Effects of Transforming Growth Factor-β1 on Parathyroid Hormone-Related Protein mRNA Expression and Protein Secretion in Canine Prostate Epithelial, Stromal, and Carcinoma Cells

BACKGROUND. 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-β1 (TGFβ1) 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). METHODS. Primary cultures of PEC, PSC, and PCC were produced. The effect of TGFβ1 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 prostrate cell cultures was measured over 24 hr. Arginine esterase (AE) activity in tissue and conditioned medium was also measured. RESULTS. TGFβ1 increased PTHrP mRNA expression in a time- and dose-dependent manner in PEC and in PCC. TGFβ1 decreased PTHrP mRNA in PSC. TGFβ1 significantly increased PTHrP secretion (P ≤ 0.05) into PEC but not PSC conditioned medium. rhPTHrP was significantly (P ≤ 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. CONCLUSIONS. TGFβ1 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.