TY - JOUR
T1 - Regulation of osteoprotegerin production by androgens and anti-androgens in human osteoblastic lineage cells
AU - Hofbauer, Lorenz C.
AU - Hicok, Kevin C.
AU - Chen, David
AU - Khosla, Sundeep
PY - 2002/8
Y1 - 2002/8
N2 - Background: Estrogens and androgens have anti-resorptive effects on bone, although recent evidence indicates that, even in men, estrogen is the dominant sex steroid regulating bone resorption. The receptor activator of NF-κB ligand is essential for osteoclastic bone resorption, and its effects are blocked by the decoy receptor, osteoprotegerin (OPG). While estrogen has been shown to induce osteoblastic OPG production, the effects of androgens on OPG production have not been defined. Methods: In this study, we assessed the regulation of OPG by androgens in hFOB/AR-6, an immortalized fetal osteoblastic cell line stably transfected with the human androgen receptor (AR), and MSC cells, primary human pluripotent marrow stromal cells capable of differentiating towards mature osteoblasts. Results and Conclusions: 5α-Dihydrotestosterone (DHT) dose-dependently decreased OPG mRNA levels and protein concentrations in hFOB/AR-6 cells by up to 50 and 60% respectively (P < 0.001). Inhibition of OPG mRNA levels and protein production by 5α-DHT was completely abrogated by the AR antagonist, hydroxyflutamide (OHF), indicating that these effects are directly mediated by the AR. Of note, OHF alone increased OPG mRNA levels and protein secretion by 2- to 3-fold. Moreover, 5α-DHT and testosterone also decreased OPG protein secretion by 40-46% in the untransformed MSC cells, while OHF stimulated it. In conclusion, we demonstrate that androgens specifically inhibit OPG mRNA levels and protein secretion by osteoblastic cells.
AB - Background: Estrogens and androgens have anti-resorptive effects on bone, although recent evidence indicates that, even in men, estrogen is the dominant sex steroid regulating bone resorption. The receptor activator of NF-κB ligand is essential for osteoclastic bone resorption, and its effects are blocked by the decoy receptor, osteoprotegerin (OPG). While estrogen has been shown to induce osteoblastic OPG production, the effects of androgens on OPG production have not been defined. Methods: In this study, we assessed the regulation of OPG by androgens in hFOB/AR-6, an immortalized fetal osteoblastic cell line stably transfected with the human androgen receptor (AR), and MSC cells, primary human pluripotent marrow stromal cells capable of differentiating towards mature osteoblasts. Results and Conclusions: 5α-Dihydrotestosterone (DHT) dose-dependently decreased OPG mRNA levels and protein concentrations in hFOB/AR-6 cells by up to 50 and 60% respectively (P < 0.001). Inhibition of OPG mRNA levels and protein production by 5α-DHT was completely abrogated by the AR antagonist, hydroxyflutamide (OHF), indicating that these effects are directly mediated by the AR. Of note, OHF alone increased OPG mRNA levels and protein secretion by 2- to 3-fold. Moreover, 5α-DHT and testosterone also decreased OPG protein secretion by 40-46% in the untransformed MSC cells, while OHF stimulated it. In conclusion, we demonstrate that androgens specifically inhibit OPG mRNA levels and protein secretion by osteoblastic cells.
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U2 - 10.1530/eje.0.1470269
DO - 10.1530/eje.0.1470269
M3 - Article
C2 - 12153751
AN - SCOPUS:0036679261
VL - 147
SP - 269
EP - 273
JO - European Journal of Endocrinology
JF - European Journal of Endocrinology
SN - 0804-4643
IS - 2
ER -