Ovariectomy selectively reduces the concentration of transforming growth factor β in rat bone: Implications for estrogen deficiency-associated bone loss

Previous work showed that production of transforming growth factor β (TGF-β) by osteoblast-like rat UMR 106 cells was increased by 17β-estradiol at physiological concentrations. To determine whether ovariectomy alters the concentration of TGF-β in rat long bones, female Sprague-Dawley rats were either sham-operated (n = 19) or ovariectomized (n = 19), pair-fed a semisynthetic diet for 6 weeks, and sacrificed. Tibial and femoral diaphyses were removed and extracted by demineralization. Ovariectomy lowered serum estrogen; did not alter body weight, serum magnesium, or serum 1,25-dihydroxyvitamin D; and produced only modest differences in serum calcium and phosphate concentrations. Hydroxyproline was higher and extractable protein was lower in bones from ovariectomized rats than in bones from sham-operated rats; calcium content did not differ between the two groups of animals. Ovariectomy lowered the concentration of TGF-β in bone but did not change the concentration of insulin-like growth factors I or II compared with values in bone from control animals. The reduction of bone TGF-β was evident 6 weeks after surgery but not at 3 weeks. Treatment of ovariectomized rats with estrogen eliminated the TGF-β deficit. To determine whether 17β-estradiol increased TGF-β production by normal bone cells, mouse osteoblasts were treated for 2 days with 17β-estradiol. The production of TGF-β was increased almost 2-fold by 1 nM 17β-estradiol, and short-term treatment stimulated the intracellular accumulation of TGF-β1 mRNA. We conclude that ovariectomy reduces deposition of TGF-β in rat bone and that diminished skeletal TGF-β could play a role in the pathogenesis of bone loss, fractures, and microfractures that occur in estrogen-deficient states. Our results support the possibility that estrogen and bone TGF-β may be necessary for normal maintenance of the skeleton in female rats.