Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism.
Parathyroid bone disease in humans is caused by chronic hyperparathyroidism (HPT). Continuous infusion of PTH into rats results in histological changes similar to parathyroid bone disease, including increased bone formation, focal bone resorption, and severe peritrabecular fibrosis, whereas pulsatile PTH increases bone formation without skeletal abnormalities. Using a cDNA microarray with over 5000 genes, we identified an association between increased platelet-derived growth factor-A (PDGF-A) signaling and PTH-induced bone disease in rats. Verification of PDGF-A overexpression was accomplished with a ribonuclease protection assay. Using immunohistochemistry, PDGF-A peptide was localized to mast cells in PTH-treated rats. We also report a novel strategy for prevention of parathyroid bone disease using triazolopyrimidine (trapidil). Trapidil, an inhibitor of PDGF signaling, did not have any effect on indexes of bone turnover in normal rats. However, dramatic reductions in marrow fibrosis and bone resorption, but not bone formation, were observed in PTH-treated rats given trapidil. Also, trapidil antagonized the PTH-induced increases in mRNA levels for PDGF-A. These results suggest that PDGF signaling is important for the detrimental skeletal effects of HPT, and drugs that target the cytokine or its receptor might be useful in reducing or preventing parathyroid bone disease.
Lotinun
Sutada
S
Department of Orthopedics, Mayo Clinic, Rochester, Minnesota 55905, USA.
Sibonga
Jean D
JD
Turner
Russell T
RT
D000818:Animals; D001847:Bone Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006961:Hyperparathyroidism / Q000188:drug therapy*; D010281:Parathyroid Hormone / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014192:Trapidil / Q000627:therapeutic use*
D010281:Parathyroid Hormone; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D014192:Trapidil