Mechanical stimulation prevents osteocyte apoptosis: requirement of integrins, Src kinases, and ERKs.
Osteocytes, former osteoblasts entombed in the bone matrix, form an extensive cell communication network that is thought to detect microdamage and mechanical strains and to transmit signals leading to repair and compensatory bone augmentation or reduction. Bone active hormones and drugs control the integrity of this network by regulating osteocyte apoptosis, which might be a determinant of bone strength. Herein we demonstrate that mechanical stimulation by stretching activates the ERKs, which in turn are responsible for the attenuation of osteocyte apoptosis. The effect of osteocyte stretching is transmitted by integrins and cytoskeletal and catalytic molecules, such as Src kinases. Stretch-induced antiapoptosis also requires nuclear translocation of ERKs and new gene transcription. The evidence linking mechanical stimulation, activation of an integrin/cytoskeleton/Src/ERK signaling pathway, and osteocyte survival provides a mechanistic basis for the profound role of mechanical forces, or lack thereof, on skeletal health and disease.
Plotkin
L I
LI
Div. of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Mathov
I
I
Aguirre
J I
JI
Parfitt
A M
AM
Manolagas
S C
SC
Bellido
T
T
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002273:Carcinogens / Q000494:pharmacology; D021941:Caveolae / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology; D016023:Integrins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010011:Osteocytes / Q000166:cytology* / Q000201:enzymology*; D010812:Physical Stimulation; D012333:RNA, Messenger / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism*
D000199:Actins; D002273:Carcinogens; D005938:Glucocorticoids; D016023:Integrins; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D014404:Tubulin; D047392:beta-Cyclodextrins; D005047:Etoposide; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C031215:betadex