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Prostate carcinoma is one of the most common malignancies affecting males, resulting in a high rate of morbidity and mortality. This hormone-dependent malignancy is characteristically associated with a high incidence of osteoblastic skeletal lesions. However, osteolytic lesions invariably accompany blastic ones. In the current study, we assessed the role of parathyroid hormone-related peptide (PTHRP), a potent bone-resorbing agent, in contributing to bone breakdown and prostatic skeletal metastasis using a syngeneic rat prostate cancer model. The full-length cDNA encoding rat PTHRP was subcloned as a Hind III insert in the sense orientation into the mammalian expression vector pRc-CMV to generate the expression vector pRc-PTHRP-S. Both control and experimental plasmids were stably transfected into low PTHRPproducing Dunning R3227, Mat Ly Lu rat prostate cancer cells. Prostatic cancer has a high propensity to metastasize to the skeleton, and skeletal metastatic disease is a major cause of morbidity (Chiarodo et al., 1991). Osteoblastic lesions are characteristic of the bone disease caused by prostate cancer, and indeed, prostate cancer is one of the most common cancers associated with osteoblastic bone disease. Several potential mediators of the osteoblastic response in bone have been described, including transforming growth factor beta (TGF-␤), fibroblast growth factor (FGF), bone morphogenetic protein (BMP) and the NH 2 -terminal region of urokinase (Harris et al., 1994;Rabbani et al., 1990Rabbani et al., , 1992. Many, if not all, skeletal lesions of prostate cancer, however, also include an osteolytic component (Franks, 1973). Both histological and biochemical evidence support the presence of osteolysis in association with prostate cancer metastases to bone; nevertheless, this component of the disease has received relatively little attention (Franks, 1973;Takeuchi et al., 1996). The most common skeletal response to cancer metastases in general is osteolysis, and the mechanisms underlying this response are now beginning to be defined. The mediators of osteolysis appear to include cytokines, growth factors and possibly prostaglandins released either by invading tumor cells or by host cells in bone in response to invading tumor cells (Jilka et al., 1992;Bonjour and Rizzoli, 1989;Francini et al., 1993).Parathyroid hormone-related peptide (PTHRP) is a moiety which was first discovered as a mediator of hypercalcemia associated with malignancy (Henderson et al., 1989;Suva et al., 1987;Asadi et al., 1996). Three PTHRP isoforms exist in humans, which are 139, 141 and 173 amino acids in length. All isoforms share homology at the NH 2 terminus with the NH 2 region of parathyroid hormone (PTH) (Moseley et al., 1987; Steward et al, 1987;Strewler et al., 1987;Rabbani et al., 1986). This homology facilitates interaction with a common PTH/PTHRP receptor and serves as the molecular basis for similar biological actions of PTH and PTHRP (Jüeppner et al., 1991;Abou-Samra et al., 1992). Included in these actions is the capacity to...

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