Abstract
Trans-resveratrol (RES), naturally produced by many plants, has a structure similar to synthetic estrogen diethylstilbestrol, but any effect on bone growth has not yet been clarified. Pre-pubertal ovary-intact New Zealand white rabbits received daily oral administration of either vehicle (control) or RES (200 mg/kg) until growth plate fusion occurred. Bone growth and growth plate size were longitudinally monitored by X-ray imaging, while at the endpoint, bone length was assessed by a digital caliper. In addition, pubertal ovariectomized (OVX) rabbits were treated with vehicle, RES or estradiol cypionate (positive control) for 7 or 10 weeks and fetal rat metatarsal bones were cultured in vitro with RES (0.03 µM–50 µM) and followed for up to 19 days. In ovary-intact rabbits, sixteen-week treatment with RES increased tibiae and vertebrae bone growth and subsequently improved final length. In OVX rabbits, RES delayed fusion of the distal tibia, distal femur and proximal tibia epiphyses and femur length and vertebral bone growth increased when compared with controls. Histomorphometrical analysis showed that RES-treated OVX rabbits had a wider distal femur growth plate, enlarged resting zone, increased number/size of hypertrophic chondrocytes, increased height of the hypertrophic zone, and suppressed chondrocyte expression of VEGF and laminin. In cultured fetal rat metatarsal bones, RES stimulated growth at 0.3 µM while at higher concentrations (10 μM and 50 μM) growth was inhibited. We conclude that RES has the potential to improve longitudinal bone growth. The effect was associated with a delay of growth plate fusion resulting in increased final length. These effects were accompanied by a profound suppression of VEGF and laminin expression suggesting that impairment of growth plate vascularization might be an underlying mechanism.
Highlights
Linear bone growth is the consequence of chondrocyte proliferation, hypertrophy and terminal differentiation in the growth plates of the long bones
Effects of RES on bone growth and final bone length in OVX rabbits When bone length was measured by a digital caliper at the end, the femur was significantly longer in RES-treated animals (102.460.6 mm vs. 100.960.4 mm in controls; p,0.05) while the tibia length did not significantly differ between the RES group and controls (107.560.5 vs. 107.160.6 mm)
We found chondrocyte expression of vascular endothelial growth factor (VEGF) to be clearly suppressed in RES-treated rabbits as compared to controls (265654 vs. 626650 VEGF positive cells/mm2; p,0.01) while in the E2 group VEGF expression was similar as in controls (6326153 vs. 626650 positive cells/mm2; Fig. 4)
Summary
Linear bone growth is the consequence of chondrocyte proliferation, hypertrophy and terminal differentiation in the growth plates of the long bones. In most cases there is no identifiable cause of their growth disorder and they are are commonly labeled as having idiopathic short or tall stature. High-dose estrogen treatment has since the 1950s been used to reduce adult height in tall girls [1]. GH therapy is applicable only to a few disorders such as GH deficiency (GHD), Turner syndrome, idiopathic short stature, small for gestational age with failure to attain normal growth percentiles, Prader-Willi syndrome, chronic renal insufficiency and Noonan syndrome. It is worth mentioning that only children and adolescents with GHD have the greatest response to GH therapy These findings emphasize the lack of suitable strategies to treat extreme short or tall adolescents while having fewer side effects
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