Regulation of osteoprotegerin production by androgens and anti-androgens in human osteoblastic lineage cells.
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-kappaB 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.


CONCLUSIONS
5Alpha-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 5alpha-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, 5alpha-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.
Hofbauer
Lorenz C
LC
Division of Endocrinology, Philipps University, Marburg, Germany. hofbauer@post.med.uni-marburg.de
Hicok
Kevin C
KC
Chen
David
D
Khosla
Sundeep
S
D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism / Q000494:pharmacology*; D015152:Blotting, Northern; D001854:Bone Marrow Cells / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D013196:Dihydrotestosterone / Q000494:pharmacology; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D010006:Osteoblasts / Q000378:metabolism*; D053244:Osteoprotegerin; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D014162:Transfection
D000726:Androgen Antagonists; D000728:Androgens; D006023:Glycoproteins; D053244:Osteoprotegerin; D012333:RNA, Messenger; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; D013196:Dihydrotestosterone