Ovariectomy selectively reduces the concentration of transforming growth factor beta in rat bone: implications for estrogen deficiency-associated bone loss.

Abstract

Previous work showed that production of transforming growth factor 13 (TGF-I) by osteoblast-like rat UMR 106 cells was increased by 17l-estradiol at physiological concentrations. To determine whether ovariectomy alters the concentration of TGF-IJ in rat long bones, female SpragueDawley rats were either sham-operated (a = 19) or ovariectomized (a = 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 shamoperated rats; calcium content did not differ between the two groups of animals. Ovariectomy lowered the concentration of TGF-3 in bone but did not change the concentration of insulin-like growth factors I or H compared with values in bone from control animals. The reduction of bone TGF-(3 was evident 6 weeks after surgery but not at 3 weeks. Treatment of ovariectomized rats with estrogen elminated the TGF-f deficit. To determine whether 17B-estradiol increased TGF-8 production by normal bone cells, mouse osteoblasts were treated for 2 days with 17f3-estradiol. The production ofTGF-j was increased almost 2-fold by 1 nM 17fl-estradiol, and short-term treatment stimulated the intracellular accumulation of TGF-fi1 mRNA. We conclude that ovariectomy reduces deposition of TGF-13 in rat bone and that diminished skeletal TGF-13 could play a role in the pathogenesis of bone loss, fractures, and microfractures that occur in estrogen-deficient states. Our results support the possibility th4t estrogen and bone TGF-8 may be necessary for normal maintenance of the skeleton in female rats.Ovariectomy has long been associated with bone loss in rats (1-5). In young adult rats ovariectomy leads to increased bone formation and resorption (6-8).

Gene Expression Profiling in Bone Tissue of Osteoporotic Mice

“…It was shown that ovariectomy enhances the production of the osteoclastogenic cytokine IL-7, and that its neutralization in vivo prevents OVX-induced bone loss (23). It has also been reported that OVX significantly reduces mRNA expression level of TGF-beta in bone (24) and that TGF-beta 3 inhibits osteoclast differentiation, suggesting its role in estrogen-mediated bone maintenance (25). We have observed an upregulation of both IL-7 and IL-7 receptor, and downregulation of TGF-beta 3 confirming strong influence of IL-7 on bone resorption (16,17), effect of TGF-beta 3 decrease on pronounced osteoclast differentiation (25) and IL-7 -TGF-beta dependent cycle (20).…”

Hormonal regulation of physiological cell turnover and apoptosis

“…Transgenic mice overexpressing OPG develop osteopetrosis, while OPG knockout mice have excessive osteoclast activity and are osteoporotic (Boyce et al 1999). The synthesis of TGFβ, another osteoclastogenesis inhibitor, also is stimulated by estrogens in osteoblast cells (Finkelman et al 1992). As in other tissues, TGFβ also induces osteoclast apoptosis, thus suppressing bone resorption.…”

Association of transforming growth factor (TGF) p1 T(861-20)C polymorphism with bone mineral density and TGFip gene expression in postmenopausal osteoporosis

“…Поэтому пониженная экспрессия гена TФР β1 в крови больных ОП потенциально может быть связана с пониженной концентрацией этого ростового фактора в костной ткани. Это подтверждается исследованиями, которые показали снижение концентрации TФР β1 и его мРНК в кости при недостатке эстрогенов у животных, тогда как сам недостаток эстрогенов ассоциировался с потерей костной ткани как при овариэктомии, так и при постменопаузальном ОП [23,30,31,45,46]. Сле-довательно, будучи индикатором развития ОП, генотип …”