Connexin 43 hemichannels and intracellular signaling in bone cells

Plotkin, Lilian I.

doi:10.3389/fphys.2014.00131

Cited by 66Connexins and lens biologyBone Metabolism and DiseasesExtracellular vesicles in disease

Connexin 43 hemichannels and intracellular signaling in bone cells

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Plotkin, Lilian I.·2014·Frontiers in Physiology

DOI 10.3389/fphys.2014.00131PMC PMC3983496

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Abstract

Cell function and survival are controlled by intracellular signals, and modulated by surrounding cells and the extracellular environment. Connexin channels participate in these processes by mediating cell-to-cell communication. In bone cells, gap junction channels were detected in the early 1970s, and are present among bone resorbing osteoclasts, bone forming osteoblasts, and osteocytes - mature osteoblasts embedded in the mineralized matrix. These channels are composed mainly by Cx43, although the expression of other connexins (45, 46, and 37) has also been reported. It is now believed that undocked Cx43 hemichannels (connexons) formed in unopposed cell membranes facing the extracellular environment participate in the interaction of bone cells with the extracellular environment, and in their communication with neighboring cells. Thus, we and others demonstrated the presence of active hemichannels in osteoblastic and osteocytic cells. These hemichannels open in response to pharmacological and mechanical stimulation. In particular, preservation of the viability of osteoblasts and osteocytes by the anti-osteoporotic drugs bisphosphonates depends on Cx43 expression in vitro and in vivo, and is mediated by undocked hemichannels. Cx43 hemichannels are also required for the release of prostaglandins and ATP by osteocytes, and for cell survival induced by mechanical stimulation in vitro. Moreover, they are required for the anti-apoptotic effect of parathyroid hormone in osteoblastic cells. This review summarizes the current knowledge on the presence and function of undocked connexons, and the role of hemichannel regulation for the maintenance of bone cell viability and, potentially, bone health.

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Disruption in cell-to-cell communication between osteocytes may induce release of local proosteoclastogenic cytokines.
“In addition, an increase in RANKL/OPG ratio expressed by osteocytes was also observed in connexin43-deficient rats, suggesting that a disruption in cell-to-cell communication between osteocytes may induce the release of local proosteoclastogenic cytokines [33, 196, 197].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [197]
In connexin43-deficient rats, osteocytes show increased RANKL/OPG ratio.
“In addition, an increase in RANKL/OPG ratio expressed by osteocytes was also observed in connexin43-deficient rats, suggesting that a disruption in cell-to-cell communication between osteocytes may induce the release of local proosteoclastogenic cytokines [33, 196, 197].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [197]

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BackgroundMethodInfluential
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BackgroundInfluentialSelf-citation
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BackgroundInfluentialSelf-citation
Connexin43 mediates direct intercellular communication in human osteoblastic cell networks.
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Background
Connexin 43 Is Required for the Anti-Apoptotic Effect of Bisphosphonates on Osteocytes and Osteoblasts In Vivo
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Background
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Background
Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43
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Cyclic Stretch Enhances Gap Junctional Communication Between Osteoblastic Cells
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BackgroundMethod
Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts/osteocytes with novel analogs
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BackgroundSelf-citation
Beyond gap junctions: Connexin43 and bone cell signaling
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Gap junctions in skeletal development and function
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BackgroundMethodInfluential
Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling
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Background
A Novel Ligand-independent Function of the Estrogen Receptor Is Essential for Osteocyte and Osteoblast Mechanotransduction
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Background
Gap Junctional Intercellular Communication Contributes to Hormonal Responsiveness in Osteoblastic Networks
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Background
Absence of Cx43 selectively from osteocytes enhances responsiveness to mechanical force in mice
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Some Oculodentodigital Dysplasia-Associated Cx43 Mutations Cause Increased Hemichannel Activity in Addition to Deficient Gap Junction Channels
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Background
Gap junctions and fluid flow response in MC3T3-E1 cells
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An ultrastructural study of bone cells: The occurrence of microtubules, microfilaments and tight junctions
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“…Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive MS 5035, Indianapolis, IN 46202-5120, USA e-mail: lplotkin@iupui.edu Cell function and survival are controlled by intracellular signals, and modulated by surrounding cells and the extracellular environment.”
Background
Gap junction and hemichannel functions in osteocytes
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Direct Regulation of Osteocytic Connexin 43 Hemichannels through AKT Kinase Activated by Mechanical Stimulation
Batra, N. R., Riquelme, M. A., Burra, S., Kar, R., Gu, S., & Jiang, J. X. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.550608 · Cited by 88 · cited 1× · see citing works
“Thus, Cx43 interacts with α5β1 integrin, an interaction enhanced by mechanical stimulation (Batra et al., 2012, 2014).”
Background
Dual Mechanism of Intercellular Communication in HOBIT Osteoblastic Cells: A Role for Gap-Junctional Hemichannels
Romanello, M., & D’Andrea, P. (2001) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2001.16.8.1465 · Cited by 85 · cited 1× · see citing works
“Scale bar indicates 50 μm. osteoblastic cells was not reported until 2001 (Romanello and D’Andrea, 2001).”
Background
Connexin 43 deficiency desensitizes bone to the effects of mechanical unloading through modulation of both arms of bone remodeling
Lloyd, S. A., Loiselle, A. E., Zhang, Y., & Donahue, H. J. (2013) · Bone · doi:10.1016/j.bone.2013.07.022 · Cited by 82 · cited 2× · see citing works
“This research was supported by National Institutes of Health (R01-AR053643) and by a Biomedical Research Grant and a Developing Diverse Researchers with InVestigative Expertise (DRIVE) Grant from Indiana University School of Medicine.”
MethodResult
Enhanced Periosteal and Endocortical Responses to Axial Tibial Compression Loading in Conditional Connexin43 Deficient Mice
Grimston, S. K., Watkins, M. P., Brodt, M. D., Silva, M. J., & Civitelli, R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044222 · Cited by 81 · cited 2× · see citing works
“On the contrary, removal of Cx43 from osteoblasts and/or osteocytes results in increased anabolic response to mechanical stimulation of osteoblast on the periosteal bone surface (Zhang et al., 2011; Grimston et al., 2012; Bivi et al., 2013).”
Background
A bisphosphonate that does not affect osteoclasts prevents osteoblast and osteocyte apoptosis and the loss of bone strength induced by glucocorticoids in mice
Plotkin, L. I., Bivi, N., & Bellido, T. (2010) · Bone · doi:10.1016/j.bone.2010.08.011 · Cited by 79 · see citing works
Self-citation
The effects of spinal cord injury and exercise on bone mass: A literature review
Dolbow, D. R., Gorgey, A. S., Daniels, J. A., Adler, R. A., Moore, J. R., & Gater, D. R. (2011) · Neurorehabilitation · doi:10.3233/nre-2011-0702 · Cited by 77 · cited 2× · see citing works
“The requirement of connexins, and in particular Cx43, for bone cell differentiation and function, as well as for the response of the cells to bone-acting stimuli has been clearly established in vitro and in vivo.”
Background
Functional Expression in Xenopus Oocytes of Gap-junctional Hemichannels Formed by a Cysteine-less Connexin 43
Bao, X., Chen, Y., Reuss, L., & Altenberg, G. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311438200 · Cited by 67 · cited 1× · see citing works
“A similar result is obtained by transfecting a Cx43 mutant in which cysteine residues of the extracellular domain have been mutated, rendering it unable to dock with other connexin molecules to form gap junction channels (Bao et al., 2004).”
Background
Connexin43 interacts with βarrestin: A pre-requisite for osteoblast survival induced by parathyroid hormone
Bivi, N., Lezcano, V., Romanello, M., Bellido, T., & Plotkin, L. I. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.23208 · Cited by 66 · see citing works
Self-citation
High Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiation
Pacheco‐Costa, R., Hassan, I., Reginato, R. D., Davis, H. M., Bruzzaniti, A., Allen, M. R., & Plotkin, L. I. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.529735 · Cited by 65 · cited 1× · see citing works
“In particular, Cx37 is required for osteoclast differentiation and mice lacking Cx37 exhibit high bone mass due to defective bone resorption (Pacheco-Costa et al., 2014).”
BackgroundSelf-citation
Deletion of Cx43 from Osteocytes Results in Defective Bone Material Properties but Does Not Decrease Extrinsic Strength in Cortical Bone
Bivi, N., Nelson, M. T., Faillace, M. E., Li, J., Miller, L. M., & Plotkin, L. I. (2012) · Calcified Tissue International · doi:10.1007/s00223-012-9628-z · Cited by 64 · see citing works
Self-citation
Molecular Mechanisms of Osteoblast/Osteocyte Regulation by Connexin43
Stains, J. P., Watkins, M. P., Grimston, S. K., HEBERT, C. A., & Civitelli, R. (2013) · Calcified Tissue International · doi:10.1007/s00223-013-9742-6 · Cited by 61 · cited 1× · see citing works
“The small molecules that are transferred through connexin channels, and might act as second messengers in bone cells have not been completely identified (see Stains et al., 2014 for a recent revision).”
Background
Space Flight and the Skeleton: Lessons for the Earthbound
Bikle, D. D., Halloran, B. P., & Morey-Holton, E. R. (1997) · The Endocrinologist · doi:10.1097/00019616-199707010-00003 · Cited by 57 · see citing works
Delayed Osteoblastic Differentiation and Bone Development in Cx43 Knockout Mice
Chaible, L. M., Sanches, D. S., Cogliati, B., Mennecier, G., & Dagli, M. L. (2011) · Toxicologic Pathology · doi:10.1177/0192623311422075 · Cited by 49 · cited 1× · see citing works
“The expression of Cx45, Cx46 and, more recently, Cx37 has also been demonstrated in bone cells (Kruger et al., 2000; Stains and Civitelli, 2005; Paic et al., 2009; Chaible et al., 2011; PachecoCosta et al., 2014).”
Background
Connexin43 and Pannexin1 Channels in Osteoblasts: Who Is the “Hemichannel”?
Thi, M. M., Islam, S., Suadicani, S. O., & Spray, D. C. (2012) · The Journal of Membrane Biology · doi:10.1007/s00232-012-9462-2 · Cited by 47 · cited 2× · see citing works
“Other authors have postulated, however, that P2X7 receptors (Li et al., 2005) and/or pannexin1 (Thi et al., 2012) are involved in the release of PGE2 induced by mechanical stimulation in bone cells.”
BackgroundMethod
Mechanisms of Exercise Effects on Bone
Marcus, R. (2002) · Elsevier eBooks · doi:10.1016/b978-012098652-1.50188-8 · Cited by 47 · cited 2× · see citing works
“The requirement of connexins, and in particular Cx43, for bone cell differentiation and function, as well as for the response of the cells to bone-acting stimuli has been clearly established in vitro and in vivo.”
Background
The regulation of runt-related transcription factor 2 by fibroblast growth factor-2 and connexin43 requires the inositol polyphosphate/protein kinase Cδ cascade
Niger, C., Luciotti, M. A., Buo, A. M., HEBERT, C. A., Ma, V., & Stains, J. P. (2013) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1867 · Cited by 46 · cited 1× · see citing works
“…induced by parathyroid hormone requires Cx43 expression in osteoblastic cells (Vander Molen et al., 1996; Bivi et al., 2011), and Cx43-mediated amplification of FGF2 effect on the osteoblast gene RUNX2 depends on the production of water-soluble inositol polyphosphates (Niger et al., 2013).”
Background
17β Estradiol regulation of connexin 43-based gap junction and mechanosensitivity through classical estrogen receptor pathway in osteocyte-like MLO-Y4 cells
Ren, J., Wang, X.-H., Wang, G.-C., & Wu, J. (2012) · Bone · doi:10.1016/j.bone.2012.12.004 · Cited by 40 · cited 5× · see citing works
“We found that bisphosphonates protect osteoblasts and osteocytes from apoptosis induced by several agents (Figure 2A) in vitro using osteoblastic cell isolated from neonatal calvaria bone and osteocytic MLO-Y4 cells, and by glucocorticoid excess in vivo using a mouse model of glucocorticoid-induced bone disease Fronti…”
BackgroundInfluential
14-3-3θ Facilitates plasma membrane delivery and function of mechanosensitive connexin 43 hemichannels
Batra, N. R., Riquelme, M. A., Burra, S., & Jiang, J. X. (2013) · Journal of Cell Science · doi:10.1242/jcs.133553 · Cited by 40 · cited 2× · see citing works
“This research was supported by National Institutes of Health (R01-AR053643) and by a Biomedical Research Grant and a Developing Diverse Researchers with InVestigative Expertise (DRIVE) Grant from Indiana University School of Medicine.”
BackgroundMethod
Bisphosphonates improve trabecular bone mass and normalize cortical thickness in ovariectomized, osteoblast connexin43 deficient mice
Watkins, M. P., Norris, J. Y., Grimston, S. K., Zhang, X., Phipps, R. J., Ebetino, F. H., & Civitelli, R. (2012) · Bone · doi:10.1016/j.bone.2012.06.018 · Cited by 38 · see citing works
Allelotype analysis of uterine leiomyoma: Localization of a potential tumor suppressor gene to a 4-cM region of chromosome 7q
van der Heijden, O., Chiu, H.-C., Park, T.-C., Takahashi, H., LiVolsi, V. A., Risinger, J. I., Barrett, J. C., Berchuck, A., Evans, A. C., Behbakht, K., et al. (1998) · Molecular Carcinogenesis · doi:10.1002/(sici)1098-2744(199812)23:4 · Cited by 36 · see citing works
Bone Cells
Bellido, T., Plotkin, L. I., & Bruzzaniti, A. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-416015-6.00002-2 · Cited by 33 · cited 1× · see citing works
“Scale bar indicates 5 μm (C) Scanning electron microscope image of an acid-etched bone showing two osteocytes highly communicated through their cytoplasmic projections (Bellido et al., 2014).”
BackgroundSelf-citation
Protein phosphatase modulation of the intercellular junctional communication: Importance in cardiac myocytes
Hervé, J., & Sarrouilhe, D. (2005) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2005.06.005 · Cited by 32 · cited 2× · see citing works
“…(Morelli et al., 2011) Changes in the phosphorylation status of Cx43 C-terminus tail are associated with channel activity (reviewed in Herve and Sarrouilhe, 2006), suggesting that bisphosphonates might induce opening of Cx43 hemichannels thought their interaction with membrane bound…”
Background
Role of connexin 43 in the mechanism of action of alendronate: Dissociation of anti-apoptotic and proliferative signaling pathways
Lezcano, V., Bellido, T., Plotkin, L. I., Boland, R., & Morelli, S. (2012) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2011.12.022 · Cited by 32 · cited 1× · see citing works
“However, we found that bisphosphonates not only bind to cells that express Cx43 but also to Cx43-deficient cells (Lezcano et al., 2012).”
BackgroundSelf-citation
Protein phosphatases: Possible bisphosphonate binding sites mediating stimulation of osteoblast proliferation
Morelli, S. R., Bilbao, P., Katz, S., Lezcano, V., Ej, R., Boland, R., & Santillán, G. E. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.12.013 · Cited by 31 · cited 1× · see citing works
“Furthermore, these substrates inhibit the anti-apoptotic effect of bisphosphonates (Morelli et al., 2011) Changes in the phosphorylation status of Cx43 C-terminus tail are associated with channel activity (reviewed in Herve and Sarrouilhe, 2006), suggesting that bisphosphonates might induce opening…”
Background
Mechanosensitivity and intercellular communication in HOBIT osteoblastic cells: A possible role for gap junction hemichannels
Romanello, M., Veronesi, V., & D’Andrea, P. (2003) · Biorheology · doi:10.1177/0006355x2003040001003018 · Cited by 25 · cited 2× · see citing works
“However, based on previous studies showing that mechanical stimulation increases hemichannel opening in osteoblastic cells in vitro (Romanello et al., 2003), work from Jiang’s group demonstrated that PGE2 released induced by mechanical stimulation requires opening of Cx43 hemichannels in osteocytic…”
BackgroundMethod
Spaceflight and the skeleton: lessons for the earthbound.
Bikle, D. D., Halloran, B. P., & Morey-Holton, E. R. (1997) · PubMed · Cited by 22 · see citing works

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Bellido T. Plotkin L. I. Bruzzaniti A. (2014). Bone cells in Basic and Applied Bone Biology, eds Burr D. B. Allen M. R. (Academic Press/Elsevier), 27– 45

Sorted by citations

Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells
Florencio-Silva, R., Sasso, G. R. D. S., Sasso-Cerri, E., Simões, M. J., & Cerri, P. S. (2015) · BioMed Research International · doi:10.1155/2015/421746 · Cited by 2,044 · see citing works
“In addition, an increase in RANKL/OPG ratio expressed by osteocytes was also observed in connexin43-deficient rats, suggesting that a disruption in cell-to-cell communication between osteocytes may induce the release of local proosteoclastogenic cytokines [33, 196, 197].”
Background
Bone physiology as inspiration for tissue regenerative therapies
Lopes, D., Martins‐Cruz, C., Oliveira, M. B., & Mano, J. F. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.09.028 · Cited by 438 · see citing works
The connexin 43 C-terminus: A tail of many tales
Leithe, E., Mesnil, M., & Aasen, T. (2017) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2017.05.008 · Cited by 208 · see citing works
Targeting strategies for bone diseases: signaling pathways and clinical studies
Xu, H., Wang, W., Liu, X., Huang, W. H., Chen, Z., Xu, Y., Yang, H., Bai, J., & Geng, D. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01467-8 · Cited by 173 · see citing works
“Mechanistically, CX43 gap junctions account for intercellular communication, and CX43 hemichannels are responsible for signal and mediator exchange with the extracellular bone matrix, which is fundamental for the maintenance of dendrite network function.(59) Impairment of CX43 expression induced by aging, estrogen def…”
Background
Porous nanofibrous poly(l-lactic acid) scaffolds supporting cardiovascular progenitor cells for cardiac tissue engineering
Liu, Q., Tian, S., Zhao, C., Chen, X., Lei, I., Wang, Z., & Ma, P. X. (2015) · Acta Biomaterialia · doi:10.1016/j.actbio.2015.08.017 · Cited by 111 · see citing works
“As gap junctions are essential for many physiological processes, increased expression of connexin 43 with increasing 3D culture time indicated that these cells on the NF matrix were robust enough to communicate with one another for tissue construction [38, 39].”
Background
Osteocytic connexin hemichannels suppress breast cancer growth and bone metastasis
Zhou, J., Riquelme, M. A., Gu, S., Kar, R., Gao, X., Sun, L., & Jiang, J. X. (2016) · Oncogene · doi:10.1038/onc.2016.101 · Cited by 101 · see citing works
“Cx43 hemichannels are permeable to ATP in osteocytes, astrocytes and other types of cells 13 , 58 , 59 , 60 .”
Diseases associated with leaky hemichannels
Retamal, M. A., Reyes, E. P., GarcÃa, I. E., Pinto, B. I., MartÃnez, A. D., & GonzÃ¡lez, C. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00267 · Cited by 92 · see citing works
“, 2014b), and bone cell physiology and pathology (Plotkin, 2014).”
Background
A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction
Sato, T., Verma, S., Andrade, C. D. C., Omeara, M., Campbell, N., Wang, J. S., Cetinbas, M., Lang, A., Ausk, B. J., Brooks, D. J., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17099-3 · Cited by 86 · see citing works
Biological Events in Periodontal Ligament and Alveolar Bone Associated with Application of Orthodontic Forces
Feller, L., Khammissa, R. A. G., Schechter, I., Thomadakis, G., Fourie, J., & Lemmer, J. (2015) · The Scientific World JOURNAL · doi:10.1155/2015/876509 · Cited by 75 · see citing works
“A gap junction is a channel connecting the cytoplasm of two adjacent cells, which allows the passage of ions, metabolites, and small signalling molecules such as ATP and Ca2+ [34].”
BackgroundInfluential
Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation
Moorer, M. C., HEBERT, C. A., Tomlinson, R. E., Iyer, S. R., Chason, M., & Stains, J. P. (2017) · Journal of Cell Science · doi:10.1242/jcs.197285 · Cited by 71 · see citing works
“Another mechanism contributing to the cortical phenotype of Cx43 deficiency is osteocyte apoptosis (Plotkin, 2014).”
Background
Connexins and Pannexins in Bone and Skeletal Muscle
Plotkin, L. I., Davis, H. M., Cisterna, B. A., & Sáez, J. C. (2017) · Current Osteoporosis Reports · doi:10.1007/s11914-017-0374-z · Cited by 49 · see citing works
Self-citation
Connexin43 and Runx2 Interact to Affect Cortical Bone Geometry, Skeletal Development, and Osteoblast and Osteoclast Function
Buo, A. M., Tomlinson, R. E., Eidelman, E. R., Chason, M., & Stains, J. P. (2017) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3152 · Cited by 49 · see citing works
“Cx43 acts through both direct gap junctional communication and by unopposed Cx43 hemichannels to regulate osteoblast differentiation, bone mass accrual, and bone remodeling.((4,5)) Mutations in the Cx43 gene GJA1 have been linked to the clinical hereditary disorders oculodentodigital dysplasia (ODDD) and craniometaphy…”
Background
Connexin channel and its role in diabetic retinopathy
Roy, S., Jiang, J. X., Li, A.-F., & Kim, D. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.06.001 · Cited by 48 · see citing works
“Bone formation and remodeling is influenced by hemichannels that facilitate transmission of signals elicited by mechanical stimulation to other bone cells and the extracellular matrix (for review, see (Jiang et al., 2007; Plotkin, 2014)).”
Background
Connexin 43 hemichannels protect bone loss during estrogen deficiency
Ma, L., Hua, R., Tian, Y., Cheng, H., Fajardo, R. J., Pearson, J. J., Guda, T., Shropshire, D. B., Gu, S., & Jiang, J. X. (2019) · Bone Research · doi:10.1038/s41413-019-0050-2 · Cited by 48 · see citing works
Osteoporosis-decreased extracellular matrix stiffness impairs connexin 43-mediated gap junction intercellular communication in osteocytes
Zhang, D., Li, X., Pi, C., Cai, L., Liu, Y., Du, W. T., Yang, W., & Xie, J. (2020) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmaa025 · Cited by 45 · see citing works
Connexin Gap Junctions and Hemichannels Link Oxidative Stress to Skeletal Physiology and Pathology
Hua, R., Zhang, J., Riquelme, M. A., & Jiang, J. X. (2021) · Current Osteoporosis Reports · doi:10.1007/s11914-020-00645-9 · Cited by 43 · see citing works
Gap junction channels as potential targets for the treatment of major depressive disorder
Ren, Q., Wang, Z., Chu, S., Xia, C., & Chen, N. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4782-7 · Cited by 41 · see citing works
Connexin 43: a New Therapeutic Target Against Chronic Kidney Disease
Prakoura, N., Kavvadas, P., & Chadjichristos, C. E. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000493230 · Cited by 42 · see citing works
Connexin43 enhances the expression of osteoarthritis-associated genes in synovial fibroblasts in culture
Gupta, A., Niger, C., Buo, A. M., Eidelman, E. R., Chen, R. J., & Stains, J. P. (2014) · BMC Musculoskeletal Disorders · doi:10.1186/1471-2474-15-425 · Cited by 39 · see citing works
“Cx43 can function as unopposed hemichannels in articular cartilage [8,51,52], and the mechanisms that govern signal transduction in the context of classic cell-to-cell communication through gap junctions are likely different than with hemichannels [53].”
Communication of cAMP by connexin43 gap junctions regulates osteoblast signaling and gene expression
Gupta, A., Anderson, H., Buo, A. M., Moorer, M. C., Ren, M., & Stains, J. P. (2016) · Cellular Signalling · doi:10.1016/j.cellsig.2016.04.014 · Cited by 39 · see citing works
Osteogenic differentiation capacity of human mesenchymal stromal cells in response to extracellular calcium with special regard to connexin 43
Wagner, A., Glenske, K., Wolf, V., Fietz, D., Mazurek, S., Hanke, T., Moritz, A., Arnhold, S., & Wenisch, S. (2016) · Annals of Anatomy - Anatomischer Anzeiger · doi:10.1016/j.aanat.2016.09.005 · Cited by 36 · see citing works
Connexin43-containing gap junctions potentiate extracellular Ca2+-induced odontoblastic differentiation of human dental pulp stem cells via Erk1/2
Li, S., He, H., Zhang, G., Wang, F., Zhang, P., & Tan, Y. (2015) · Experimental Cell Research · doi:10.1016/j.yexcr.2015.09.008 · Cited by 31 · see citing works
Glucocorticoid Suppresses Connexin 43 Expression by Inhibiting the Akt/mTOR Signaling Pathway in Osteoblasts
Shen, C., Kim, J.-H., Noh, J. M., Kim, S. J., Ka, S., Kim, J. H., Park, B., & Park, J. H. (2016) · Calcified Tissue International · doi:10.1007/s00223-016-0121-y · Cited by 29 · see citing works
The C-terminal domain of connexin43 modulates cartilage structure via chondrocyte phenotypic changes
Gago‐Fuentes, R., Bechberger, J. F., Varela-Eirín, M., Varela-Vázquez, A., Nebril, B. A., Fonseca, E., Naus, C. C. G., & Mayán, M. D. (2016) · Oncotarget · doi:10.18632/oncotarget.12197 · Cited by 26 · see citing works
“It is well known that bisphosphonates and other bone/cartilage protecting drugs such as the parathyroid hormone (PTH) require the expression of Cx43 to be effective [51, 52].”
Osteocytes and Diabetes: Altered Function of Diabetic Osteocytes
Gortázar, A. R., & Ardura, J. A. (2020) · Current Osteoporosis Reports · doi:10.1007/s11914-020-00641-z · Cited by 26 · see citing works
High Glucose Downregulates Connexin 43 Expression and Its Gap Junction and Hemichannel Function in Osteocyte-like MLO-Y4 Cells Through Activation of the p38MAPK/ERK Signal Pathway
Yang, L., Zhou, G., Li, M., Li, Y., Yang, L., Fu, Q., & Tian, Y. E. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s239892 · Cited by 24 · see citing works
“12 Interestingly, the osteocyte network is profoundly altered in diabetic mice compared with wild-type mice.”
Background
Brucella abortus Invasion of Osteocytes Modulates Connexin 43 and Integrin Expression and Induces Osteoclastogenesis via Receptor Activator of NF-κB Ligand and Tumor Necrosis Factor Alpha Secretion
Viglietti, A. I. P., Benítez, P. C. A., Gentilini, M. V., Velásquez, L. N., Fossati, C. A., Giambartolomei, G. H., & Delpino, M. V. (2015) · Infection and Immunity · doi:10.1128/iai.01049-15 · Cited by 24 · see citing works
Cell behavior of human mesenchymal stromal cells in response to silica/collagen based xerogels and calcium deficient culture conditions
Wagner, A., Glenske, K., Henß, A., Kruppke, B., Rößler, S., Hanke, T., Moritz, A., Rohnke, M., Kressin, M., Arnhold, S., et al. (2017) · Biomedical Materials · doi:10.1088/1748-605x/aa6e29 · Cited by 17 · see citing works
Osteocytic connexin 43 is not required for the increase in bone mass induced by intermittent PTH administration in male mice.
Pacheco‐Costa, R., Davis, H. M., Atkinson, E. G., Katchburian, E., Plotkin, L. I., & Reginato, R. D. (2016) · PubMed Central · Cited by 16 · see citing works
Self-citation
Calcium response in bone cells at different osteogenic stages under unidirectional or oscillatory flow
Wang, S., Li, S., Hu, M., & Huo, B. (2019) · Biomicrofluidics · doi:10.1063/1.5128696 · Cited by 15 · see citing works
Sustained delivery of growth factors and alendronate using partially demineralized dentin matrix for endogenous periodontal regeneration
Gao, X., Guan, M., Liu, X., Xu, H. H. K., Huang, Q., Chen, L., Huang, S., Xiao, Y., Shi, X., & Lin, Z. (2021) · Applied Materials Today · doi:10.1016/j.apmt.2020.100922 · Cited by 15 · see citing works
Effects of mechanobiological signaling in bone marrow on skeletal health
Curtis, K. J., Oberman, A. G., & Niebur, G. L. (2019) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14232 · Cited by 14 · see citing works
SARS-CoV-2 spike protein S1 activates Cx43 hemichannels and disturbs intracellular Ca2+ dynamics
Prieto‐Villalobos, J., Lucero, C. M. J., Rovegno, M., Gómez, G. I., Retamal, M. A., & Orellana, J. A. (2023) · Biological Research · doi:10.1186/s40659-023-00468-9 · Cited by 13 · see citing works
“Within this family of channels, those formed by the connexin 43 (Cx43) are the most ubiquitous and play essential roles in the autocrine/paracrine signaling in various organs and systems [34–37].”
Background
MicroRNAs and Connexins in Bone: Interaction and Mechanisms of Delivery
Plotkin, L. I., Pacheco‐Costa, R., & Davis, H. M. (2017) · Current Molecular Biology Reports · doi:10.1007/s40610-017-0058-6 · Cited by 10 · see citing works
Self-citation
Influence of the three‐dimensional culture of human bone marrow mesenchymal stromal cells within a macroporous polysaccharides scaffold on Pannexin 1 and Pannexin 3
Guerrero, J., Oliveira, H., Aid, R., Bareille, R., Siadous, R., Letourneur, D., Mao, Y., Kohn, J., & Amédée, J. (2017) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.2625 · Cited by 9 · see citing works
“The importance of a 3D environment to cell–cell communication, in skeletal development, has been established in models using human and mouse cells (Plotkin, 2014), (Plotkin & Bellido, 2013).”
BackgroundMethodInfluential
Connexin43 regulates osteoprotegerin expression via ERK1/2 -dependent recruitment of Sp1
Gupta, A., Leser, J. M., Gould, N. R., Buo, A. M., Moorer, M. C., & Stains, J. P. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.12.173 · Cited by 9 · see citing works
“Cx43 can act not only as a source of direct intercellular communication via gap junction channels, but also as a hemichannel, serving as a direct conduit between the cytoplasm and the extracellular space [7, 44, 45].”
Background
Strontium-Doped Mesoporous Bioactive Glass-Loading Bisphosphonates Inhibit Osteoclast Differentiation and Prevent Osteoporosis in Ovariectomized Mice
Zhou, Z., Huo, S., & Li, Z. (2024) · Coatings · doi:10.3390/coatings14010097 · Cited by 8 · see citing works
Pannexin 3 is required for late stage bone growth but not for initiation of ossification in avian embryos
Bond, S. R., Abramyan, J., Fu, K., Naus, C. C. G., & Richman, J. M. (2016) · Developmental Dynamics · doi:10.1002/dvdy.24425 · Cited by 8 · see citing works
“Connexin43 (Cx43) coded by the gene gap Junction protein, Alpha 1 (GJA1) is expressed in all tissues of the body including chondrocytes, osteoblasts, and osteocytes (Plotkin, 2014; Zappitelli and Aubin, 2014).”
Spontaneous cellular vibratory motions of osteocytes are regulated by ATP and spectrin network
Wu, X., Xiao, W., Cao, R., Yang, X. Y., Pan, F., Sun, L., & Fan, Y. (2019) · Bone · doi:10.1016/j.bone.2019.07.032 · Cited by 7 · see citing works
Connexin 30 Deficiency Ameliorates Disease Progression at the Early Phase in a Mouse Model of Amyotrophic Lateral Sclerosis by Suppressing Glial Inflammation
Hashimoto, Y., Yamasaki, R., Ko, S., Matsuo, E., Kobayakawa, Y., Masaki, K., Matsuse, D., & Isobe, N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232416046 · Cited by 7 · see citing works
Connexin 43 affects thoracic ossification of ligamentum flavum by regulating the p38 MAPK-RUNX2 signaling pathway
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Connexin 43 hemichannels and related diseases
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Connexin43 in Musculoskeletal System: New Targets for Development and Disease Progression
An, S., Zheng, S., Cai, Z., Chen, S., Wang, C., Li, Y., & Deng, Z. (2022) · Aging and Disease · doi:10.14336/ad.2022.0421 · Cited by 6 · see citing works
“Cx43 has been gradually highlighted in recent research as an important regulator in the musculoskeletal system based on the discovery of its hemichannel and extracellular mechanosensing mechanism, especially in bone development and joint diseases [6], such as rheumatoid arthritis (RA), osteoarthritis (OA), osteoporosi…”
Background
The novel bisphosphonate disodium dihydrogen-4-[(methylthio) phenylthio] methanebisphosphonate increases bone mass in post-ovariectomy rats
Takizawa, A., Chiba, M., Ōta, T., Yasuda, M., Suzuki, K., Kanemitsu, T., Itoh, T., Shinoda, H., & Igarashi, K. (2016) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2016.04.011 · Cited by 5 · see citing works
The Role of Gap Junctions in Endothelial–Stromal Cell Interactions
Ездакова, М. И., Константиновна, М. Д., Валентинович, Б. С., & Andreeva, E. R. (2021) · Human Physiology · doi:10.1134/s036211972103004x · Cited by 5 · see citing works
The Bioactive Phenolic Agents Diaryl Ether CVB2-61 and Diarylheptanoid CVB4-57 as Connexin Hemichannel Blockers
Dierks, A., Vanucci‐Bacqué, C., Schäfer, A.-M., Lehrich, T., Ruhe, F., Schadzek, P., Bedos‐Belval, F., & Ngezahayo, A. (2022) · Pharmaceuticals · doi:10.3390/ph15101173 · Cited by 4 · see citing works
ZO-1 expression shows prognostic value in chronic B cell leukemia
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“3 many cell functions (Schulz et al, 2015; Evans, 2015; Oviedo-Orta et al, 2000) even in a form of undocked hemichannels (Plotkin, 2014).”
Background
A Functional Assay to Assess Connexin 43-Mediated Cell-to-Cell Communication of Second Messengers in Cultured Bone Cells
Stains, J. P., & Civitelli, R. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3664-9_14 · Cited by 4 · see citing works
“For donor cells, there should be four separate sets of plates, namely (1) pSFFV-neo, pcDNA3; (2) pSFFV-Cx43, pcDNA3; (3) pSFFV-neo, caFGFR1; (4) pSFFVCx43, caFGFR1.”
Development of multiplex PCR systems for expression profiling of human cardiomyocytes induced to proliferate by lentivirus transduction of upcyte genes
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“1B, both tissues were positive for connexin 43, the main gap junction protein of the heart, which is also expressed in other organs such as bone and brain [23, 24].”
Background
Does Defective Bone Lead to Defective Muscle?
Bonewald, L. F. (2015) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2491 · Cited by 3 · see citing works
“蛋白的主要作用是通过运输或释放小分子物质来促进细胞间的联系。Cx43构成相邻细胞间的缝隙连接, 从而允许小于1 kD的分子在相连细胞的细胞质间移动。Cx43也可以在细胞膜上形成通道,允许小于1 kD 的分子从细胞进入细胞外环境。Loiselle([17])及Plotkin([18]) 等研究表明,另一些小分子物质如前列腺素E 2(PGE 2)、三磷酸腺苷(ATP)以及其他一些物质也是通过这些渠道在骨细胞内进行移动的。Cx43另一个被报道的功能是阻止成骨细胞和骨细胞的凋亡([19])。正如Shen 等描述([15]),Cx43缺失会导致皮质骨丢失的发生。那么是Cx43其中的一个功能,还是两个,抑或都不是, 与骨表型相关?或…”
Connexin Hemichannels Contribute to the Activation of cAMP Signaling Pathway and Renin Production
Hong, J., & Yao, J. Q. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124462 · Cited by 3 · see citing works
Connexin 43 in osteogenesis
Łukowicz, K., Fijał, K., Nowak, A., & Osyczka, A. M. (2020) · Postępy Higieny i Medycyny Doświadczalnej · doi:10.5604/01.3001.0014.4153 · Cited by 2 · see citing works
Role of Cx43 on the Bone Cell Generation, Function, and Survival
Plotkin, L. I., Asad, I., Kritikos, A. E., & Sanz, N. (2023) · Bioelectricity · doi:10.1089/bioe.2023.0028 · Cited by 1 · see citing works
Self-citation
Reduction in vinculin levels with Rb1 loss is responsible for altered differentiation in preosteoblasts
Pendleton, E., Abdallah, K., & Chandar, N. (2025) · Experimental Cell Research · doi:10.1016/j.yexcr.2025.114690 · Cited by 1 · see citing works
Morphological and Immunohistochemical Characterization of Bone Structure and Cell–Cell Communication in a Rat Osteoporosis Model
Glenske, K., Eldaey, A., Schaalo, S., Arnhold, S., Heiß, C., SCHNETTLER, R., Wenisch, S., & Elashry, M. I. (2024) · Anatomia · doi:10.3390/anatomia3020008 · Cited by 1 · see citing works
“For physiological bone remodeling and skeletal homeostasis, Cx43 plays an important role in the proliferation, differentiation, and survival of bone cells [2,8–10].”
BackgroundInfluential
Low frequency‑pulsed electromagnetic fields promote osteogenic differentiation of bone marrow‑derived mesenchymal stem cells by regulating connexin 43 expression
Lü, Z., Gu, H.-Y., Li, Z., & Lin, F.-X. (2024) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2024.12736 · Cited by 1 · see citing works
Os des maxillaires et de la mandibule
Goldberg, M. (2016) · Cited by 1 · see citing works
Role of Connexins and Pannexins in Bone and Muscle Mass and Function
Plotkin, L. I., & Davis, H. M. (2019) · Springer eBooks · doi:10.1007/978-3-030-25890-0_5
Self-citation
Estudio de la fisiopatología de las alteraciones óseas asociadas a la enfermedad de Gaucher
Crivaro, A. (2020) · doi:10.35537/10915/93197
Bone Cell Communication Through Gap Junctions
Stains, J. P. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11550-8
MicroRNAs in Bone Formation and Homeostasis
Taipaleenmäki, H., & Hesse, E. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-820719-2.00014-4
Additional file 1 of SARS-CoV-2 spike protein S1 activates Cx43 hemichannels and disturbs intracellular Ca2+ dynamics
Prieto‐Villalobos, J., Lucero, C. M. J., Rovegno, M., Gómez, G. I., Retamal, M. A., & Orellana, J. A. (2023) · Figshare · doi:10.6084/m9.figshare.24432057
Additional file 2 of SARS-CoV-2 spike protein S1 activates Cx43 hemichannels and disturbs intracellular Ca2+ dynamics
Prieto‐Villalobos, J., Lucero, C. M. J., Rovegno, M., Gómez, G. I., Retamal, M. A., & Orellana, J. A. (2024) · Figshare · doi:10.6084/m9.figshare.24432146
Implication de la Connexine 43 dans le développement de métastases osseuses d'origine prostatique
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Mitochondrial transfer-mediated metabolic reprogramming and drug resistance in bone metastasis: mechanisms and therapeutic strategies
Deng, W., Liu, B. Q., & Xiang, S. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1863593
“Osteoblasts support the co-transfer of small molecules such as mitochondrial transfer RNA (mt-tRNA) through Cx43 hemichannels and can transfer mitochondria to tumor cells under osteoclast stress conditions to maintain OXPHOS function (100).”
Exercise as a Physiological Context for Connexin and Pannexin Channel Gating: A Mini Review
Liu, J., Mao, Z., Hu, Z., Shen, Y., Liu, J., & Zhang, P. (2026) · Sport Sciences for Health · doi:10.1007/s11332-026-01916-1
“In vivo evidence shows that osteocyte-derived Cx43 hemichannels are required for the full anabolic response of bone to mechanical loading [32, 74, 79, 80].”

CONNEXIN 43 AND BONE: NOT JUST A GAP JUNCTION PROTEIN.
Plotkin, L. I. (2011) · Actualizaciones en osteología · Cited by 16 · see citing works
Self-citation
Gap junction and hemichannel functions in osteocytes
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Connexin-Mediated Signaling in Bone
Plotkin, L. I., & Bonetto, A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11213-9 · Cited by 1 · see citing works
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The Role of Connexin Channels in the Response of Mechanical Loading and Unloading of Bone
Riquelme, M. A., Cardenas, E. R., Xu, H., & Jiang, J. X. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031146 · Cited by 51 · see citing works
Beyond gap junctions: Connexin43 and bone cell signaling
Plotkin, L. I., & Bellido, T. (2012) · Bone · doi:10.1016/j.bone.2012.09.030 · Cited by 153 · see citing works
Self-citation

Authors: Plotkin, L. I.
Affiliations: Indiana University Indianapolis (US)
Corresponding author: Plotkin, Lilian I.
ORCID: Plotkin, Lilian I.
Venue: Frontiers in Physiology
Publisher: Frontiers Media SA
Published: 2014-04-04
Volume: 5
Pages: 131-131
ISSN: 1664-042X (ISSN-L)
DOI: 10.3389/fphys.2014.00131
PMC: PMC3983496
OpenAlex: W2124239957
Cited by: 66
References: 79
Citations by year: 2026: 2 · 2025: 1 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 3 · 2020: 8 · 2019: 6 · 2018: 3 · 2017: 9 · 2016: 11 · 2015: 8 · 2014: 1
FWCI: 0.91
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Frontiers in Physiology (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
IUScholarWorks (Indiana University) (submittedVersion, cc-by)
Funders: National Institutes of Health
School of Medicine, Indiana University
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR053643, R01AR067210)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords: connexin 43, hemichannels, connexons, gap junctions, bone cells, osteoblasts, osteocytes, osteoclasts, intracellular signaling, cell-to-cell communication, bisphosphonates, osteoporosis, mechanical stimulation, prostaglandin release, ATP release, parathyroid hormone, apoptosis, bone health

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Connexin 43 hemichannels and intracellular signaling in bone cells

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