PSA Converts Parathyroid Hormone-Related Protein (PTHrP) from an Osteolytic to an Osteoblastic Factor: Role in Bone Metastasis
Abstract
Prostate cancer metastases cause disorganized new bone formation, despite expressing the bone- destructive factor, PThrP. We report a molecular basis for this paradox: residues 6-9 LMDK of ET- 1 and PTHrP residues 8-11 LHDK share sequence similarity. 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. We tested PTHrP peptides on bone formation in 4-day neonatal mouse calvariae. PTHrP(1-16) (100nM) caused a 2.5-fold stimulation of new bone area (p<0.001). Osteoblast numbers were correspondingly increased. The response was equivalent to ET-1 (100nM). PTHrP(1-20) (25nM) also increased bone formation. The actions of PTHrP(1-16 & 1-23) were blocked by ABT627 (0.01nM), a selective ETAR antagonist. We found a strong bone anabolic response to PTHrP(1-23) (1nM; p<0.01 vs control), while PTHrP(1-34) instead caused extensive osteolysis. Structural mimicry of ET-1 by PTHrP peptides provides a molecular basis for the osteoblastic phenotype of PTHrP-positive prostate cancer bone metastases. ETAR antagonists should be effective against PTHrP fragments, in treating osteoblastic bone metastases due to prostate cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2003
- Accession Number
- ADA423124
Entities
People
- John M. Chirgwin
Organizations
- University of Virginia