Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor.

Abstract

Interleukin-6 is an essential mediator of the bone loss caused by loss of estrogens. Because loss of androgens also causes bone loss, we have examined whether the IL-6 gene is regulated by androgens, and whether IL-6 plays a role in the bone loss caused by androgen deficiency. Both testosterone and dihydrotestosterone inhibited IL-6 production by murine bone marrow-derived stromal cells. In addition, testosterone, dihydrotestosterone, and adrenal androgens inhibited the expression of a chloramphenicol acetyl transferase reporter plasmid driven by the human 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 caused an increase in the replication of osteoclast progenitors in the bone marrow which could be prevented by androgen replacement or administration of an IL-6 neutralizing antibody. Moreover, bone histomorphometric analysis of trabecular bone revealed that, in contrast to IL-6 sufficient mice which exhibited increased osteoclast numbers and bone loss following orchidectomy, IL-6 deficient mice (generated by targeted gene disruption) did not. This evidence demonstrates that male sex steroids, acting through the androgen-specific receptor, inhibit the expression of the IL-6 gene; and that IL-6 mediates the upregulation of osteoclastogenesis and therefore the bone loss caused by androgen deficiency, as it does in estrogen deficiency. (J.

Androgen effects on bone metabolism: recent progress and controversies

“…These findings have since been confirmed by other groups using a variety of osteoblastic cell systems from various species (31)(32)(33)(34)(35)(36). Functional AR were also detected in pluripotent marrow-derived stromal cells (19), which represent osteoblast precursor cells, hypertrophic chondrocytes (20), osteocytes (20) as well as osteoclasts (21). The detection of functional AR in various bone cells has implicated bone as a target tissue for androgen action and has fueled an increase in further investigations on the direct and indirect effects of androgens on bone cells in vitro, as well as the sequelae of clinical and experimental androgen deficiency and its correction on bone metabolism in vivo.…”

“…The cloning of the human androgen receptor (AR) (16,17) and its detection and characterization in various bone cells, including osteoblasts (18), bone marrow-derived stromal cells (19), osteocytes (20), hypertrophic chondrocytes (20), and osteoclasts (21), have unequivocally identified bone as a direct androgen target tissue. In addition, subsequent studies over the last decade have identified a variety of androgen-dependent autocrine and paracrine cytokines which are produced by bone cells and mediate some of the anabolic and anti-resorptive effects of androgens.…”

p38 MAPK Regulates IL‐1β Induced IL‐6 Expression Through mRNA Stability in Osteoblasts

“…Besides IL-6, the family includes IL-11, oncostatin M (OSM), leukemia inhibitory factor (LIF), and cardiotropin 1. Several investigators have demonstrated that both estrogens and androgens suppress the production of IL-6 as well as the expression of the two subunits of the IL-6 receptor, IL-6R and gp130, in cells of the bone marrow stromal/osteoblastic lineage (1,14,34). Similar results were obtained subsequently by others in rats as well as in humans, in the bone marrow and in the peripheral blood (35,51).…”

“…Similar results were obtained subsequently by others in rats as well as in humans, in the bone marrow and in the peripheral blood (35,51). Importantly, it was shown that neutralization of IL-6 with antibodies or knockout of the IL-6 gene in mice prevents the upregulation of granulocyte macrophage-colony stimulating factor (GM-CSF) in the marrow, and the expected increase of osteoclast numbers in trabecular bone sections; and also protects the loss of bone following loss of sex steroids (1,21). This cytokine is produced by osteoblasts and is inducible by the pro-inflammatory cytokines IL-1, TNF, or bacterial-derived lipopolysacchride (LPS) as well as other osteotrophic hormones including parathyroid hormone (PTH) (6,12,19,26).…”

Androgen decreases osteoprotegerin expression in prostate cancer cells

“…The expression of interleukin-6, tartrate-resistant acid phosphatase and cathepsin B, which increase bone resorption, is decreased by androgens, [37][38][39] whereas androgens increase the expression of factors, such as TGF-b 1 , that suppress bone resorption by inhibiting osteoclast activity and promoting osteoblast proliferation. [37][38][39] Androgen withdrawal therapy and decreased androgen levels related to the 'andropause' in men are associated with an increased risk of osteoporosis, decreased bone mineral density, and increased bone resorption, detected via the bone resorption markers serum osteocalcin and urinary hydroxyproline. 9 Treatment with testosterone at least partially prevents these effects and reduces the associated risk of fracture.…”