PSA Converts Parathyroid Hormone Related Protein (PTHrP) from an Osteolytic to an Osteoblastic Factor: Role in Bone Metastasis
Annual rept. 1 Dec 2001-30 Nov 2002
TEXAS UNIV HEALTH SCIENCE CENTER AT SANANTONIO
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Two factors produced in abundance by prostate cancers are prostate-specific antigen PSA and parathyroid hormone- related protein PTHrP the latter is a major cause of osteolytic bone destruction, but the bone metastases in prostate cancer patients are usually osteoblastic, New data explain this paradox, PSA is a protease that cuts PTHrP into small fragments which cause new bone formation by binding to the endothelin receptor. Thus, PSA converts PTHrP from an osteolytic to an osteoblastic factor, We have now shown that PTHrP 1-16, 1-20, the PSA product 1-23, stimulate new bone formation by binding Kd25nM to the endothelin A receptor. Prostate cell lines do not express both PSA plus hK2 and PTHrP. We are reconstituting PSAhK2 expression in a PTHrP cell line. We hypothesize that this will change the cell line from one that causes osteolytic metastases to one that causes osteoblastic metastases in vivo. Neutralizing antibodies against PTHrP are currently in clinical trials. They would block both osteolytic and osteoblastic actions of PTHrP and its fragments. Our work will test whether such antibodies would be an effective treatment against skeletal metastases in prostate cancer.
- Anatomy and Physiology
- Medicine and Medical Research