ArticleThe Journal of biological chemistry2013
Effects of isoform-selective phosphatidylinositol 3-kinase inhibitors on osteoclasts: actions on cytoskeletal organization, survival, and resorption.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 38 citations in OpenAlex.
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- The Clinical Significance of RAS, PIK3CA, and PTEN Mutations in Non-Small Cell Lung Cancer Using Cell-Free DNA.Journal of clinical medicine · 2020Article
- Osteoclast Signal Transduction During Bone Metastasis Formation.Frontiers in cell and developmental biology · 2020Review
- From Biology to Therapy: The CLL Success Story.HemaSphere · 2019Review
- Final results of a phase 1b study of the safety and efficacy of the PI3Kδ inhibitor acalisib (GS-9820) in relapsed/refractory lymphoid malignancies.Blood cancer journal · 2018Article
- Copanlisib for treatment of B-cell malignancies: the development of a PI3K inhibitor with considerable differences to idelalisib.Drug design, development and therapy · 2018Review
- PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma.Expert opinion on investigational drugs · 2017Review
- Article
- Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia.Expert opinion on investigational drugs · 2017Review
- PI3K isoform-selective inhibitors: next-generation targeted cancer therapies.Acta pharmacologica Sinica · 2015Review
- PI3K inhibitors in inflammation, autoimmunity and cancer.Current opinion in pharmacology · 2015Review
- Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization.Nature communications · 2015Article
- Leukotriene B4 activates intracellular calcium and augments human osteoclastogenesis.Arthritis research & therapy · 2014Article
- A chemical screen identifies small molecules that regulate hepcidin expression.Blood cells, molecules & diseases · 2014Article
- Editorial: lipid kinases and bone homeostasis: lessons learned from phosphoinositide 3-kinase isoform-specific knockouts.Arthritis & rheumatology (Hoboken, N.J.) · 2014Article
- PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML.Blood · 2014Article
- PI-3 kinase p110β: a therapeutic target in advanced prostate cancers.American journal of clinical and experimental urology · 2014Review
- TAT-protein blockade during ischemia/reperfusion reveals critical role for p85 PI3K-PTEN interaction in cardiomyocyte injury.PloS one · 2014Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
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