Secretory products from PC-3 and MCF-7 tumor cell lines upregulate osteopontin in MC3T3-E1 cells

Tumor cells frequently have pronounced effects on the skeleton including bo ne destruction, bone pain, hypercalcemia, and depletion of bone marrow cell s. Despite the serious sequelae associated with skeletal metastasis, the me chanisms by which tumor cells alter bone homeostasis remain largely unknown . In this study, we tested the hypothesis that the disruption of bone homeo stasis by tumor cells is due in part to the ability of tumor cells to upreg ulate osteopontin (OPN) mRNA in osteoblasts. Conditioned media were collect ed from tumor cells that elicit either osteolytic (MCF-7, PC-3) or osteobla stic responses (LNCaP) in animal models and their effects on OPN gene expre ssion were compared using an osteoblast precursor cell line, MC3T3-E1 cells . Secretory products from osteolytic but not osteoblastic tumor cell lines were demonstrated to upregulate OPN in osteoblasts while inhibiting osteobl ast proliferation and differentiation. Signal transduction studies revealed that regulation of OPN was dependent on both protein kinase C (PKC) and th e mitogen-activated protein (MAP) kinase cascade. These results suggest tha t the upregulation of OPN may play a key role in the development of osteoly tic lesions. Furthermore, these results suggest that drugs that prevent act ivation of the MAP kinase pathway may be efficacious in the treatment of os teolytic metastases. J. Cell. Biochem. 78:607-616, 2000. (C) 2000 Wiley-Lis s, Inc.