Adaptation of connexin 43-hemichannel prostaglandin release to mechanical loading.
Bone tissues respond to mechanical loading/unloading regimens to accommodate (re)modeling requirements; however, the underlying molecular mechanism responsible for these responses is largely unknown. Previously, we reported that connexin (Cx) 43 hemichannels in mechanosensing osteocytes mediate the release of prostaglandin, PGE(2), a crucial factor for bone formation in response to anabolic loading. We show here that the opening of hemichannels and release of PGE(2) by shear stress were significantly inhibited by a potent antibody we developed that specifically blocks Cx43-hemichannels, but not gap junctions or other channels. The opening of hemichannels and release of PGE(2) are magnitude-dependent on the level of shear stress. Insertion of a rest period between stress enhances this response. Hemichannels gradually close after 24 h of continuous shear stress corresponding with reduced Cx43 expression on the cell surface, thereby reducing any potential negative effects of channels staying open for extended periods. These data suggest that Cx43-hemichannel activity associated with PGE(2) release is adaptively regulated by mechanical loading to provide an effective means of regulating levels of extracellular signaling molecules responsible for initiation of bone (re)modeling.
Siller-Jackson
Arlene J
AJ
Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
Burra
Sirisha
S
Gu
Sumin
S
Xia
Xuechun
X
Bonewald
Lynda F
LF
Sprague
Eugene
E
Jiang
Jean X
JX
D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D002460:Cell Line; D002645:Chickens; D018031:Connexin 43 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism*; D013314:Stress, Mechanical; D013997:Time Factors
D018031:Connexin 43; D007473:Ion Channels; D015232:Dinoprostone