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Connexin 43 hemichannels are regulated by mechanical stress and α5 integrin in osteocyte -like cells
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Connexin 43 hemichannels are regulated by mechanical stress and α5 integrin in osteocyte -like cells
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Connexin 43 hemichannels are regulated by mechanical stress and α5 integrin in osteocyte -like cells
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Dissertation
Connexin 43 hemichannels are regulated by mechanical stress and α5 integrin in osteocyte -like cells
2007
Overview
Osteocytes are thought to be the mechanosensors in bone. The MLO-Y4 cell line has been established and characterized to provide a model in which to study osteocyte properties and functions. They express large amounts of the protein connexin 43 (Cx43), which forms hemichannels on the cell surface. Integrins are also expressed on the cell surface where they are proposed to be mechanical sensors that convey the signals elicited by mechanical stress in many cell types, including osteocytes. We report here that functions of Cx43-hemichannels are closely regulated by mechanical stimulation, causing the opening of hemichannels and release of prostaglandin E2 (PGE 2), an important bone modulator. Both of which were magnitude-dependent, that is increasing response to increased fluid flow shear stress (FFSS). Hemichannels are dynamic, gradually closed over time during post-stress periods and becoming increasingly \"desensitized\" to continuous shear. However, allowing a rest period between mechanical loadings enhanced the hemichannel response. Using a potent hemichannel blocking antibody, developed in our laboratory, significantly inhibited the opening of hemichannels and release of PGE2 induced by FFSS, suggesting the direct involvement of Cx43 in forming functional hemichannels. We found that regulation of Cx43-hemichannels by mechanical stimulation is facilitated by its interaction with α5 integrin. Immunofluorescence microscopy and reciprocal co-immunoprecipitation experimental results show that α5 integrin associates with Cx43. α5 integrin blocking antibody or knockdown of α5 integrin in MLO-Y4 cells by siRNA inhibited the opening of hemichannels induced by FFSS, as measured by dye uptake, and α5 integrin siRNA caused a change in the intracellular distribution pattern of Cx43. Together, these results imply hemichannels formed by Cx43 are tightly regulated by mechanical stimulation and α5 integrin functions as a regulator for the opening of Cx43-forming hemichannels in response to mechanical stress. Establishing the novel role(s) that α5 integrin plays in the regulation of hemichannel activities will reveal a major mechanism for osteocyte signaling in response to mechanical stress, and may provide potential therapeutic targets for treatment of bone diseases.
