Editors' ChoiceBONE

Osteocytes Losing Their Grip?

Science's STKE  21 Aug 2007:
Vol. 2007, Issue 400, pp. tw298
DOI: 10.1126/stke.4002007tw298

Glucocorticoid hormones, which are produced in response to stress, exhibit immunosuppressive and anti-inflammatory activity, properties that lead to their use in treating various medical conditions. Long-term use of glucocorticoids, however, leads to increased bone fragility, an undesirable side effect associated with an increase in osteocyte apoptosis. Plotkin et al. found that dexamethasone treatment of cultured osteocytic MLO-Y4 cells elicited apoptosis even in the presence of inhibitors of protein or RNA synthesis but failed to do so in the presence of the glucocorticoid receptor antagonist RU486. Dexamethasone also stimulated an RU486-sensitive decrease in the number of cytoplasmic processes (an indicator of cell detachment), as well as cytoskeletal reorganization, both of which occurred substantially before apoptosis. In contrast, apoptosis in response to etoposide was not preceded by cell detachment. A cell-permeable caspase inhibitor prevented apoptosis, but not dexamethasone-mediated cell detachment. Cells overexpressing focal adhesion kinase (FAK) are resistant to dexamethasone-induced apoptosis. In contrast, expression of an inactive mutant form of Pyk2--a FAK-related kinase that was rapidly phosphorylated on tyrosine 402 in response to dexamethasone--or a form that could not be phosphorylated on tyrosine 402 (Y402F Pyk2) prevented dexamethasone-mediated apoptosis. Furthermore, Pyk2 knockdown rendered cells resistant to both dexamethasone-mediated detachment and apoptosis. c-Jun N-terminal kinase (JNK) is a target of Pyk2, and both pharmacological inhibition of JNK and expression of a dominant-negative JNK mutant inhibited dexamethasone-dependent cell detachment and apoptosis. Moreover, JNK overexpression (or overexpression of an upstream JNK activator) counteracted the antiapoptotic effects of Y402F Pyk2. Thus, the authors conclude that glucocorticoids elicit osteocyte apoptosis by inhibiting cell adhesion through a pathway involving Pyk2 and JNK.

L. I. Plotkin, S. C. Manolagas, T. Bellido, Glucocorticoids induce osteocyte apoptosis by blocking focal adhesion kinase-mediated survival: Evidence for inside-out signaling leading to anoikis. J. Biol. Chem. 282, 24120-24130 (2007). [Abstract] [Full Text]