ERK 1,2 and p38 pathways are involved in the proliferative stimuli mediated by urokinase in osteoblastic SaOS-2 cell line

Bone metastases from prostate origin generate an osteoblastic reaction that is expressed in vitro by increased osteoblast proliferation. The urokinase -like plasminogen activator (u-PA) present in the media conditioned by tumo ral prostatic cells acting as a ligand of the cellular membrane receptor W- PAR), has been identified as the specific factor that modulates this prolif erative reaction. The present study represents an effort to unravel the int racellular pathway by which u-PA activates osteoblastic proliferation and t o evaluate the role of cellular receptor u-PAR in this proliferative phenom enon. Our results show that in vitro u-PA stimulates proliferation of SaOS- 2 osteoblastic cells by activating the MAP kinase route of ERK1 and 2 and t he p38 pathway. These results are in accordance with the inhibition of inte rmediate activation and cell proliferation by PD 098059 and SB 203580, spec ific inhibitors of MEK and p38, respectively. We also show that SaOS-2 cell s increase their proliferative response when cells are plated onto vitronec tin, the second natural ligand of u-PAR, and that culturing SaOS-2 cells in the presence of u-PA represents a stimuli for u-PAR expression. On the bas is of these, results we propose that osteoblastic cel Is respond to the pro state-derived u-PA stimuli in a very efficient manner that includes the uti lization of two different signaling routes and the stimulation of the expre ssion of the u-PA receptor. J. Cell. Biochem. 83: 92-98, 2001. (C) 2001 Wil ey-Liss, Inc.