Glenda L. Evans

Is resveratrol an estrogen agonist in growing rats

Trans-3,4,5-trihydroxystilbene (resveratrol), a polyphenolic compound found in juice and wine from dark-skinned grape cultivars, was recently shown to bind to estrogen receptors in vitro, where it activated transcription of estrogen-responsive reporter genes. The purpose of this 6-day study in weanling rats was to determine the dose response (1, 4, 10, 40, and 100 microg/day) effects of orally administered resveratrol on estrogen target tissues. The solvent (10% ethanol) had no significant effect on any measurement or derived value. 17Beta-estradiol treatment (100 microg/day) decreased the growth rate, final body weight, serum cholesterol, and radial bone growth (periosteal bone formation and mineral apposition rates) at the tibia-fibula synostosis. In the uterus, 17beta-estradiol treatment increased wet weight, epithelial cell height, and steady state messenger RNA levels for insulin-like growth factor I. In contrast, resveratrol treatment had no significant effect on body weight, serum cholesterol, radial bone growth, epithelial cell height, or messenger RNA levels for insulin-like growth factor I. Resveratrol treatment resulted in slight increases in uterine wet weight, but significance was achieved at the 10-microg dose only. A second experiment was performed to determine whether a high dose of resveratrol (1000 microg/day) antagonizes the ability of estrogen to lower serum cholesterol. As was shown for the lower doses, resveratrol had no effect on body weight, uterine wet weight, uterine epithelial cell height, cortical bone histomorphometry, or serum cholesterol. 17Beta-estradiol significantly lowered serum cholesterol, and this response was antagonized by cotreatment with resveratrol. These in vivo results suggest, in contrast to prior in vitro studies, that resveratrol has little or no estrogen agonism on reproductive and nonreproductive estrogen target tissues and may be an estrogen antagonist.

Moderate Alcohol Consumption Suppresses Bone Turnover in Adult Female Rats

Chronic alcohol abuse is a major risk factor for osteoporosis but the effects of moderate drinking on bone metabolism are largely uninvestigated. Here, we studied the long‐term dose‐response (0, 3, 6, 13, and 35% caloric intake) effects of alcohol on cancellous bone in the proximal tibia of 8‐month‐old female rats. After 4 months of treatment, all alcohol‐consuming groups of rats had decreased bone turnover. The inhibitory effects of alcohol on bone formation were dose dependent. A reduction in osteoclast number occurred at the lowest level of consumption but there were no further reductions with higher levels of consumption. An imbalance between bone formation and bone resorption at higher levels of consumption of alcohol resulted in trabecular thinning. Our observations in rats raise the concern that moderate consumption of alcoholic beverages in humans may reduce bone turnover and potentially have detrimental effects on the skeleton.

Differential Effects of Estrogen Metabolites on Bone and Reproductive Tissues of Ovariectomized Rats

The effects of 17β‐estradiol and the important estrogen metabolites, 2‐hydroxyestrone (2‐OHE1) and 16α‐hydroxyestrone (16α‐OHE1) on bone, mammary gland, and uterine histology, and on blood cholesterol were investigated in ovariectomized growing rats. Rats were treated with 200 μg/kg of body weight/day of each of the test compounds for 3 weeks. Ovariectomy resulted in uterine and mammary gland atrophy, increased body weight, bone turnover and tibia growth, and hypercholesterolemia. 17β‐estradiol treatment prevented these changes, with the exception that this high dose of estrogen did not prevent hypercholesterolemia. 2‐OHE1 had no effect on any of the measurements. 16α‐OHE1 resulted in bone measurements that did not differ from the 17β‐estradiol–treated rats and prevented the increase in serum cholesterol. In contrast, 16α‐OHE1 resulted in increases in uterine weight, uterine epithelial cell height, and mammary gland cell proliferation that were significantly less than the 17β‐estradiol treatment. These findings demonstrate that 16α‐hydroxylation of estrone results in tissue‐selective estrogen agonistic activity, whereas 2‐hydroxylation resulted in no measured activity. Furthermore, they suggest that factors that modulate the synthesis of these metabolites could selectively influence estrogen target tissues.

Dose—Response Effects of Intermittent PTH on Cancellous Bone in Hindlimb Unloaded Rats†

HLU suppressed bone formation and resulted in bone loss in the tibial metaphysis of 6‐month‐old male rats. A human therapeutic dose of intermittent PTH (1 μg/kg/day) prevented the skeletal changes associated with HLU.

PARALLEL CHANGES IN EXTRACELLULAR MATRIX PROTEIN GENE EXPRESSION, BONE FORMATION AND BIOMECHANICAL PROPERTIES IN AGING RAT BONE

The effect of aging on long bone mechanical properties and bone formative capacity was characterized in the male Fisher 344 rat. The femurs of rats from three age groups (4 mo., 12 mo. and 28 mo.) were tested in three-point bending to determine their structural properties. The apparent material properties were then calculated by adjusting for bone geometry. Bone formation was assessed by dynamic histomorphometry of both cortical and cancellous bone as well as by Northern blot analysis for the expression of the osteoblast phenotypic proteins osteopontin (OP), osteocalcin (OC), type I collagen (COL) and alkaline phosphatase (AP). Aging resulted in a decline in the apparent material properties that was associated with a compensatory alteration of bone geometry that preserved structural strength and stiffness. Histomorphometric analysis revealed significant age-related decreases in cancellous bone volume, trabecular number and increased trabecular separation suggesting the existence of senile osteopenia in the proximal tibia of the male Fisher 344 rat. A significant decline in bone formation rate (BFR), but not mineral apposition rate, suggests that a reduction in osteoblast number, but not osteoblast activity, contributes to age-related bone loss. The decline in BFR with aging was reflected in a decreased mRNA expression for OP, OC and COL but not AP. Further, the pattern of mRNA expression was consistent with reduced osteoblast differentiation with aging. The present study indicates the age-related decline in material properties of long bones is paralleled by a decrease in osteogenesis.