Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis

Abstract

The importance of estrogens for the regulation of longitudinal bone growth is unequivocal. However, any local effect of estrogens in growth plate cartilage has been debated. Recently, several enzymes essential for estrogen synthesis were shown to be expressed in rat growth plate chondrocytes. Local production of 17 -estradiol (E2) has also been demonstrated in rat costal chondrocytes. We aimed to determine the functional role of locally produced estrogen in growth plate cartilage. The human chondrocyte-like cell line HCS-2/8 was used to study estrogen effects on cell proliferation ( 3 H-labeled thymidine uptake) and apoptosis (cell death detection ELISA kit). Chondrocyte production of E2 was measured by RIA and organ cultures of fetal rat metatarsal bones were used to study the effects of estrogen on longitudinal growth rate. We found that significant amounts of E2 were produced by HCS-2/8 chondrocytes (64·1 5·3 fmol/3 days/10 6 cells). The aromatase inhibitor letrozole (1 µM) and the pure estrogen receptor antagonist ICI 182,780 (10 µM) inhibited proliferation of HCS-2/8 chondrocytes by 20% (P<0·01) and almost 50% (P<0·001), respectively. Treatment with ICI 182,780 (10 µM) increased apoptosis by 228% (P<0·05). Cotreatment with either caspase-3 or pan-caspase inhibitors completely blocked ICI 182,780-induced apoptosis (P<0·001 vs ICI 182,780 only). Moreover, both ICI 182,780 (10 µM) and letrozole (1 µM) decreased longitudinal growth of fetal rat metatarsal bones after 7 days of culture (P<0·01). In conclusion, our data clearly show that chondrocytes endogenously produce E2 and that locally produced estrogen stimulates chondrocyte proliferation and protects from spontaneous apoptosis. In addition, longitudinal growth is promoted by estrogens locally produced within the epiphyseal growth plate.

17β-Estradiol promotes cell proliferation in rat osteoarthritis model chondrocytes via PI3K/Akt pathway

“…1). These data are in agreement with those from previous studies that showed that E2 could stimulate chondrocyte proliferation and protect against spontaneous apoptosis [2,18]. In addition, lots of evidence has shown that estrogens exert antiapoptotic effects on various cell types such as vascular endothelial, smooth and skeletal muscles, and breast cancer cells [6,17].…”

“…Women taking estrogen replacement therapy have a lower than expected risk of OA than controls. However, the possible local effect of estrogens in cartilage has been debated recently, partly due to the unelucidated pathologic mechanism [1,2]. It is widely accepted that chondrocyte apoptosis plays an important role in the pathogenesis of OA, and the regulative mechanism of chondrocyte apoptosis was supposed to be targeted for new treatment strategies for OA [1,3,4].…”

The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

“…(17) Despite the well-known effects of estrogens on longitudinal bone growth, data from in vitro experiments are inconclusive. There are reports of estrogens stimulating, (1,(23)(24)(25) inhibiting, (26,27) or having no effect (28) on chondrocyte proliferation. In addition, it has not yet been possible to evaluate in vivo the role of ERa in growth plate cartilage.…”

“…(1) Low estradiol (E2) levels enhance skeletal growth during early sexual maturation (ie, the pubertal growth spurt), whereas high E2 levels during late puberty result in growth plate fusion and thereby cessation of longitudinal bone growth in humans. (1,2) The mechanisms of action for these two seemingly opposite effects of estrogens on longitudinal bone growth are not fully understood but clearly depend on maturational stage and serum levels of E2.…”

“…(1) Low estradiol (E2) levels enhance skeletal growth during early sexual maturation (ie, the pubertal growth spurt), whereas high E2 levels during late puberty result in growth plate fusion and thereby cessation of longitudinal bone growth in humans. (1,2) The mechanisms of action for these two seemingly opposite effects of estrogens on longitudinal bone growth are not fully understood but clearly depend on maturational stage and serum levels of E2. (2) The key role of estrogens for skeletal growth is demonstrated by the findings that both males and females with estrogen deficiency, caused by a mutation in the aromatase gene, display no clear pubertal growth spurt and continue to grow into adulthood owing to a lack of epiphyseal fusion in the long bones, which results in increased adult height.…”