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Mechanical Strain Opens Connexin 43 Hemichannels in Osteocytes: A Novel Mechanism for the Release of Prostaglandin
Open accessAbstract
Mechanosensing bone osteocytes express large amounts of connexin (Cx)43, the component of gap junctions; yet, gap junctions are only active at the small tips of their dendritic processes, suggesting another function for Cx43. Both primary osteocytes and the osteocyte-like MLO-Y4 cells respond to fluid flow shear stress by releasing intracellular prostaglandin E 2 (PGE 2 ). Cells plated at lower densities release more PGE 2 than cells plated at higher densities. This response was significantly reduced by antisense to Cx43 and by the gap junction and hemichannel inhibitors 18 β-glycyrrhetinic acid and carbenoxolone, even in cells without physical contact, suggesting the involvement of Cx43-hemichannels. Inhibitors of other channels, such as the purinergic receptor P2X 7 and the prostaglandin transporter PGT, had no effect on PGE 2 release. Cell surface biotinylation analysis showed that surface expression of Cx43 was increased by shear stress. Together, these results suggest fluid flow shear stress induces the translocation of Cx43 to the membrane surface and that unapposed hemichannels formed by Cx43 serve as a novel portal for the release of PGE 2 in response to mechanical strain.
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“For example, mechanical loading stimulates osteocyte to produce factors that exert anabolic action on bone such as PGE2, prostacyclin (PGI2), NO, and IGF-1 [181–184].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [182]
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BackgroundConnexin channel permeability to cytoplasmic molecules
Harris, A. L. (2007) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2007.03.011 · Cited by 478
“…(Kam et al., 1998) 3f IP3 (Romanello and D’Andrea, 2001) 3a 3c 3e NAD+ (Bruzzone et al., 2001a, b) 3a 3b 3c 3f Prostaglandin E2 (Jiang and Cherian, 2003; Cherian et al., 2005) 3a 3b 3c 3e 43j ADP/ATP (Goldberg et al., 1998) 1a f adenosine (Goldberg et al., 1999) 1a cAMP (Bedner et al., 2003, 2006)…”
Mechanobiology and Developmental Control
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The gap junction cellular internet: connexin hemichannels enter the signalling limelight
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Decrock, E., Vinken, M., Vuyst, E. D., Krysko, D. V., D'Herde, K. G. M. A., Vanhaecke, T., Vandenabeele, P., Rogiers, V., & Leybaert, L. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2008.196 · Cited by 247
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Adaptation of Connexin 43-Hemichannel Prostaglandin Release to Mechanical Loading
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Self-citationThe participation of plasma membrane hemichannels to purinergic signaling
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“For example, it is reported that prostaglandin E2 can permeate through Cx43 hemichannels [206,207], and it has been recently found that P2X4 receptors increase the release of prostaglandin E2 from macrophages and contribute to pain sensation [208].”
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“…Science 119, 4187-4198 Published by The Company of Biologists 2006 doi:10.1242/jcs.03162 Jo ur na l o f C el l S ci en ce 4188 Cx43 expression hinders osteoblast responses to fluid flow (Cherian et al., 2005; Saunders et al., 2001), or to mechanically induced calcium waves (Jørgensen et al., 2000).”
BackgroundInfluentialExtracellular NAD and ATP: Partners in immune cell modulation
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In vitro and in vivo approaches to study osteocyte biology
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“Some of them include integrins [131], Cx43 hemichannels [96,108] and ion channels like L-type voltage-dependent calcium channels [132].”
BackgroundInfluentialSelf-citationFrom streaming‐potentials to shear stress: 25 years of bone cell mechanotransduction
Riddle, R. C., & Donahue, H. J. (2009) · Journal of Orthopaedic Research · doi:10.1002/jor.20723 · Cited by 157
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 158
“The reasons for the apparent discrepancy between the studies showing a requirement of Cx43 expression for PGE2 release induced by mechanical stimulation in vitro versus the enhanced periosteal response to loading of mice lacking Cx43 are not known.”
BackgroundMethodInfluentialPannexins, distant relatives of the connexin family with specific cellular functions?
D’hondt, C., Ponsaerts, R., SMEDT, H. D., Bultynck, G., & Himpens, B. (2009) · BioEssays · doi:10.1002/bies.200800236 · Cited by 153
Gap junctions in skeletal development and function
Stains, J. P., & Civitelli, R. (2005) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2005.10.012 · Cited by 149
“Hemichannels have been shown to regulate the release of NAD and ATP [32,33], and recently, prostaglandin E2 (PGE2) [34].”
BackgroundMethodResultInfluentialKamel, M. A., Picconi, J. L., Lara-Castillo, N., & Johnson, M. L. (2010) · Bone · doi:10.1016/j.bone.2010.08.007 · Cited by 147
“Mechanistically increased Cox-2 activity (Ptgs2 gene expression) and PGE2 secretion are known to be an early event in the response to mechanical loading [7,29–36].”
BackgroundThe roles of exercise in bone remodeling and in prevention and treatment of osteoporosis
Yuan, Y. J., Chen, X., Zhang, L., Wu, J., Guo, J., Zou, D., Chen, B., Sun, Z., Shen, C., & Zou, J. (2015) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2015.11.005 · Cited by 146
Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling
Watkins, M. P., Grimston, S. K., Norris, J. Y., Guillotin, B., Shaw, A., Beniash, E., & Civitelli, R. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-07-0571 · Cited by 144
“Cx43-deficient mice are less sensitive to anabolic mechanical load (Grimston et al., 2008) and skeletal unloading (Grimston et al., unpublished data); and Cx43 has been implicated in mechanotransduction, primarily in osteocytes (Cherian et al., 2005; Genetos et al., 2007).”
BackgroundJiang, J. X. (2006) · Frontiers in bioscience · doi:10.2741/2159 · Cited by 140
“activated protein kinase A, which in turn, stimulates gap junction function and Cx43 expression (76,77,127).”
BackgroundSelf-citationOgawa, H., Kozhemyakina, E. A., Hung, H.-H. K., Grodzinsky, A. J., & Lassar, A. B. (2014) · Genes & Development · doi:10.1101/gad.231969.113 · Cited by 137
“…mechanical motion in osteocytes via both connexin and pannexin channels, which release both ATP and PGE2 into the extracellular space that in turn interact with their cognate receptors to alter gene expression in these cells (Bao et al. 2004; Cherian et al. 2005; Li et al. 2005; Batra et al. 2012).”
InfluentialKnight, M. M., McGlashan, S. R., Garcia, M., Jensen, C. G., & Poole, C. A. (2009) · Journal of Anatomy · doi:10.1111/j.1469-7580.2008.01021.x · Cited by 134
“In this case the expression was also confined to the superficial region; however, the authors concluded that connexin expression was indicative of intercellular gap junction formation, in agreement with similar dye-transfer studies in adult rabbit cartilage (Chi et al. 2004).”
ResultBiomechanics of Cardiac Electromechanical Coupling and Mechanoelectric Feedback
Pfeiffer, E. R., Tangney, J. R., Omens, J. H., & McCulloch, A. D. (2014) · Journal of Biomechanical Engineering · doi:10.1115/1.4026221 · Cited by 131
“Cardiac conduction is thus dependent on the integrity of mechanical junctions between cells, and alterations in connexin expression due to disease [79,81–83] Connexon mechanosensitivity in cardiac cells is unknown, although increased conductivity with stretch has been shown in other cell types [84].”
BackgroundThe Role of the Osteocyte in Bone and Nonbone Disease
Bonewald, L. F. (2016) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2016.09.003 · Cited by 134
Self-citationOsteocytes and WNT: the Mechanical Control of Bone Formation
Galli, C., Passeri, G., & Macaluso, G. M. (2010) · Journal of Dental Research · doi:10.1177/0022034510363963 · Cited by 136
“This requires the opening of Cx43 membrane hemichannels, similar to the gap junctions between cells (Cherian et al., 2005; Siller-Jackson et al., 2008; Burra and Jiang, 2009).”
BackgroundXu, J. P., & Nicholson, B. J. (2012) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2012.06.024 · Cited by 127
“In fact, they have been implicated in ATP release associated with Ca2+ wave propagation [4], nicotinamide-adenine dinucleotide (NAD+) release to allow access to CD38 and conversion to cADP ribose [5], and PGE2 release to regulate bone formation [6].”
BackgroundIrisin Prevents Disuse-Induced Osteocyte Apoptosis
Storlino, G., Colaianni, G., Sanesi, L., Lippo, L., Brunetti, G., Errede, M., Colucci, S. C., Passeri, G., & Grano, M. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3944 · Cited by 125
The Mechanosensory Role of Osteocytes and Implications for Bone Health and Disease States
Choi, J. U. A., Kijas, A. W., Lauko, J., & Rowan, A. E. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.770143 · Cited by 138
Jähn, K., Lara-Castillo, N., Brotto, L. S., Mo, C., Johnson, M., Brotto, M., & Bonewald, L. F. (2012) · European Cells and Materials · doi:10.22203/ecm.v024a14 · Cited by 117
“We and others have postulated that the Wnt/β-catenin pathway is activated in response to the initial PGE2 release from connexin 43 hemichannels (Cherian et al., 2005) leading to β-catenin nuclear translocation and transcription of target genes (for review see Bonewald and Johnson, 2008).”
BackgroundSelf-citationGrimston, S. K., Brodt, M. D., Silva, M. J., & Civitelli, R. (2008) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.080222 · Cited by 114
“lular communication (GJIC) and/or Gja1 gene expression hinders osteoblast responses to fluid flow((12,13)) and mechanically induced calcium waves.”
BackgroundRoles of gap junctions, connexins, and pannexins in epilepsy
Mylvaganam, S., Ramani, M., Krawczyk, M., & Carlen, P. L. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00172 · Cited by 112
“…such as glucose and glutathione and also the release of autocrine/paracrine molecules such as ATP, glutamate, NADP+ and adenosine into the extracellular medium (Sohl and Willecke, 2004; Bruzzone et al., 2005; Cherian et al., 2005; Retamal et al., 2007; Lin et al., 2008; Stridh et al., 2008).”
BackgroundFunctions of the osteocyte network in the regulation of bone mass
Komori, T. (2013) · Cell and Tissue Research · doi:10.1007/s00441-012-1546-x · Cited by 113
Mechanotransduction in osteogenesis
Stewart, S. K., Darwood, A. R. J., Masouros, S. D., Higgins, C. A., & Ramasamy, A. (2020) · Bone and Joint Research · doi:10.1302/2046-3758.91.bjr-2019-0043.r2 · Cited by 111
Connexin 43 Channels Are Essential for Normal Bone Structure and Osteocyte Viability
Xu, H., Gu, S., Riquelme, M. A., Burra, S., Callaway, D. A., Cheng, H., Guda, T., Schmitz, J. E., Fajardo, R. J., Werner, S. L., et al. (2014) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2374 · Cited by 108
“(19) Cell‐based studies suggested that hemichannels are responsive to mechanical stimulation, resulting in the opening of these channels, and the release of factors including prostaglandins and ATP.”
BackgroundInfluentialSelf-citationLong-Chain Polyunsaturated Fatty Acids and the Regulation of Bone Metabolism
Poulsen, R. C., Moughan, P. J., & Kruger, M. C. (2007) · Experimental Biology and Medicine · doi:10.3181/0704-mr-100 · Cited by 105
“They detect mechanical strain and initiate signaling pathways, leading to both osteoclastogenesis and osteoblastogenesis (18).”
BackgroundOsteocytic 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 100
“In response to stimuli such as bisphosphonates and mechanical loading, Cx43 hemichannels found in osteocytes are known portals for the release of molecules such as PGE 2 and ATP 15,12,13,14 .”
InfluentialSelf-citationGap junction and hemichannel functions in osteocytes
Loiselle, A. E., Jiang, J. X., & Donahue, H. J. (2012) · Bone · doi:10.1016/j.bone.2012.08.132 · Cited by 103
“These studies suggest that hemichannels, rather than gap junctions, may play the predominate role in transmitting the effects of fluid flow, via PGE2 secretion [54,60].”
BackgroundSelf-citationATP Release Mediates Fluid Flow–Induced Proliferation of Human Bone Marrow Stromal Cells
Riddle, R. C., Taylor, A. F., Rogers, J. R., & Donahue, H. J. (2007) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.070113 · Cited by 100
“On the day of the experiment, cells were washed in flow media and incubated for 10 minutes in the presence or absence of 5 mM EGTA or exposed to oscillatory fluid flow, in flow media containing 1 mg/ml Lucifer Yellow and 1 mg/ml Rhodamine Dextran.”
MethodInfluentialResponsiveness of human bone marrow stromal cells to shear stress
Grellier, M., Bareille, R., Bourget, C., & Amédée, J. (2009) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.166 · Cited by 99
“However, cell surface biotinylation analysis of Cx43 would throw more light on the effect of shear stress on Cx43 trafficking, as already observed for osteocytes (Cherian et al., 2005).”
BackgroundHemichannels: New pathways for gliotransmitter release
Montero, T. D., & Orellana, J. A. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.11.048 · Cited by 100
Deletion of Connexin43 in Osteoblasts/Osteocytes Leads to Impaired Muscle Formation in Mice
Shen, H., Grimston, S. K., Civitelli, R., & Thomopoulos, S. (2014) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2389 · Cited by 94
“Among the soluble factors produced by bone cells, prostaglandin E2 (PGE2) may be released by OCYs via Cx43 hemichannels (ie, half of a gap junction) after mechanical stimuli((36)) and has been reported to facilitate myogenesis and muscle function.”
BackgroundGalea, G. L., Sunters, A., Meakin, L. B., Zaman, G., Sugiyama, T., Lanyon, L. E., & Price, J. S. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.06.019 · Cited by 99
“For instance, strain-related PGE2 release occurs through connexin-43 hemi-channels [30] which may result in, and be a response to, activation of many local signaling events in addition to those resulting from a single high dose of PGE2.”
BackgroundDiseases associated with leaky hemichannels
Retamal, M. A., Reyes, E. P., GarcÃa, I. E., Pinto, B. I., MartÃnez, A. D., & González, C. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00267 · Cited by 93
Pericyte mechanics and mechanobiology
Dessalles, C. A., Babataheri, A., & Barakat, A. I. (2021) · Journal of Cell Science · doi:10.1242/jcs.240226 · Cited by 99
Effects of cyclic hydraulic pressure on osteocytes
Liu, C., Zhao, Y., Cheung, W.-Y., Gandhi, R., Wang, L., & You, L. (2010) · Bone · doi:10.1016/j.bone.2010.02.006 · Cited by 88
“This is in agreement with earlier results [75, 76].”
Signaling networks and transcription factors regulating mechanotransduction in bone
Papachristou, D. J., Papachroni, K. K., Basdra, E. K., & Papavassiliou, A. G. (2009) · BioEssays · doi:10.1002/bies.200800223 · Cited by 92
“Notably, PGE2 stimulates gap junction function and Cx 43 expression in an autocrine fashion.((84)) The expression of COX-2, the inducible isozyme for PGE2 synthesis, is directly upregulated by mechanical loading through the formation of focal adhesions and subsequent ERK and PKA signaling pathways in osteoblasts.”
BackgroundBatra, 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
“prevents the release of PGE2 in osteocytic cells (8;27).”
BackgroundSelf-citationCurrently Used Methods for Identification and Characterization of Hemichannels
Schalper, K. A., Palacios‐Prado, N., Orellana, J. A., & Sáez, J. C. (2008) · Cell Communication & Adhesion · doi:10.1080/15419060802014198 · Cited by 89
“Recent studies by our group and others have used this approach to demonstrate changes in the relative amount of surface connexins forming hemichannels under different conditions (Cooper and Lampe 2002; Cherian et al. 2005; Lai et al. 2006; Retamal et al. 2006, 2007a, 2007b).”
BackgroundMethodResultInfluentialGarrett, F. G., & Durham, P. L. (2008) · Neuron Glia Biology · doi:10.1017/s1740925x09990093 · Cited by 88
“In support of this notion, hemichannels have been found to act through paracrine signaling by releasing molecules such as ATP, NAD+, glutamate and prostaglandins, which can modulate neuronal and glial cell activity (Goodenough et al., 1996; Bruzzone, 2001; Bennett, 2003; Ebihara, 2003; Ye, 2003; Cheriann et al., 2005).”
BackgroundIordachescu, A., Hughes, E. A. B., Joseph, S., Hill, E. J., Grover, L. M., & Metcalfe, A. D. (2021) · npj Microgravity · doi:10.1038/s41526-021-00146-8 · Cited by 89
Glial hemichannels and their involvement in aging and neurodegenerative diseases
Orellana, J. A., Rommy von Bernhardi, M., Giaume, C., & Sáez, J. C. (2012) · Reviews in the Neurosciences · doi:10.1515/revneuro-2011-0065 · Cited by 88
Grubišić, V., & Gulbransen, B. D. (2017) · The Journal of Physiology · doi:10.1113/jp273492 · Cited by 87
Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease
Lapato, A. S., & Tiwari-Woodruff, S. K. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24088 · Cited by 89
“Gliotransmission continues to draw attention to Cx and Panx HCs, whereby release of purinergic mediators and other gliotransmitters has proven essential to synaptic strength and plasticity (Cherian et al., 2005; Montero & Orellana, 2015; Stout, Costantin, Naus, & Charles, 2002).”
BackgroundCancer Connectors: Connexins, Gap Junctions, and Communication
Sinyuk, M., Mulkearns-Hubert, E. E., Reizes, O., & Lathia, J. D. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00646 · Cited by 88
Gap junction channels and hemichannels in the CNS: Regulation by signaling molecules
Orellana, J. A., Martı́nez, A. D., & Retamal, M. A. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.02.020 · Cited by 92
Metadata
- Authors
- Cherian, P. P., Siller-Jackson, A. J., Gu, S., Wang, X., Bonewald, L. F., Sprague, E., & Jiang, J. X.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- University of Missouri–Kansas City (US)
- Venue
- Molecular Biology of the Cell
- Published
- 2005-07
- Volume
- 16
- Issue
- 7
- Pages
- 3100-3106
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC1165395
- OpenAlex
- W2101299206
- Cited by
- 481
- References
- 39
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 18 · 2023: 15 · 2022: 17 · 2021: 23 · 2020: 22 · 2019: 25 · 2018: 15 · 2017: 23 · 2016: 21 · 2015: 23 · 2014: 40 · 2013: 27 · 2012: 31
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Biology of the Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AQ‐1507, AR46798)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P01AR046798, AR 46798)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- connexin 43, hemichannels, osteocytes, prostaglandin E2 release, fluid shear stress, mechanotransduction, gap junctions, MLO-Y4 cells, 18β-glycyrrhetinic acid, carbenoxolone, cell surface translocation, bone mechanosensing
- MeSH terms
- Animals, Bone and Bones, Carbenoxolone, Cell Line, Cell Membrane, Cells, Cultured, Chickens, Dendrites, Glycyrrhetinic Acid, Microscopy, Fluorescence, Osteocytes, Prostaglandins, Stress, Mechanical, Blotting, Western, Oligonucleotides, Antisense, Gap Junctions, Connexin 43, Receptors, Purinergic P2, Biotinylation, Mice, Rats, Receptors, Purinergic P2X7
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