Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Mol. Biol. Cell 16 (7): 3100-3106

Copyright © 2005 by The American Society for Cell Biology.

Mechanical Strain Opens Connexin 43 Hemichannels in Osteocytes: A Novel Mechanism for the Release of Prostaglandin


Priscilla P. Cherian *, Arlene J. Siller-Jackson *, Sumin Gu *, Xin Wang *, Lynda F. Bonewald {dagger}, Eugene Sprague {ddagger}, and Jean X. Jiang *

* Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900
{ddagger} Department of Radiology, University of Texas Health Science Center, San Antonio, TX 78229-3900 {dagger} Department of Oral Biology, School of Dentistry, University of Missouri, Kansas City, MO 64108

Received for publication October 19, 2004. Revision received March 18, 2005. Accepted for publication April 8, 2005.

Monitoring Editor: Asma Nusrat

Abstract: 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 E2 (PGE2). Cells plated at lower densities release more PGE2 than cells plated at higher densities. This response was significantly reduced by antisense to Cx43 and by the gap junction and hemichannel inhibitors 18 {beta}-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 P2X7 and the prostaglandin transporter PGT, had no effect on PGE2 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 PGE2 in response to mechanical strain.

This article was published online ahead of print in MBC in Press (–10–0912) on April 20, 2005.

Abbreviations used: {beta}-GA, 18 {beta}-glycyrrhetinic acid; Cx43, connexin 43; DIDS, 4,4'-diisothiocyanatostilbene 2,2'-disulfonate; LY, Lucifer yellow; oATP, oxidized ATP; ODN, oligodeoxynucleotide; PGE2, prostaglandin E2; RD, rhodamine dextran.


The online version of this article contains supplemental material at MBC Online (

Address correspondence to: Jean X. Jiang (jiangj{at}

Direct Regulation of Osteocytic Connexin 43 Hemichannels through AKT Kinase Activated by Mechanical Stimulation.
N. Batra, M. A. Riquelme, S. Burra, R. Kar, S. Gu, and J. X. Jiang (2014)
J. Biol. Chem. 289, 10582-10591
   Abstract »    Full Text »    PDF »
Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways.
H. Ogawa, E. Kozhemyakina, H.-H. Hung, A. J. Grodzinsky, and A. B. Lassar (2014)
Genes & Dev. 28, 127-139
   Abstract »    Full Text »    PDF »
Hydrostatic pressure activates ATP-sensitive K+ channels in lung epithelium by ATP release through pannexin and connexin hemichannels.
K. Richter, K. P. Kiefer, B. A. Grzesik, W. G. Clauss, and M. Fronius (2014)
FASEB J 28, 45-55
   Abstract »    Full Text »    PDF »
14-3-3{theta} facilitates plasma membrane delivery and function of mechanosensitive connexin 43 hemichannels.
N. Batra, M. A. Riquelme, S. Burra, and J. X. Jiang (2014)
J. Cell Sci. 127, 137-146
   Abstract »    Full Text »    PDF »
Developmental Truncations of Connexin 50 by Caspases Adaptively Regulate Gap Junctions/Hemichannels and Protect Lens Cells against Ultraviolet Radiation.
K. Wang, S. Gu, X. Yin, S. T. Weintraub, Z. Hua, and J. X. Jiang (2012)
J. Biol. Chem. 287, 15786-15797
   Abstract »    Full Text »    PDF »
ERK acts in parallel to PKC{delta} to mediate the connexin43-dependent potentiation of Runx2 activity by FGF2 in MC3T3 osteoblasts.
C. Niger, A. M. Buo, C. Hebert, B. T. Duggan, M. S. Williams, and J. P. Stains (2012)
Am J Physiol Cell Physiol 302, C1035-C1044
   Abstract »    Full Text »    PDF »
Mechanical stress-activated integrin {alpha}5{beta}1 induces opening of connexin 43 hemichannels.
N. Batra, S. Burra, A. J. Siller-Jackson, S. Gu, X. Xia, G. F. Weber, D. DeSimone, L. F. Bonewald, E. M. Lafer, E. Sprague, et al. (2012)
PNAS 109, 3359-3364
   Abstract »    Full Text »    PDF »
Phosphorylation of Connexin 50 by Protein Kinase A Enhances Gap Junction and Hemichannel Function.
J. Liu, J. F. Ek Vitorin, S. T. Weintraub, S. Gu, Q. Shi, J. M. Burt, and J. X. Jiang (2011)
J. Biol. Chem. 286, 16914-16928
   Abstract »    Full Text »    PDF »
Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling.
M. Watkins, S. K. Grimston, J. Y. Norris, B. Guillotin, A. Shaw, E. Beniash, and R. Civitelli (2011)
Mol. Biol. Cell 22, 1240-1251
   Abstract »    Full Text »    PDF »
Aquaporin 0 enhances gap junction coupling via its cell adhesion function and interaction with connexin 50.
J. Liu, J. Xu, S. Gu, B. J. Nicholson, and J. X. Jiang (2011)
J. Cell Sci. 124, 198-206
   Abstract »    Full Text »    PDF »
Connexin 43 hemichannels mediate the Ca2+ influx induced by extracellular alkalinization.
K. A. Schalper, H. A. Sanchez, S. C. Lee, G. A. Altenberg, M. H. Nathanson, and J. C. Saez (2010)
Am J Physiol Cell Physiol 299, C1504-C1515
   Abstract »    Full Text »    PDF »
Characterization of hTERT-immortalized osteoblast cell lines generated from wild-type and connexin43-null mouse calvaria.
M. M. Thi, M. Urban-Maldonado, D. C. Spray, and S. O. Suadicani (2010)
Am J Physiol Cell Physiol 299, C994-C1006
   Abstract »    Full Text »    PDF »
Mechanotransduction in bone repair and regeneration.
C. Huang and R. Ogawa (2010)
FASEB J 24, 3625-3632
   Abstract »    Full Text »    PDF »
Dendritic processes of osteocytes are mechanotransducers that induce the opening of hemichannels.
S. Burra, D. P. Nicolella, W. L. Francis, C. J. Freitas, N. J. Mueschke, K. Poole, and J. X. Jiang (2010)
PNAS 107, 13648-13653
   Abstract »    Full Text »    PDF »
Osteocytes and WNT: the Mechanical Control of Bone Formation.
C. Galli, G. Passeri, and G. M. Macaluso (2010)
Journal of Dental Research 89, 331-343
   Abstract »    PDF »
Gap junction hemichannels contribute to the generation of diarrhoea during infectious enteric disease.
J. A. Guttman, A. En-Ju Lin, Y. Li, J. Bechberger, C. C. Naus, A. W. Vogl, and B. B. Finlay (2010)
Gut 59, 218-226
   Abstract »    Full Text »    PDF »
On a Path to Unfolding the Biological Mechanisms of Orthodontic Tooth Movement.
V. Krishnan and Z. Davidovitch (2009)
Journal of Dental Research 88, 597-608
   Abstract »    PDF »
Connexin43 Potentiates Osteoblast Responsiveness to Fibroblast Growth Factor 2 via a Protein Kinase C-Delta/Runx2-dependent Mechanism.
F. Lima, C. Niger, C. Hebert, and J. P. Stains (2009)
Mol. Biol. Cell 20, 2697-2708
   Abstract »    Full Text »    PDF »
Advancing our understanding of osteocyte cell biology..
Dayong Guo and L. F. Bonewald (2009)
Therapeutic Advances in Musculoskeletal Diseases 1, 87-96
   Abstract »    PDF »
The P2X7 Receptor Drives Microglial Activation and Proliferation: A Trophic Role for P2X7R Pore.
M. Monif, C. A. Reid, K. L. Powell, M. L. Smart, and D. A. Williams (2009)
J. Neurosci. 29, 3781-3791
   Abstract »    Full Text »    PDF »
Gap Junction Inhibitors Reduce Endothelium-Dependent Contractions in the Aorta of Spontaneously Hypertensive Rats.
E. H. C. Tang and P. M. Vanhoutte (2008)
J. Pharmacol. Exp. Ther. 327, 148-153
   Abstract »    Full Text »    PDF »
Adaptation of Connexin 43-Hemichannel Prostaglandin Release to Mechanical Loading.
A. J. Siller-Jackson, S. Burra, S. Gu, X. Xia, L. F. Bonewald, E. Sprague, and J. X. Jiang (2008)
J. Biol. Chem. 283, 26374-26382
   Abstract »    Full Text »    PDF »
Mechanisms of conduction slowing during myocardial stretch by ventricular volume loading in the rabbit.
R. W. Mills, S. M. Narayan, and A. D. McCulloch (2008)
Am J Physiol Heart Circ Physiol 295, H1270-H1278
   Abstract »    Full Text »    PDF »
Mechanobiology of tooth movement.
S. Henneman, J. W. Von den Hoff, and J. C. Maltha (2008)
Eur J Orthod 30, 299-306
   Abstract »    Full Text »    PDF »
Cx43 Hemichannels and Gap Junction Channels in Astrocytes Are Regulated Oppositely by Proinflammatory Cytokines Released from Activated Microglia.
M. A. Retamal, N. Froger, N. Palacios-Prado, P. Ezan, P. J. Saez, J. C. Saez, and C. Giaume (2007)
J. Neurosci. 27, 13781-13792
   Abstract »    Full Text »    PDF »
In vivo analysis of undocked connexin43 gap junction hemichannels in ovarian granulosa cells.
D. Tong, T. Y. Li, K. E. Naus, D. Bai, and G. M. Kidder (2007)
J. Cell Sci. 120, 4016-4024
   Abstract »    Full Text »    PDF »
Long-Chain Polyunsaturated Fatty Acids and the Regulation of Bone Metabolism.
R. C. Poulsen, P. J. Moughan, and M. C. Kruger (2007)
Experimental Biology and Medicine 232, 1275-1288
   Abstract »    Full Text »    PDF »
Promotion of lens epithelial-fiber differentiation by the C-terminus of connexin 45.6 a role independent of gap junction communication.
E. A. Banks, X. S. Yu, Q. Shi, and J. X. Jiang (2007)
J. Cell Sci. 120, 3602-3612
   Abstract »    Full Text »    PDF »
Mechanically stimulated osteocytes regulate osteoblastic activity via gap junctions.
A. F. Taylor, M. M. Saunders, D. L. Shingle, J. M. Cimbala, Z. Zhou, and H. J. Donahue (2007)
Am J Physiol Cell Physiol 292, C545-C552
   Abstract »    Full Text »    PDF »
Connexin Hemichannels and Gap Junction Channels Are Differentially Influenced by Lipopolysaccharide and Basic Fibroblast Growth Factor.
E. De Vuyst, E. Decrock, M. De Bock, H. Yamasaki, C. C. Naus, W. H. Evans, and L. Leybaert (2007)
Mol. Biol. Cell 18, 34-46
   Abstract »    Full Text »    PDF »
Species specificity of mammalian connexin-26 to form open voltage-gated hemichannels.
D. Gonzalez, J. M. Gomez-Hernandez, and L. C. Barrio (2006)
FASEB J 20, 2329-2338
   Abstract »    Full Text »    PDF »
Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43.
D. J. Chung, C. H. M. Castro, M. Watkins, J. P. Stains, M. Y. Chung, V. L. Szejnfeld, K. Willecke, M. Theis, and R. Civitelli (2006)
J. Cell Sci. 119, 4187-4198
   Abstract »    Full Text »    PDF »
S-nitrosylation and permeation through connexin 43 hemichannels in astrocytes: Induction by oxidant stress and reversal by reducing agents.
M. A. Retamal, C. J. Cortes, L. Reuss, M. V. L. Bennett, and J. C. Saez (2006)
PNAS 103, 4475-4480
   Abstract »    Full Text »    PDF »
Intracellular calcium changes trigger connexin 32 hemichannel opening.
E. De Vuyst, E. Decrock, L. Cabooter, G. R. Dubyak, C. C. Naus, W. H. Evans, and L. Leybaert (2006)
EMBO J. 25, 34-44
   Abstract »    Full Text »    PDF »
The P2X7 Nucleotide Receptor Mediates Skeletal Mechanotransduction.
J. Li, D. Liu, H. Z. Ke, R. L. Duncan, and C. H. Turner (2005)
J. Biol. Chem. 280, 42952-42959
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882