Effects of Isoform-selective Phosphatidylinositol 3-Kinase Inhibitors on Osteoclasts

Phosphatidylinositol 3-kinases (PI3K) participate in numerous signaling pathways, and control distinct biological functions. Studies using pan-PI3K inhibitors suggest roles for PI3K in osteoclasts, but little is known about specific PI3K isoforms in these cells. Our objective was to determine effect...

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Published in:The Journal of biological chemistry 2013-12, Vol.288 (49), p.35346-35357
Main Authors: Shugg, Ryan P.P., Thomson, Ashley, Tanabe, Natsuko, Kashishian, Adam, Steiner, Bart H., Puri, Kamal D., Pereverzev, Alexey, Lannutti, Brian J., Jirik, Frank R., Dixon, S.Jeffrey, Sims, Stephen M.
Format: Article
Language:English
Subjects:
Actin
Bone
Bone Resorption
Cytoskeleton
GS-9820
Lamellipod
Osteoclast
Phosphatidylinositol 3-Kinase
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Summary:Phosphatidylinositol 3-kinases (PI3K) participate in numerous signaling pathways, and control distinct biological functions. Studies using pan-PI3K inhibitors suggest roles for PI3K in osteoclasts, but little is known about specific PI3K isoforms in these cells. 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-p110), PIK75 (α), GDC0941 (α, δ), TGX221 (β), AS252424 (γ), and IC87114 (δ). In addition, we characterized a new potent and selective PI3Kδ inhibitor, GS-9820, and explored roles of PI3K isoforms in regulating osteoclast function. Osteoclasts were isolated from long bones of neonatal rats and rabbits. Wortmannin, LY294002, GDC0941, IC87114, and GS-9820 induced a dramatic retraction of osteoclasts within 15–20 min to 65–75% of the initial area. In contrast, there was no significant retraction in response to vehicle, PIK75, TGX221, or AS252424. Moreover, wortmannin and GS-9820, but not PIK75 or TGX221, disrupted actin belts. We examined effects of PI3K inhibitors on osteoclast survival. Whereas PIK75, TGX221, and GS-9820 had no significant effect on basal survival, all blocked RANKL-stimulated survival. When studied on resorbable substrates, osteoclastic resorption was suppressed by wortmannin and inhibitors of PI3Kβ and PI3Kδ, but not other isoforms. These data are consistent with a critical role for PI3Kδ in regulating osteoclast cytoskeleton and resorptive activity. In contrast, multiple PI3K isoforms contribute to the control of osteoclast survival. Thus, the PI3Kδ isoform, which is predominantly expressed in cells of hematopoietic origin, is an attractive target for anti-resorptive therapeutics. Background: Little is known about the function of specific phosphatidylinositol 3-kinase (PI3K) isoforms in osteoclasts. Results: Using a panel of isoform-selective inhibitors, we found that PI3Kδ regulates osteoclast morphology, actin cytoskeletal organization, and resorptive activity. Conclusion: The PI3Kδ isoform plays a critical role in regulating osteoclast resorptive activity. Significance: PI3Kδ is an attractive target for anti-resorptive therapeutics.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.507525