@article {Murrills676, author = {Richard J. Murrills and Shoichi Fukayama and Frank Boschelli and Jeanne J. Matteo and Jane Owens and Jennifer M. Golas and Dharmesh Patel and Giovan Lane and Yao-Bin Liu and Laura Carter and Jason Jussif and Vikki Spaulding and Yanong D. Wang and Diane H. Boschelli and John C. McKew and X. Jian Li and Susan Lockhead and Colleen Milligan and Yogendra P. Kharode and Veronica Diesl and Yuchen Bai and Max Follettie and Frederick J. Bex and Barry Komm and Peter V. N. Bodine}, title = {Osteogenic Effects of a Potent Src-over-Abl-Selective Kinase Inhibitor in the Mouse}, volume = {340}, number = {3}, pages = {676--687}, year = {2012}, doi = {10.1124/jpet.111.185793}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 (IC50 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{\textendash}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{\textquoteright}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{\textquoteright}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.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/340/3/676}, eprint = {https://jpet.aspetjournals.org/content/340/3/676.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }