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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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Sun, Y., Hills, M. D., Ye, W. G., Tong, X., & Bai, D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0095125 · Cited by 25
“These hemichannels can provide a direct passage between the intracellular environment and the extracellular space, which allows for the release of small intracellular molecules such as ATP [3], glutamate [4], NAD [5] and prostaglandin E2 [6].”
BackgroundYang, 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
“25,34,35 Previous studies have described disordered osteocyte networks in T2DM mice.”
BackgroundGrubišić, V., & Parpura, V. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00242 · Cited by 25
“Some of the glia-derived factors, e.g., prostaglandins, could be released through the Cx43 hemichannels (Cherian et al., 2005).”
BackgroundInterdependence of Pulsed Ultrasound and Shear Stress Effects on Cell Morphology and Gene Expression
McCormick, S. M., Saini, V., Yazıcıoğlu, Y., Demou, Z. N., & Royston, T. J. (2006) · Annals of Biomedical Engineering · doi:10.1007/s10439-005-9057-5 · Cited by 24
“The three controls for these conditions were: (1) no stimulation, ( 2 ) sham US exposure for 20 min followed by no stimulation, and (3) sham US exposure plus shear stress.”
MethodOsteocytes: Mechanosensors of Bone and Orchestrators of Mechanical Adaptation
Klein‐Nulend, J., & Bakker, A. D. (2007) · Clinical Reviews in Bone and Mineral Metabolism · doi:10.1007/s12018-008-9014-6 · Cited by 25
“Hemichannels expressed in bone cells such as MLO-Y4 osteocyte-like cells appear to function as essential transducers of the anti-apoptotic effects of bisphosphonates [93], and serve as portal for the exit of elevated intracellular PGE2 induced by fluid flow shear stress in osteocytes [ 94 ].”
BackgroundBone Development and Remodeling
Maes, C., & Kronenberg, H. M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-18907-1.00060-3 · Cited by 26
Bone mechanobiology in health and disease
Verbruggen, S. W., & McNamara, L. M. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812952-4.00006-4 · Cited by 24
Connexin43 enhances Wnt and PGE2-dependent activation of β-catenin in osteoblasts
Gupta, A., Chatree, S., Buo, A. M., Moorer, M. C., & Stains, J. P. (2019) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-019-02295-y · Cited by 23
Harnessing the therapeutic potential of antibodies targeting connexin hemichannels
Buratto, D., Donati, V., Zonta, F., & Mammano, F. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.166047 · Cited by 23
Multiple Roles of Connexins in Atherosclerosis- and Restenosis-Induced Vascular Remodelling
Morel, S. (2014) · Journal of Vascular Research · doi:10.1159/000362122 · Cited by 23
Permeant-specific gating of connexin 30 hemichannels
Nielsen, B. S., Alstrøm, J. S., Nicholson, B. J., Nielsen, M. S., & MacAulay, N. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.805986 · Cited by 23
“Opening of hemichannels has been proposed to occur by a range of diverse molecular cues, such as removal of divalent cations (12–15), metabolic inhibition (16 –18), membrane potentials more positive than 40 mV (in the case of Cx43 (19, 20)), membrane stretch (21, 22), and exposure to cytokines or growth factors (23, 2…”
BackgroundCelil, A. B., Minematsu, H., Gardner, T. R., Kim, K. O., Ahn, J. M., & Lee, F. Y. (2009) · Bone · doi:10.1016/j.bone.2009.08.061 · Cited by 23
Connexin-43 in Cancer: Above and Beyond Gap Junctions!
Paunikar, S., & Tamagnone, L. (2024) · Cancers · doi:10.3390/cancers16244191 · Cited by 22
Degradation of Connexins Through the Proteasomal, Endolysosomal and Phagolysosomal Pathways
Su, V., Cochrane, K., & Lau, A. F. (2012) · The Journal of Membrane Biology · doi:10.1007/s00232-012-9461-3 · Cited by 22
Cxs and Panx- hemichannels in peripheral and central chemosensing in mammals
Reyes, E. P., Cerpa, V., Corvalán, L., & Retamal, M. A. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00123 · Cited by 22
“Once functional hemichannels opened, they release NAD+, ATP, glutamate and prostaglandin E2 to the extracellular space (Bruzzone et al., 2001; Stout et al., 2002; Ye et al., 2003; Cherian et al., 2005).”
Two Different Functions of Connexin43 Confer Two Different Bone Phenotypes in Zebrafish
Misu, A., Yamanaka, H., Aramaki, T., Kondo, S., Skerrett, I. M., Iovine, M. K., & Watanabe, M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.720110 · Cited by 21
“This movement of fluid causes shear stress that induces effusion of prostaglandin E2 through hemichannels (38).”
BackgroundLi, G., Zhang, L., Lu, Z., Yang, B., Yang, H., Shang, P., Jiang, J. X., Wang, D., & Xu, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113506 · Cited by 23
“Moreover, previous studies by our group and others have proved that PGE2 released through Cx43 HCs could protect osteocytes against glucocorticoid-induced cell death [28,38].”
BackgroundResultSelf-citationConnexin 43 Hemichannels Regulate Osteoblast to Osteocyte Differentiation
Hua, R., Gu, S., & Jiang, J. X. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.892229 · Cited by 21
“In contrast, Cx43KDgroupswere not responding to FFSS-inducedHCs opening, indicating an impaired Cx43HCs activity in undifferentiated IDG-SW3 cells with Cx43 KD. Cx43 Knockdown in IDG-SW3 Cells Decreases Alkaline Phosphatase and Type I Collagen Expression at Early Differentiation Stage IDG-SW3 cells express osteoblasti…”
BackgroundInfluentialSelf-citationOsteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk
Li, G., Zhang, L., Ning, K., Yang, B., Acosta, F. M., Shang, P., Jiang, J. X., & Xu, H. (2021) · Cells · doi:10.3390/cells10020237 · Cited by 20
“We have previously reported that PGE2, released by Cx43 HCs in response to mechanical strain [37], is also critical for GJmediated intercellular communication [38], indicating that alteration in the function of the two channels may directly affect the diffusion of PGE2.”
BackgroundSelf-citationP2X7Rs: new therapeutic targets for osteoporosis
Huang, H., He, Y.-M., Lin, M., Wang, Y., Zhang, X., Li, L., & He, X. (2022) · Purinergic Signalling · doi:10.1007/s11302-021-09836-0 · Cited by 21
Perin, M., Chinigò, G., Genova, T., Mussano, F. D., & Munaron, L. (2023) · Antioxidants · doi:10.3390/antiox12030689 · Cited by 19
Zhao, D., Wu, J., Acosta, F. M., Xu, H., & Jiang, J. X. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1151838 · Cited by 21
Self-citationCalcium Regulation of Connexin Hemichannels
Bayraktar, E., Lopez‐Pigozzi, D., & Bortolozzi, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126594 · Cited by 20
Over-activated hemichannels: A possible therapeutic target for human diseases
Retamal, M. A., Fernández-Olivares, A., & Stehberg, J. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166232 · Cited by 19
Functional Roles of Connexins and Gap Junctions in Osteo-Chondral Cellular Components
Zappalà, A., Romano, I. R., D’Angeli, F., Musumeci, G., Furno, D. L., Giuffrida, R., & Mannino, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24044156 · Cited by 19
Riquelme, M. A., Wang, X., Acosta, F. M., Zhang, J., Chavez, J., Gu, S., Zhao, P., Xiong, W., Zhang, N., Li, G., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114377 · Cited by 19
Self-citationConnexin43 modulates post-natal cortical bone modeling and mechano-responsiveness
Grimston, S. K., Watkins, M. P., Stains, J. P., & Civitelli, R. (2013) · BoneKEy Reports · doi:10.1038/bonekey.2013.180 · Cited by 19
Biological responses of osteocytic connexin 43 hemichannels to simulated microgravity
Xu, H., Liu, R., Ning, D., Zhang, J., Yang, R., Riquelme, M. A., Li, J., Jiang, J. X., & Shang, P. (2016) · Journal of Orthopaedic Research® · doi:10.1002/jor.23224 · Cited by 19
“Moreover, previous studies have shown that osteocytes release PGE2 by Cx43 hemichannels in response to mechanical stress.(6,28,31,41,42) Both mechanical loading and simulated weightlessness cause PGE2 release, which may indicate a common response of osteocytes to changed physical environment,.”
Self-citation
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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