PARATHYROID-HORMONE INHIBITS MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION IN OSTEOSARCOMA CELLS VIA A PROTEIN-KINASE A-DEPENDENT PATHWAY

Osteoblast-like cells, such as UMR 106 osteosarcoma cells, are known t o be growth stimulated by growth factors such as EGF. In contrast, fac tors such as PTH and prostaglandin E(2) inhibit their growth. The exac t signal transduction mechanisms by which these latter factors act rem ain to be elucidated. Here we show that simultaneous treatment of UMR 106 cells with EGF and PTH-(1-34) resulted in a level of DNA synthesis intermediate between the levels of treatment with epidermal growth fa ctor (EGF) and PTH alone. This correlated with the interference of PTH (1-34) early in an EGF receptor-linked signal transduction pathway, i. e. the EGF-induced activation of p42 mitogen-activated protein (MAP) k inase. This effect was also found for prostaglandin E(2), and could be potentiated by the phosphodiesterase inhibitor isobutylmethylxanthine and mimicked by forskolin and 8-bromo-cAMP. There was a strict correl ation between the lowest concentration of PTH-(1-34) required to enhan ce protein kinase A (PKA) activity and that required to inhibit MAP ki nase activation, whereas saturating amounts of PTH-(3-34), a PTH analo g unable to elevate PKA activity, had no effect. Lysophosphatidic acid - and 12-O-tetracanoylphorbol-13-acetate-induced MAP kinase activation were also inhibited by PTH-(1-34) and forskolin in these cells. Simil ar effects were seen on basic fibroblast growth factor-mediated MAP ki nase activation in ROS 17/2.8 cells, indicating that this mechanism is a general feature of PTH in osteosarcoma cells. The inhibition of thi s mitogenic pathway through activation of PKA might play an important role in PTH-induced changes in proliferation and differentiation of os teoblasts.