PSA Converts Parathyroid Hormone Related Protein (PTHrP) from an Osteolytic to an Osteoblastic Factor: Role in Bone Metastasis

Abstract

Abstract : Prostate cancer metastases cause disorganized new bone formation, despite expressing the bone- destructive factor, PTHrP. We report a molecular basis for this paradox: PTHrP is cleaved at residues 22 and 23 by the serine protease, prostate-specific antigen (PSA). The fragments generated by PSA are too short to activate the PTH1 receptor but stimulate new bone by activating the ETA receptor by an unknown, indirect mechanism. PTHrP peptides in neonatal mouse calvariae caused a 2.5- fold stimulation of new bone area (p<0.001). Osteoblast numbers were correspondingly increased. The response was equivalent to ET-l. The actions were blocked by atrasentan (0.01mM), a selective ETAR antagonist. PTHrP(1-23) gave a strong bone anabolic response at 1nM (p<0.01 vs control), while PTHrP(1-34) instead caused extensive osteolysis. We found that PTHrP1-23 does not bind to endothelin or PTH receptors but the peptide increases cellular expression of both muscle- and bone-specific genes. An animal model has been developed in which a human prostate cell line makes PSA-derived PTHrP fragments but not intact PTHrP or endothelin-1. In 2005 this model will be used for preclinical testing of atresantan and of PTHrP-neutralizing antibody. These treatments should be effective against PTHrP fragments, in treating osteoblastic bone metastases due to prostate cancer.