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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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Items 101–200 of 481
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InfluentialConnexins: Key Players in the Control of Vascular Plasticity and Function
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BackgroundP2X7 receptors: role in bone cell formation and function
Agrawal, A., & Gartland, A. (2015) · Journal of Molecular Endocrinology · doi:10.1530/jme-14-0226 · Cited by 76
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Whitten, S. J., & Miller, M. A. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.08.038 · Cited by 69
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Decrock, E., Vinken, M., Bol, M., D'Herde, K. G. M. A., Rogiers, V., Vandenabeele, P., Krysko, D. V., Bultynck, G., & Leybaert, L. (2011) · Cell Calcium · doi:10.1016/j.ceca.2011.05.007 · Cited by 72
A New Method to Investigate How Mechanical Loading of Osteocytes Controls Osteoblasts
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Diezmos, E. F., Bertrand, P. P., & Liu, L. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00311 · Cited by 67
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Chandrasekhar, A., & Bera, A. K. (2012) · Cell Biochemistry and Function · doi:10.1002/cbf.2794 · Cited by 68
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Lima, F., Niger, C., HEBERT, C. A., & Stains, J. P. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e08-10-1079 · Cited by 66
“It is important to note that although we model that the effects of Cx43 function are mediating gap junction intercellular communication, a compelling and expanding body of research has demonstrated that Cx43 can also function as unopposed hemichannels to regulate responses to fluid flow (Cherian et al., 2005; Genetos…”
BackgroundInner Ear Connexin Channels: Roles in Development and Maintenance of Cochlear FunctionPreprint
Mammano, F. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a033233 · Cited by 68
“…glutamate (Ye et al. 2003), lactate (Karagiannis et al. 2016), oxidized nicotinamide adenine dinucleotide (Bruzzone et al. 2001), prostaglandin E2 (Cherian et al. 2005), reduced glutathione (Rana and Dringen 2007; Tong et al. 2015), which are critical for cell–cell communication (Wang et al.…”
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Bone Loss after Temporarily Induced Muscle Paralysis by Botox Is Not Fully Recovered After 12 Weeks
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“such as fluid flow and membrane stretch (hypotonic swelling) increase VSCC-dependent (voltage sensitive Ca2+ channels) ATP release mediated via ERK1/2 [12,13].”
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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
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Connexins in the Central Nervous System: Physiological Traits and Neuroprotective Targets
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Kotini, M. P., & Mayor, R. (2014) · Developmental Biology · doi:10.1016/j.ydbio.2014.12.023 · Cited by 59
“In response to stress factors or specific physiological signals (Buvinic et al., 2009; Cherian et al., 2005) opening of hemichannels can lead to autocrine-paracrine cell signalling.”
BackgroundNeuronal involvement in muscular atrophy
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“…products such as glutathione (Rana and Dringen, 2007), as well as of autocrine and paracrine signals such as ATP (Stout et al., 2002), NAD+ (Bruzzone et al., 2001), cADPR (Song et al., 2011), IP3 (Gossman and Zhao, 2008), glutamate (Ye et al., 2003), and prostaglandin E2 (Cherian et al., 2005).”
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Gajardo‐Gómez, R., Labra, V. C., & Orellana, J. A. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00086 · Cited by 62
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Begandt, D., Good, M. E., Keller, A. S., DeLalio, L. J., Rowley, C. A., Isakson, B. E., & Figueroa, X. F. (2017) · BMC Cell Biology · doi:10.1186/s12860-016-0119-3 · Cited by 60
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“In addition to the role of GJs in bone cell response to mechanical load, emerging evidence suggests that Cx43 hemichannels may also be a key component in the transduction of osteogenic signals in response to mechanical stimulation.((68,69))”
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“Of interest, PGE2 with a molecular weight of 352 Da can be released via hemichannels [342].”
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Chan, M. E., Lu, X. L., Huo, B., Baik, A. D., Chiang, V., Guldberg, R. E., Lu, H. H., & Guo, X.-D. E. (2009) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-009-0075-5 · Cited by 51
A paradigm shift for bone quality in dentistry: A literature review
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“The release of both factors is sensitive to an unspecific connexin/pannexin channel chemical blocker, β-glycyrrhetinic acid, and specific inhibitors, Cx43 anti-sense oligonucleotides and Cx43 hemichannel blocker Cx43E2 antibody [56,59,60].”
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Wang, X., Nyman, J. S., Dong, X., Leng, H., & Reyes, M. (2010) · Synthesis lectures on tissue engineering · doi:10.2200/s00246ed1v01y200912tis004 · Cited by 51
Self-citationConnexins and pannexins in the skeleton: gap junctions, hemichannels and more
Plotkin, L. I., & Stains, J. P. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1963-6 · Cited by 51
“Furthermore, fluid flow shear stress has been shown to activate Cx43-based hemichannels in cultured chondrocytes, which in turn affects extracellular prostaglandin E2 levels [139], a model that closely mimics observations made in osteocytes [65, 67].”
ResultEndocytosis and post-endocytic sorting of connexins
Leithe, E., Sirnes, S., Fykerud, T. A., Kjenseth, A., & Rivedal, E. (2011) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2011.09.029 · Cited by 50
Rough surface topography enhances the activation of Wnt/β‐catenin signaling in mesenchymal cells
Galli, C., Passeri, G., Ravanetti, F., Elezi, E., Pedrazzoni, M., & Macaluso, G. M. (2010) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.32887 · Cited by 50
Meyer, R. A., Desai, B. R., Heiner, D. E., Fiechtl, J. F., Porter, S. E., & Meyer, M. H. (2006) · Journal of Orthopaedic Research® · doi:10.1002/jor.20124 · Cited by 50
Connexin Channels at the Glio-Vascular Interface: Gatekeepers of the Brain
Bock, M. D., Leybaert, L., & Giaume, C. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2313-x · Cited by 54
“Today, PGE2 has been shown to be released in a Cx43HC-dependent manner only in osteocytes [193].”
BackgroundMolecular signaling in bone cells: Regulation of cell differentiation and survival
Plotkin, L. I., & Bruzzaniti, A. (2019) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2019.01.002 · Cited by 50
Gluhak‐Heinrich, J., Gu, S., Pavlin, D., & Jiang, J. X. (2006) · Cell Communication & Adhesion · doi:10.1080/15419060600634619 · Cited by 50
“We recently found that in addition to gap junctions, Cx43 forming hemichannels mediate the biological responses elicited by fluid flow, such as the release of PGE2 (Cherian et al. 2005).”
BackgroundInfluentialSelf-citationKirmizidis, G., & Birch, M. A. (2009) · Tissue Engineering Part A · doi:10.1089/ten.tea.2008.0137 · Cited by 49
Bone fracture healing: perspectives according to molecular basis
Ruggieri, I. N. C., Cícero, A. M., Issa, J. P. M., & Feldman, S. (2020) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-020-01168-0 · Cited by 52
Phosphorylation of Connexin 50 by Protein Kinase A Enhances Gap Junction and Hemichannel Function
Liu, J., Ek-Vitorín, J. F., Weintraub, S. T., Gu, S., Shi, Q., Burt, J. M., & Jiang, J. X. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.218735 · Cited by 49
Self-citationSato, K., ADACHI, T., Ueda, D., Hojo, M., & TOMITA, Y. (2006) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2006.05.028 · Cited by 49
Riquelme, M. A., Burra, S., Kar, R., Lampe, P. D., & Jiang, J. X. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.683417 · Cited by 49
“We have previously shown that PGE2 is released by osteocyte-like cells, MLO-Y4 cells through Cx43 hemichannels in response to FFSS (2).”
BackgroundMethodInfluentialSelf-citationBuo, 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
Mechanosignaling in Bone Health, Trauma and Inflammation
Knapik, D. M., Perera, P., Nam, J., Blazek, A. D., Rath, B., Leblebicioğlu, B., Das, H., Wu, L., Hewett, T. E., Agarwal, S., et al. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5467 · Cited by 51
“Mechanical signals are shown to induce transient secretion of PGE 2 as an osteogenic signal (15).”
Zarka, M., Étienne, F., Bourmaud, M., Szondi, D. C., Schwartz, J., Kampmann, K., Hélary, C., Rannou, F., Haÿ, E., & Cohen-Solal, M. E. (2021) · Laboratory Investigation · doi:10.1038/s41374-021-00668-5 · Cited by 52
Bock, M. D., Wang, N., Decrock, E., Bultynck, G., & Leybaert, L. (2015) · Mediators of Inflammation · doi:10.1155/2015/257471 · Cited by 48
Connexin Hemichannels: Methods for Dye Uptake and Leakage
Johnson, R. G., Le, H. C., Evenson, K., Loberg, S. W., Myslajek, T. M., Prabhu, A., Manley, A.-M., O’Shea, C., Grunenwald, H. L., Haddican, M. M., et al. (2016) · The Journal of Membrane Biology · doi:10.1007/s00232-016-9925-y · Cited by 48
“When osteocytes, containing Cx43, were stimulated to open mechanically (Cherian et al. 2005), signaling via phosphoinositide-3 kinase and AKT kinase led to the phosphorylation of both alpha5-integrin and Cx43, a direct integrin–connexin interaction and the subsequent hemichannel opening (Batra et al.”
BackgroundInfluentialConnexin 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 49
“…of these channels is involved in autocrine/paracrine signaling, which provides a pathway for release of ATP (Cotrina et al., 1998), glutamate (Ye et al., 2003), NADþ (Bruzzone et al., 2001) and prostaglandins (Cherian et al., 2005), and mediate various aspects of cell signaling and function.”
BackgroundSelf-citationConnexin 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
Self-citationLow-intensity pulsed ultrasound (LIPUS) and cell-to-cell communication in bone marrow stromal cells
Sena, K., Angle, S. R., Kanaji, A., Aher, C. V., Karwo, D., Sumner, D. R., & Virdi, A. S. (2011) · Ultrasonics · doi:10.1016/j.ultras.2011.01.007 · Cited by 47
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
“To study whether Cx43 was involved in dye uptake resulting from the mechanical stimulation induced by medium displacement in the imaging dish, we performed control basal level YoPro dye-uptake experiments in LDPBS, a condition reported to favor hemichannel opening (Contreras et al. 2003; Cherian et al. 2005; Burra et…”
BackgroundMethodInfluentialA note on stress-driven anisotropic diffusion and its role in active deformable media
Cherubini, C., Filippi, S., Gizzi, A., & Ruíz-Baier, R. (2017) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2017.07.013 · Cited by 47
Guttman, J. A., Lin, A. E., Li, Y., Bechberger, J. F., Naus, C. C. G., Vogl, A. W., & Finlay, B. B. (2009) · Gut · doi:10.1136/gut.2008.170464 · Cited by 46
“Should the Cx43 alterations seen during these murine infections prove homologous to infectious diarreal disease in humans there are a variety of drugs that have been used to inhibit connexons hemichannels in cultured cells.(5) 32 33 These chemical inhibitors will require examination for their ability to block this mec…”
BackgroundInhibition of astrocyte hemichannel improves recovery from spinal cord injury
Zhang, C., Yan, Z., Maknojia, A., Riquelme, M. A., Gu, S., Booher, G. A., Wallace, D. J., Bartanusz, V., Goswami, A., Xiong, W., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.134611 · Cited by 45
“We have previously shown that mechanical stress activates Cx43 hemichannels (24, 25).”
BackgroundSelf-citationRetamal, M. A., Alcayaga, J., Verdugo, C. A., Bultynck, G., Leybaert, L., Sáez, P. J., Fernández, R., León, L. E., & Sáez, J. C. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00158 · Cited by 45
“ORIGINAL RESEARCH ARTICLE published: 20 June 2014 doi: 10.3389/fncel.2014.00158 Opening of pannexin- and connexin-based channels increases the excitability of nodose ganglion sensory neurons”
InfluentialProtein-Mediated Interactions of Pancreatic Islet Cells
Meda, P. (2013) · Scientifica · doi:10.1155/2013/621249 · Cited by 45
Zhang, J., Zhang, H. Y., Zhang, M., Qiu, Z. Y., Wu, Y. P., Callaway, D. A., Jiang, J. X., Lu, L., Jing, L., Yang, T., et al. (2014) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2014.03.017 · Cited by 45
“To verify that hemichannels were induced to open in response to FFSS stimulation, we conducted dye uptake experiments following the methods used for osteocytes [11].”
BackgroundMethodResultInfluentialSelf-citationRole of Astroglial Hemichannels and Pannexons in Memory and Neurodegenerative Diseases
Orellana, J. A., Retamal, M. A., Moraga‐Amaro, R., & Stehberg, J. (2016) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2016.00026 · Cited by 44
“…glutamate, NAD+ and PGE2) to the extracellular milieu, as well as the influx of small molecules and ions of up to ∼1.5 kDa (e.g., glucose, cADPR and Ca2+) (Bruzzone et al., 2001; Stout et al., 2002; Ye et al., 2003; Cherian et al., 2005; Retamal et al., 2007; Song et al., 2011; Fiori et al., 2012).”
BackgroundInfluentialCurrent perspectives on NMDA-type glutamate signalling in bone
Spencer, G. J., McGrath, C. J., & Genever, P. G. (2006) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2006.11.002 · Cited by 45
Mechanosensory Mechanisms in Bone
Sharma, U., Mikos, A. G., & Cowin, S. C. (2007) · Elsevier eBooks · doi:10.1016/b978-012370615-7/50065-2 · Cited by 45
Gordeladze, J. O., Reseland, J. E., Duroux-Richard, I., Apparailly, F., & Jørgensen, C. (2010) · ILAR Journal · doi:10.1093/ilar.51.1.42 · Cited by 45
“These channels are often located to dendritic outgrowths (processes) on osteocytes, which increase PGE2 (an anabolic bone factor) when mechanically stimulated (Cherian et al. 2005; Donahue 2000; Yellowley et al. 2000).”
BackgroundCardiac to cancer: Connecting connexins to clinical opportunity
Grek, C. L., Rhett, J. M., & Ghatnekar, G. S. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.02.047 · Cited by 44
Connexin 43 is a potential regulator in fluid shear stress‐induced signal transduction in osteocytes
Li, X., Liu, C., Li, P., Li, S., Zhao, Z., Chen, Y., Huo, B., & Zhang, D. (2013) · Journal of Orthopaedic Research® · doi:10.1002/jor.22448 · Cited by 43
Li, S., Zhang, H., Li, S., Yang, Y., Huo, B., & Zhang, D. (2015) · Journal of Orthopaedic Research® · doi:10.1002/jor.22830 · Cited by 43
Casagrande, D. J., Stains, J. P., & Murthi, A. M. (2015) · Journal of Shoulder and Elbow Surgery · doi:10.1016/j.jse.2014.11.039 · Cited by 43
“In addition to the impact of inflammation on Cx43 expression, Cx43 has long been linked to mechanical load.(5) Cx43 expression is dramatically increased by mechanical loading in skeletal tissues, and its function has been implicated in the production of prostaglandins in response to mechanical perturbation in bone cel…”
BackgroundHOW DO BONE CELLS SENSE MECHANICAL LOADING?
de Gusmão, C. V. B., & Belangero, W. D. (2009) · Revista Brasileira de Ortopedia (English Edition) · doi:10.1016/s2255-4971(15)30157-9 · Cited by 43
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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