期刊
ARCHIVES OF PHARMACAL RESEARCH
卷 42, 期 8, 页码 712-721出版社
PHARMACEUTICAL SOC KOREA
DOI: 10.1007/s12272-019-01163-8
关键词
Phosphoinositide 3-kinases; Idelalisib; Osteoclast differentiation
资金
- National Research Foundation of Korea [KN-1331]
- Korea Research Institute of Chemical Technology [KK1703-F02, KK1803-F00, KK1932-20]
- National Research Council of Science & Technology (NST), Republic of Korea [KK1932-20, KK1803-F00] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Since increased number of osteoclasts could lead to impaired bone structure and low bone mass, which are common characteristics of bone disorders including osteoporosis, the pharmacological inhibition of osteoclast differentiation is one of therapeutic strategies for preventing and/or treating bone disorders and related facture. However, little data are available regarding the functional relevance of phosphoinositide 3-kinase (PI3K) isoforms in the osteoclast differentiation process. To elucidate the functional involvement of PI3K delta in osteoclastogenesis, here we investigated how osteoclast differentiation was influenced by idelalisib (also called CAL-101), which is p110 delta-selective inhibitor approved for the treatment of specific human B cell malignancies. Here, we found that receptor activator of nuclear factor kappa B ligand (RANKL) induced PI3K delta protein expression, and idelalisib inhibited RANKL-induced osteoclast differentiation. Next, the inhibitory effect of idelalisib on RANKL-induced activation of the Akt-c-Fos/NFATc1 signaling cascade was confirmed by western blot analysis and real-time PCR. Finally, idelalisib inhibited pre-osteoclast migration in the last stage of osteoclast differentiation through down-regulation of the Akt-c-Fos/NFATc1 signaling cascade. It may be possible to expand the clinical use of idelalisib for controlling osteoclast differentiation. Together, the present results contribute to our understanding of the clinical value of PI3K delta as a druggable target and the efficacy of related therapeutics including osteoclastogenesis.
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