Glucocorticoid-induced osteoporosis in the rat is prevented by the tyrosine phosphatase inhibitor, sodium orthovanadate.
Glucocorticoid-induced osteoporosis is characterized by decreased osteoblast numbers and a marked impairment of new bone formation. We found that, in vitro, dexamethasone inhibits both preosteoblast proliferation and mitogenic kinase activity in response to mitogens, and that inhibition of protein tyrosine phosphatases (PTPs) using sodium orthovanadate prevents this. Therefore, dexamethasone may act by either upregulating antiproliferative PTPs or downregulating promitogenic tyrosine-phosphorylated substrates. In this study, osteoporosis was induced in 3.5-month-old rats by subcutaneous injection with methylprednisolone 3.5 mg/kg per day for 9 weeks. Rats were treated with steroid alone or in combination with 0.5 mg/mL sodium orthovanadate, administered continuously in drinking water. Steroid-treated bones were significantly (p < 0.005) osteopenic (according to dual-energy X-ray absorptiometry) and physically weaker (p < 0.05) than controls. Quantitative bone histology confirmed a significant decrease in osteoid surfaces (p < 0.001), osteoblast numbers (p < 0.05), and rate of bone formation (p < 0.001). Concomitant treatment with vanadate largely prevented the densitometric, histologic, and physical abnormalities induced by prednisolone. This study supports our finding that PTPs are central to the negative regulation of osteoblast proliferation by glucocorticoids and, furthermore, suggests that PTP inhibitors such as sodium orthovanadate should be considered as novel anabolic agents for the treatment of steroid-induced osteoporosis.
Department of Endocrinology and Metabolism, University of Stellenbosch Medical School, Tygerberg, Cape Town, South Africa. phul@sun.ac.za
P A
PA
Hulley
M M
MM
Conradie
C R
CR
Langeveldt
F S
FS
Hough
D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005938:Glucocorticoids / Q000633:toxicity*; D008775:Methylprednisolone / Q000633:toxicity; D010024:Osteoporosis / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014638:Vanadates / Q000494:pharmacology / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D014638:Vanadates; D017027:Protein Tyrosine Phosphatases; D008775:Methylprednisolone