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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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“These features, along with connexin-based (notably the Cx43 subunit) gap junctions in the connections between osteocyte processes contribute to making dendrites more sensitive sensors of mechanical stimuli than osteocyte cells bodies (Cheng et al., 2001; Cherian et al., 2005; Adachi et al., 2009; Burra et al., 2010; T…”
BackgroundConnexins in Cancer, the Possible Role of Connexin46 as a Cancer Stem Cell-Determining Protein
León-Fuentes, I. M., Salgado-Gil, M. G., Novoa, M. S., & Retamal, M. A. (2023) · Biomolecules · doi:10.3390/biom13101460 · Cited by 5
“Furthermore, they have been found to be involved in osmotic regulation [56], light processing in the retina [57], CO 2 sensing [58], and PGE 2 release [59].”
Backgroundvan Megen, W. H., Canki, E., Wagenaar, V. H. A., van Waes, C. R. M. M., Peters, D. J. M., van der Wijst, J., & Hoenderop, J. G. J. (2023) · The FASEB Journal · doi:10.1096/fj.202301434r · Cited by 5
“58 Importantly, fluid shear stress strongly upregulated Ptgs2 expression in the current study and in previous studies.”
ResultConnexin 43 in the function and homeostasis of osteocytes: a narrative review
Ma, L., Wang, W., Xu, G., Li, H., Liu, F., Shao, H., Zhang, X., Ma, Y., Li, G., Li, H. Y., et al. (2024) · Annals of Joint · doi:10.21037/aoj-23-65 · Cited by 5
“In addition, mechanical signals detected by bone cells can be communicated to osteoblasts through GJIC (51,52).”
InfluentialLee, S. J., Jung, D. K., Im, S. U., You, C., Kim, J.-E., Bae, J., Kim, M.-S., Yea, K., & Park, E. K. (2024) · Animal Cells and Systems · doi:10.1080/19768354.2024.2409460 · Cited by 6
“Osteo-cytes act as sensors sensitive to fluid shear stress and utilize these biophysical signals to release molecules that modulate bone metabolism, including bone remodeling (Cheng et al. 2001; Cherian et al. 2005; Kulkarni et al. 2010; Li et al. 2012; Spatz et al. 2015).”
BackgroundRole of osteocytes in the adaptation of bone to mechanical loading
Bakker, A. D., & Klein‐Nulend, J. (2008) · Future Rheumatology · doi:10.2217/17460816.3.6.571 · Cited by 5
Mo, C., Wang, Z., Bonewald, L. F., & Brotto, M. A. P. (2017) · Molecular and integrative toxicology · doi:10.1007/978-3-319-56192-9_9 · Cited by 5
Self-citationSrivastava, T., Garola, R. E., Zhou, J., Boinpelly, V. C., Priya, L., Ali, M. F., Rezaiekhaligh, M. H., Heruth, D. P., Novák, J., Alon, U. S., et al. (2022) · The FASEB Journal · doi:10.1096/fj.202200875r · Cited by 5
Shang, P. (2016) · Frontiers in bioscience · doi:10.2741/4516 · Cited by 5
“Cx43 hemichannels in osteocytes have been shown to mediate the release of metabolic molecules in response to stress stimulation, including prostaglandins (PGs), ATP, etc (33-35).”
BackgroundRole of Connexin Hemichannels in Neurodegeneration
Juan, A., Giaume, C., & Cheng, J. (2011) · InTech eBooks · doi:10.5772/28054 · Cited by 5
“…allow cellular release of relevant quantities of autocrine/paracrine signaling molecules (e.g., ATP, glutamate, NAD + and PGE 2 ) to the extracellular milieu (Bruzzone et al. 2001; Cherian et al. 2005; Stout et al. 2002), as well as uptake of small molecules (e.g., glucose) (Retamal et al. 2007a).”
Anabolic Effect of Prostaglandins
Raisz, L. G. (2006) · Clinical Reviews in Bone and Mineral Metabolism · doi:10.1385/bmm:4:2:123 · Cited by 5
“In addition to increasing prostaglandin production through COX-2, mechanical strain may act by other mechanisms, these include opening of hemi channels that may allow release of prostaglandins and increasing nitric oxide production ( 29 ,30).”
BackgroundConnexin in Lens Physiology and Cataract Formation
Retamal, M. A. (2011) · Journal of Clinical & Experimental Ophthalmology · doi:10.4172/2155-9570.s1-001 · Cited by 8
“The presence of undocked functional hemichannels acting as channels at the plasma membrane has been demonstrated in several cell types, using morphological [8284], biochemical [12,60,61,85,86], electrophysiological [13,87-92], optical [81,93] and functional [i.”
BackgroundAcoustic Therapy as Mechanical Stimulation of Osteogenesis
de Gusmão, C. V. B., Alves, J. M., & Belangero, W. D. (2016) · InTech eBooks · doi:10.5772/63745 · Cited by 5
Cell–Cell and Cell–Matrix Interactions in Bone
Bonewald, L. F. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00313-2 · Cited by 5
Self-citationLian, J. B., & Stein, G. S. (2008) · Elsevier eBooks · doi:10.1016/b978-012370544-0.50008-2 · Cited by 5
Cells Involved in Mechanotransduction Including Mesenchymal Stem Cells
Zuckerman, P. C., Liu, C., & Castillo, A. B. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11209-7 · Cited by 5
Osteocyte Cell-Cell Communication Within and Beyond Bone
Bakker, A. D., & van Santen, V. J. B. (2026) · Current Osteoporosis Reports · doi:10.1007/s11914-026-00964-3 · Cited by 4
Bonewald, L. F. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-813073-5.00007-1 · Cited by 8
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Coelho‐Aguiar, J. D. M., Veríssimo, C. P., Costa, D. V. D. S., Thomasi, B. B. D. M., Bon‐Frauches, A. C., Ribeiro, F. P., Gomes, A. L. T., Brito, G. A. D. C., & Moura‐Neto, V. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.89170 · Cited by 8
“Some of the glia-derived factors, for example, ATP and prostaglandins, could be released through the Cx43 hemichannels [26].”
Genetic deletion of connexin 37 causes polyuria and polydipsia
Xue, J., Thomas, L., Dominguez, J. A., Fenton, R. A., & Rieg, T. (2020) · PLoS ONE · doi:10.1371/journal.pone.0244251 · Cited by 4
“PGE2 is an important regulator of urinary concentrating ability [73,74] and Cx43 has been shown to regulate PGE2 release from osteocytes [75].”
BackgroundWang, X., Nyman, J. S., Dong, X., Leng, H., & Reyes, M. (2010) · Synthesis lectures on tissue engineering · doi:10.1007/978-3-031-02579-2_1 · Cited by 4
Self-citationOsteoblast Biology and Mechanosensing
Marie, P. J., & Marie, P. J. (2010) · Springer eBooks · doi:10.1007/978-4-431-89757-6_8 · Cited by 4
Effects of Spinal Cord Injury and Related Conditions
Yarrow, J. F., & Cardozo, C. P. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11219-x · Cited by 5
Wang, G., Quan, Y., Ma, B., Gu, S., & Jiang, J. X. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103767 · Cited by 3
Self-citationBone Biology for Implant Dentistry in Atrophic Alveolar Ridge - Theory and Practice
Keun, J. (2011) · InTech eBooks · doi:10.5772/16509 · Cited by 3
“Connexons can work even without coupling with apposing connexons letting the PG E2 or ATP out of the cell in response to mechanical stimulation (Cherian et al., 2005).”
BackgroundCommunication intercellulaire et remodelage osseux
Talbot, J., & Verrecchia, F. (2012) · Biologie Aujourd hui · doi:10.1051/jbio/2012016 · Cited by 3
Connective tissue responses to mechanical stress
Salter, D. M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-09138-1.00008-5 · Cited by 3
Unloading of intercellular tension induces the directional translocation of PKCα
Sera, T., Masataka, A. R. A. I., Cui, Z., ONOSE, K., Karimi, A., & Susumu, K. U. D. O. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27662 · Cited by 3
“In addition, mechanical stress reportedly induces the direct opening of hemichannels in osteocytes (Batra et al., 2014; Cherian et al., 2005) and keratinocytes (Takada et al., 2014).”
Background
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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