Modulation of adhesion-dependent cAMP signaling by echistatin and alendronate.
We measured intracellular cAMP levels in cells during attachment and spreading on different extracellular matrix (ECM) proteins. Increases in cAMP were observed within minutes when cells attached to fibronectin, vitronectin, and a synthetic RGD-containing fibronectin peptide (Petite 2000), but not when they adhered to another integrin alpha nu beta 3 ligand, echistatin. Because echistatin also inhibits bone resorption, we measured the effects of adding another osteoporosis inhibitor, alendronate, in this system. Alendronate inhibited the cAMP increase induced by ligands that primarily utilize integrin alpha nu beta 3 (vitronectin, Peptite 2000), but not by fibronectin which can also use integrin alpha 5 beta 1. These results show that cell adhesion to ECM can increase intracellular cAPM levels and raise the possibility that inhibitors of osteoporosis may act, in part, by preventing activation of this pathway by integrins.
Fong
J H
JH
Department of Surgery, Children's Hospital & Harvard Medical School, Boston, Massachusetts 02115, USA.
Ingber
D E
DE
D019386:Alendronate; D001665:Binding Sites; D002448:Cell Adhesion; D000242:Cyclic AMP / Q000378:metabolism*; D004164:Diphosphonates / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D004164:Diphosphonates; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; D010455:Peptides; C057986:echistatin; C047981:arginyl-glycyl-aspartic acid; D000242:Cyclic AMP; D019386:Alendronate