title: Signal pathways that transduce growth factor-stimulated mitogenesis in bone cells.
abstract: This investigation examined which signal pathways are of relevance in growth factor-stimulated bone cell mitogenesis. Platelet-derived growth factor (PDGF) and insulin-like growth factor-II (IGF-II) were potent mitogens for both the MG-63 osteoblast cell line and for primary cultures of human osteoblasts (HObs). The mitogenic action of both IGF-II and PDGF was attenuated by pertussis toxin (Ptx), by indomethacin, and by the lipoxygenase inhibitors BW755C74 and BW4AC. A combination of Ptx and indomethacin caused much greater inhibition but failed to abolish mitogenesis completely. PDGF significantly elevated inositol phosphates levels in both cell types; IGF-II had no effect on this pathway. In MG-63 cells, we demonstrated tyrosine phosphorylation of high-molecular-weight substrates elicited by both PDGF and IGF-II. Genistein inhibited the phosphorylation and mitogenic response to PDGF, but had no effect on IGF-II-induced tyrosine phosphorylation or mitogenesis. Another inhibitor of tyrosine kinases, methyl 2,5-dihydroxycinnamate, (MDHC), inhibited PDGF-stimulated mitogenesis effectively in both cell types but only blocked IGF-II-induced mitogenesis in MG-63 cells. The specificity of these inhibitors suggests that particular tyrosine kinases may regulate growth factor-induced stimulation of bone cells.
authors.affiliation: Department of Oral and Dental Science, University of Bristol, UK. Jonathan.Sandy@bris.ac.uk
authors.forename: J
authors.initials: J
authors.lastname: Sandy
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.forename: S
authors.initials: S
authors.lastname: Prime
authors.forename: R
authors.initials: R
authors.lastname: Farndale
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004261:DNA Replication; D005260:Female; D005269:Femur / Q000166:cytology; D019833:Genistein / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D037342:Pertussis Toxin; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D002934:Cinnamates; D006133:Growth Substances; D007295:Inositol Phosphates; D016859:Lipoxygenase Inhibitors; D010566:Virulence Factors, Bordetella; C067472:methyl 2,5-dihydroxycinnamate; D019833:Genistein; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; D007213:Indomethacin