دورية أكاديمية
Osteogenic effects of a potent Src-over-Abl-selective kinase inhibitor in the mouse.
| العنوان: | Osteogenic effects of a potent Src-over-Abl-selective kinase inhibitor in the mouse. |
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| المؤلفون: | Murrills RJ; Department of Osteoporosis and Frailty, Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, Pennsylvania, USA. murrills@aol.com, Fukayama S, Boschelli F, Matteo JJ, Owens J, Golas JM, Patel D, Lane G, Liu YB, Carter L, Jussif J, Spaulding V, Wang YD, Boschelli DH, McKew JC, Li XJ, Lockhead S, Milligan C, Kharode YP, Diesl V, Bai Y, Follettie M, Bex FJ, Komm B, Bodine PV |
| المصدر: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2012 Mar; Vol. 340 (3), pp. 676-87. Date of Electronic Publication: 2011 Dec 09. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0376362 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0103 (Electronic) Linking ISSN: 00223565 NLM ISO Abbreviation: J Pharmacol Exp Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics Original Publication: Baltimore : Williams & Wilkins |
| مواضيع طبية MeSH: | Osteogenesis/*drug effects , Protein Kinase Inhibitors/*pharmacology , Proto-Oncogene Proteins c-abl/*antagonists & inhibitors , src-Family Kinases/*antagonists & inhibitors, Amino Acid Sequence ; Animals ; Cell Differentiation ; Gene Expression Profiling ; Humans ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Osteoblasts/cytology ; Osteoblasts/drug effects ; Osteoclasts/cytology ; Osteoclasts/drug effects |
| مستخلص: | Src-null mice have higher bone mass because of decreased bone resorption and increased bone formation, whereas Abl-null mice are osteopenic, because of decreased bone formation. Compound I, a potent inhibitor of Src in an isolated enzyme assay (IC(50) 0.55 nM) and a Src-dependent cell growth assay, with lower activity on equivalent Abl-based assays, potently, but biphasically, accelerated differentiation of human mesenchymal stem cells to an osteoblast phenotype (1-10 nM). Compound I (≥0.1 nM) also activated osteoblasts and induced bone formation in isolated neonatal mouse calvariae. Compound I required higher concentrations (100 nM) to inhibit differentiation and activity of osteoclasts. Transcriptional profiling (TxP) of calvaria treated with 1 μM compound I revealed down-regulation of osteoclastic genes and up-regulation of matrix genes and genes associated with the osteoblast phenotype, confirming compound I's dual effects on bone resorption and formation. In addition, calvarial TxP implicated calcitonin-related polypeptide, β (β-CGRP) as a potential mediator of compound I's osteogenic effect. In vivo, compound I (1 mg/kg s.c.) increased vertebral trabecular bone volume 21% (microcomputed tomography) in intact female mice. Increased trabecular volume was also detected histologically in a separate bone, the femur, particularly in the secondary spongiosa (100% increase), which underwent a 171% increase in bone formation rate, a 73% increase in mineralizing surface, and a 59% increase in mineral apposition rate. Similar effects were observed in ovariectomized mice with established osteopenia. We conclude that the Src inhibitor compound I is osteogenic, presumably because of its potent stimulation of osteoblast differentiation and activation, possibly mediated by β-CGRP. |
| المشرفين على المادة: | 0 (Protein Kinase Inhibitors) EC 2.7.10.2 (Proto-Oncogene Proteins c-abl) EC 2.7.10.2 (src-Family Kinases) |
| تواريخ الأحداث: | Date Created: 20111216 Date Completed: 20120504 Latest Revision: 20120215 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1124/jpet.111.185793 |
| PMID: | 22171089 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0103 |
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| DOI: | 10.1124/jpet.111.185793 |