomedcentral.com/articles/ 10.1186/s12860-016-0088-6. doi: 10.1186/s12860-016-0088-6.
    [18]
    陈骞, 蒋科, 陈路, 等. 连接蛋白43在骨关节炎发病机制中的研究进展. 川北医学院学报,2016,31(6): 799–804. doi: 10.3969/j.issn.1005-3697.2016.06.006
    [19]
    STAINS J P, CIVITELLI R. Connexins in the skeleton. Semin Cell Dev Biol,2016,50: 31–39. doi: 10.1016/j.semcdb.2015.12.017
    [20]
    PACHECO-COSTA R, DAVIS H M, SORENSON C, 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: 632–643. doi: 10.1016/j.bone.2015.09.011
    [21]
    LIN F X, ZHENG G Z, CHANG B, et al. Connexin 43 modulates osteogenic differentiation of bone marrow stromal cells through gsk-3beta/beta-catenin signaling pathways. Cell Physiol Biochem,2018,47(1): 161–175. doi: 10.1159/000489763
    [22]
    BUO A M, TOMLINSON R E, EIDELMAN E R, et al. Connexin43 and Runx2 interact to affect cortical bone geometry, skeletal development, and osteoblast and osteoclast function. J Bone Miner Res,2017,32(8): 1727–1738. doi: 10.1002/jbmr.3152
    [23]
    WU X T, SUN L W, YANG X, et al. The potential role of spectrin network in the mechanotransduction of MLO-Y4 osteocytes. Sci Rep, 2017, 7: 40940[2020-05-25]. https://www.nature.com/articles/srep40940. doi: 10.1038/srep40940.
    [24]
    PLOTKIN L I, SPEACHT T L, DONAHUE H J. Cx43 and mechanotransduction in bone. Curr Osteoporos Rep,2015,13(2): 67–72. doi: 10.1007/s11914-015-0255-2
    [25]
    BATRA N, RIQUELME M A, BURRA S, et al. Direct regulation of osteocytic Connexin 43 hemichannels through AKT kinase activated by mechanical stimulation. J Biol Chem,2014,289(15): 10582–10591. doi: 10.1074/jbc.M114.550608
    [26]
    RIQUELME M A, BURRA S, KAR R, et al. Mitogen-activated protein kinase (MAPK) activated by prostaglandin E2 phosphorylates Connexin 43 and closes osteocytic hemichannels in response to continuous flow shear stress. J Biol Chem,2015,290(47): 28321–28328. doi: 10.1074/jbc.M115.683417
    [27]
    BUO A M, STAINS J P. Gap junctional regulation of signal transduction in bone cells. FEBS Lett,2014,588(8): 1315–1321. doi: 10.1016/j.febslet.2014.01.025
    [28]
    RIQUELME M A, CARDENAS E R, XU H, et al. The role of Connexin channels in the response of mechanical loading and unloading of bone. Int J Mol Sci, 2020, 21(3): 1146[2020-05-25]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038207/. doi: 10.3390/ijms21031146.
    [29]
    WEI C J, FRANCIS R, XU X, et al. Connexin43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells. J Biol Chem,2005,280(20): 19925–19936. doi: 10.1074/jbc.M412921200
    [30]
    CHUNG D J, CASTRO H M, WATKINS M. 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): 4187–4198.
    [31]
    PACHECO-COSTA R, HASSAN I, REGINATO R D, et al. High bone mass in mice lacking Cx37 because of defective osteoclast differentiation. J Biol Chem,2014,289(12): 8508–8520. doi: 10.1074/jbc.M113.529735
    [32]
    BIVI N, CONDON K W, ALLEN M R, 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): 374–389. doi: 10.1002/jbmr.548
    [33]
    CHAIBLE L M, SANCHES D S, COGLIATI B, et al. Delayed osteoblastic differentiation and bone development in Cx43 knockout mice. Toxicol Pathol,2011,39(7): 1046–1055. doi: 10.1177/0192623311422075
    [34]
    WATKINS M, GRIMSTON S K, NORRIS J Y, et al. Osteoblast Connexin43 modulates skeletal architecture by regulating both arms of bone remodeling. Mol Biol Cell,2011,22(8): 1240–1251. doi: 10.1091/mbc.e10-07-0571
    [35]
    HASHIDA Y, NAKAHAMA K, SHIMIZU K, et al. Communication-dependent mineralization of osteoblasts via gap junctions. Bone, 2014, 61: 19-26[2020-05-25]. https://doi.org/10.1016/j.bone.2013.12.031.
    [36]
    LLOYD S A, LOISELLE A E, ZHANG Y, et al. 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[2020-05-25]. https://bmcmusculoskeletdisord.biomedcentral.com/articles/ 10.1186/1471-2474-15-122. doi: 10.1186/1471-2474-15-122.
    [37]
    SADR-ESHKEVARI P, ASHNAGAR S, RASHAD A, et al. Bisphosphonates and Connexin 43: a critical review of evidence. Cell Commun Adhes,2014,21(5): 241–247. doi: 10.3109/15419061.2014.927869
    [38]
    SMIT M A, VAN KINSCHOT C M J, VAN DER LINDEN J, et al. Clinical guidelines and PTH measurement: does assay generation matter? Endocr Rev,2019,40(6): 1468–1480. doi: 10.1210/er.2018-00220
    [39]
    CHUNG D J, CASTRO C H M, WATKINS M, 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(20): 4187–4198. doi: 10.1242/jcs.03162
    [40]
    RIQUELME M A, CARDENAS E R, XU H, et al. The role of Connexin channels in the response of mechanical loading and unloading of bone. Int J Mol Sci, 2020, 21(3): 1146[2020-05-25]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038207/. doi: 10.3390/ijms21031146.
    [41]
    GRIMSTON S K, BRODT M D, SILVA M J, et al. 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): 879–886. doi: 10.1359/jbmr.080222
    [42]
    LOISELLE A E, PAUL E M, LEWIS G S, et al. Osteoblast and osteocyte-specific loss of Connexin43 results in delayed bone formation and healing during murine fracture healing. J Orthop Res,2013,31(1): 147–154. doi: 10.1002/jor.22178
    [43]
    MA L, HUA R, TIAN Y, et al. Connexin 43 hemichannels protect bone loss during estrogen deficiency. Bone Res, 2019, 7: 11[2020-05-25]. https://www.nature.com/articles/s41413-019-0050-2. doi: 10.1038/s41413-019-0050-2.
    [44]
    XU H Y, GU S M, RIQUELME M A, et al. Connexin 43 channels are essential for normal bone structure and osteocyte viability. J Bone Miner Res,2015,30(3): 436–448. doi: 10.1002/jbmr.2374
    [45]
    CHEN Y, CHEN M, XUE T, et al. Osteocytic Connexin 43 channels affect fracture healing. J Cell Physiol,2019,234(11): 19824–19832. doi: 10.1002/jcp.28581
    [46]
    BOND S R, LAU A, PENUELA S, et al. Pannexin 3 is a novel target for Runx2, expressed by osteoblasts and mature growth plate chondrocytes. J Bone Miner Res,2011,26(12): 2911–2922. doi: 10.1002/jbmr.509
    [47]
    ISHIKAWA M, IWAMOTO T, NAKAMURA T, et al. Pannexin 3 functions as an ER Ca2+ channel, hemichannel, and gap junction to promote osteoblast differentiation. J Cell Biol,2011,193(7): 1257–1274. doi: 10.1083/jcb.201101050
    [48]
    ISHIKAWA M, IWAMOTO T, FUKUMOTO S, et al. Pannexin 3 inhibits proliferation of osteoprogenitor cells by regulating Wnt and p21 signaling. J Biol Chem,2014,289(5): 2839–2851. doi: 10.1074/jbc.M113.523241
    [49]
    HANSTEIN R, NEGORO H, PATEL N K, et al. Promises and pitfalls of a Pannexin1 transgenic mouse line. Front Pharmacol, 2013, 4: 61[2020-05-25]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648696/. doi: 10.3389/fphar.2013.00061.
    [50]
    ISHIKAWA M, YAMADA Y. The role of Pannexin 3 in bone biology. J Dent Res,2017,96(4): 372–379. doi: 10.1177/0022034516678203
    [51]
    IWAMOTO T, NAKAMURA T, DOYLE A, et al. Pannexin 3 regulates intracellular ATP/cAMP levels and promotes chondrocyte differentiation. J Biol Chem,2010,285(24): 18948–18958. doi: 10.1074/jbc.M110.127027
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