Estrogens cause growth plate closure in both males and females, by decreasing proliferation and inducing apoptosis of postproliferative growth plate chondrocytes. In vitro studies using 17β-estradiol (E2) conjugated to bovine serum albumin (E2-BSA) show that rat costochondral growth plate resting zone chondrocytes also respond to E 2. Moreover, they are regulated by E2-BSA via a protein kinase C and ERK MAPK signaling pathway that is functional only in female cells. To better understand how E2 regulates apoptosis of growth plate chondrocytes, rat resting zone chondrocytes cells were treated with E 2 or E2-BSA. E2 caused apoptosis in male and female resting zone and growth zone chondrocytes inadose-dependentmanner, basedonelevatedDNAfragmentation, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and caspase-3 activation. E2 also up-regulated p53 and Bax protein (Bcl-2-associatedXprotein) levelsandinduced release of cytochromeCfrom the mitochondria, indicatingamitochondrial apoptoticpathway. Theapoptotic effect of E2 didnotinvolve elevated nitric oxide production orMAPKs.ItwasreducedbyICI 182780, whichisanestrogen receptor (ER) antagonist and blocked by antibodies to Erα36, a membrane-associated ER. E2-BSA reduced cell viability and increased caspase-3 activity; ICI182780hadnoeffect, butanti-ERα36antibodiesblockedthe effect. The results indicate that estrogen is able to directly affect the cell population kinetics of growth plate chondrocytes by regulating apoptosis, as well as proliferation and differentiation in both resting zone and growth zone cells. They also have provided further information about the physiological functions of estrogen on longitudinal bone growth.
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