Date of Award
Master of Science
Dr. Stephen M. Sims
Dr. S. Jeffrey Dixon
Phosphatidylinositol 3-kinases (PI3K) are key intracellular signaling molecules. Our objective was to determine effects of isoform-selective PI3K inhibitors on osteoclasts. The following inhibitors were investigated (targets in parentheses): wortmannin and LY294002 (pan-pllO), PIK75 (a), GDC0941 (a, 5), TGX221 (p), AS252424 (y), IC87114 (5) and CAL-120 (5). Wortmannin, GDC0941, IC87114 and CAL-120 induced dramatic retraction of rat osteoclasts. In contrast, there was no significant retraction in response to vehicle, PIK75, TGX221 or AS252424. Moreover, wortmannin and CAL- 120, but not PIK75 or TGX221, disrupted filamentous F-actin belts; and CAL-120 inhibited the formation of sealing zones. In contrast to their selective actions on cytoskeletal organization, PIK75, TGX221 and CAL-120 blocked RANKL-stimulated osteoclast survival. Thus, PI3K8 appears to play a specific role in regulating osteoclast cytoskeleton. In contrast, multiple PI3K isoforms control osteoclast survival. The PI3K5 isoform, which has more limited tissue distribution than PI3Ka and PI3KP, is an attractive target for anti-resorptive therapeutics
Shugg, Ryan P.P., "EFFECTS OF ISOFORM-SELECTIVE PHOSPHATIDYLINOSITOL-3 KINASE INHIBITORS ON OSTEOCLASTS" (2011). Digitized Theses. 3336.