Effects of transforming growth factor-beta1 on parathyroid hormone-related protein mRNA expression and protein secretion in canine prostate epithelial, stromal, and carcinoma cells.

Abstract

Bone metastases of prostate carcinoma are associated with osteoblastic metastases. Tumor-derived factors, such as parathyroid hormone-related protein (PTHrP), may promote the development of osteoblastic metastases. We examined the effect of transforming growth factor-beta1 (TGF beta 1) on PTHrP mRNA expression and PTHrP secretion in normal canine prostate epithelial cells (PEC) and stromal cells (PSC), and in canine prostate carcinoma cells (PCC). Primary cultures of PEC, PSC, and PCC were produced. The effect of TGF beta 1 on PTHrP mRNA expression was measured by Northern blot, and secretion of PTHrP into culture medium was measured by immunoradiometric assay (IRMA). Degradation of recombinant-human PTHrP (rhPTHrP) (1-84) inoculated in prostate cell cultures was measured over 24 hr. Arginine esterase (AE) activity in tissue and conditioned medium was also measured. TGF beta 1 increased PTHrP mRNA expression in a time- and dose-dependent manner in PEC and in PCC. TGF beta 1 decreased PTHrP mRNA in PSC. TGF beta 1 significantly increased PTHrP secretion (P < or = 0.05) into PEC but not PSC conditioned medium. rhPTHrP was significantly (P < or = 0.05) degraded in PEC conditioned medium as compared to PSC conditioned medium. AE activity was present in prostate and prostate carcinoma tissue, but not in conditioned medium from PEC or PSC. TGF beta 1 increased PTHrP mRNA expression in canine PEC and PCC, and decreased expression in PSC. This regulatory pathway may be important in the pathogenesis of osteoblastic metastases.