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Since phosphoinositide 3-kinase (PI3-K) plays a critical role in osteoclastogenesis and bone resorption, we examined the effects of ZSTK474, a novel phosphoinositide 3-kinase (PI3-K)-specific inhibitor, on murine OCs <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>The inhibitory effect of ZSTK474 on OC formation was determined and compared with other PI3-K inhibitors by counting tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells after culturing murine bone marrow monocytic OC precursors, and RAW264.7 cells. Activation of Akt and expression of nuclear factor of activated T cells (NFAT) c1 in cultured RAW264.7 cells were examined. The suppressing effect of ZSTK474 on bone resorption was assessed by the pit formation assay. The <jats:italic>in vivo<\/jats:italic> effects of ZSTK474 were studied in collagen-induced arthritis (CIA) in the mouse. Oral daily administration of ZSTK474 was started either when more than half or when all mice developed arthritis. Effects of ZSTK474 were evaluated using the arthritis score and histological score of the hind paws.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>ZSTK474 inhibited the differentiation of bone marrow OC precursors and RAW264.7 cells in a dose-dependent manner. The inhibitory effect of ZSTK474 was much stronger than that of LY294002, the most commonly used PI3-K inhibitor. In addition, ZSTK474 suppressed the bone resorbing activity of mature OCs. Moreover, oral daily administration of ZSTK474, even when begun after the development of arthritis, ameliorated CIA in mice without apparent toxicity. Histological examination of the hind paw demonstrated noticeable reduction of inflammation and of cartilage destruction in ZSTK474-treated mice. ZSTK474 also significantly decreased OC formation adjacent to the tarsal bone of the hind paw.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>These findings suggest that inhibition of PI3-K with ZSTK474 may potentially suppress synovial inflammation and bone destruction in patients with RA.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/ar3019","type":"journal-article","created":{"date-parts":[[2010,5,18]],"date-time":"2010-05-18T18:14:49Z","timestamp":1274206489000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Inhibitory effects of ZSTK474, a novel phosphoinositide 3-kinase inhibitor, on osteoclasts and collagen-induced arthritis in mice"],"prefix":"10.1186","volume":"12","author":[{"given":"Shoko","family":"Toyama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Tamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Haruta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeo","family":"Karakida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeyuki","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Yamori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinari","family":"Takasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2010,5,18]]},"reference":[{"key":"2854_CR1","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1136\/ard.2005.044354","volume":"66","author":"B Combe","year":"2007","unstructured":"Combe B, Landewe R, Lukas C, Bolosiu HD, Breedveld F, Dougados M, Emery P, Ferraccioli G, Hazes JM, Klareskog L, Machold K, Martin-Mola E, Nielsen H, Silman A, Smolen J, Yazici H: EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). 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