REGULATION OF INTERLEUKIN-6, OSTEOCLASTOGENESIS, AND BONE MASS BY ANDROGENS THE ROLE OF THE ANDROGEN RECEPTOR

Interleukin-6 is an essential mediator of the bone loss caused by loss of estrogens, Because loss of androgens also causes bone loss, we hav e examined whether the IL-6 gene is regulated by androgens, and whethe r IL-6 plays a role in the bone loss caused by androgen deficiency, Bo th testosterone and dihydrotestosterone inhibited IL-6 production by m urine bone marrow-derived stromal cells, In addition, testosterone, di hydrotestosterone, and adrenal androgens inhibited the expression of a chloramphenicol acetyl transferase reporter plasmid driven by the hum an IL-6 promoter in HeLa cells cotransfected with an androgen receptor expression plasmid; however, these steroids were ineffective when the cells were cotransfected with an estrogen receptor expression plasmid , In accordance with the in vitro findings, orchidectomy in mice cause d an increase in the replication of osteoclast progenitors in the bone marrow which could be prevented by androgen replacement or administra tion of an IL-6 neutralizing antibody, Moreover, bone histomorphometri c analysis of trabecular bone revealed that, in contrast to IL-6 suffi cient mice which exhibited increased osteoclast numbers and bone loss following orchidectomy, IL-6 deficient mice (generated by targeted gen e disruption) did not, This evidence demonstrates that male sex steroi ds, acting through the androgen-specific receptor, inhibit the express ion of the IL-6 gene; and that IL-6 mediates the upregulation of osteo clastogenesis and therefore the bone loss caused by androgen deficienc y, as it does in estrogen deficiency.