Linked Life Data

17581824

Source:http://linkedlifedata.com/resource/pubmed/id/17581824

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
33
pubmed:dateCreated
2007-8-13
pubmed:abstractText
Bone fragility induced by chronic glucocorticoid excess is due, at least in part, to induction of osteocyte apoptosis through direct actions on these cells. However, the molecular mechanism by which glucocorticoids shorten osteocyte life span has remained heretofore unknown. We report that apoptosis of osteocytic MLO-Y4 cells induced by the synthetic glucocorticoid dexamethasone is abolished by the glucocorticoid receptor antagonist RU486, but not by inhibition of protein or RNA synthesis. Dexamethasone-induced apoptosis is preceded by a decrease in the number of cytoplasmic processes, an indicator of cell detachment. In addition, the focal adhesion kinase FAK prevents dexamethasone-induced apoptosis, whereas the FAK-related kinase Pyk2 increases the basal levels of apoptosis. Dexamethasone-induced apoptosis is also prevented in cells expressing kinase-deficient or phosphorylation-defective (Y402F) dominant negative mutants of Pyk2. Consistent with the requirement of tyrosine 402, dexamethasone induces rapid Pyk2 phosphorylation in this residue. Moreover, knocking down Pyk2 expression abolishes apoptosis and cell detachment induced by dexamethasone, and transfection with human Pyk2 rescues both responses. Furthermore, induction of apoptosis as well as cell detachment by dexamethasone is abolished by inhibiting the activity of JNK, a recognized downstream target of Pyk2 activation. These results demonstrate that glucocorticoids promote osteocyte apoptosis via a receptor-mediated mechanism that does not require gene transcription and that is mediated by rapid activation of Pyk2 and JNK, followed by inside-out signaling that leads to cell detachment-induced apoptosis or anoikis.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
17
pubmed:volume
282
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
24120-30
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Glucocorticoids induce osteocyte apoptosis by blocking focal adhesion kinase-mediated survival. Evidence for inside-out signaling leading to anoikis.
pubmed:affiliation
Division of Endocrinology and Metabolism, the Center for Osteoporosis and Metabolic Bone Diseases, the Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural