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

Teresita Bellido, Robert L. Jilka, Brendan F. Boyce, Giuseppe Girasole, Hal Broxmeyer, Stacie A. Dalrymple, Richard Murray, Stavros C. Manolagas

Research output: Contribution to journalArticle

367 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2886-2895
Number of pages10
JournalJournal of Clinical Investigation
Volume95
Issue number6
StatePublished - Jun 1995

Fingerprint

Androgen Receptors
Osteogenesis
Androgens
Interleukin-6
Bone and Bones
Plasmids
Orchiectomy
Dihydrotestosterone
Osteoclasts
Testosterone
Estrogens
Steroids
Genes
Chloramphenicol
Transferases
Neutralizing Antibodies
Mesenchymal Stromal Cells
HeLa Cells
Estrogen Receptors
Up-Regulation

Keywords

  • Adrenal androgens
  • Interleukin-6 knockout mouse
  • Osteoclast development
  • Osteoporosis
  • Testosterone

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bellido, T., Jilka, R. L., Boyce, B. F., Girasole, G., Broxmeyer, H., Dalrymple, S. A., ... Manolagas, S. C. (1995). Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens: The role of the androgen receptor. Journal of Clinical Investigation, 95(6), 2886-2895.

Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens : The role of the androgen receptor. / Bellido, Teresita; Jilka, Robert L.; Boyce, Brendan F.; Girasole, Giuseppe; Broxmeyer, Hal; Dalrymple, Stacie A.; Murray, Richard; Manolagas, Stavros C.

In: Journal of Clinical Investigation, Vol. 95, No. 6, 06.1995, p. 2886-2895.

Research output: Contribution to journalArticle

Bellido, T, Jilka, RL, Boyce, BF, Girasole, G, Broxmeyer, H, Dalrymple, SA, Murray, R & Manolagas, SC 1995, 'Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens: The role of the androgen receptor', Journal of Clinical Investigation, vol. 95, no. 6, pp. 2886-2895.
Bellido, Teresita ; Jilka, Robert L. ; Boyce, Brendan F. ; Girasole, Giuseppe ; Broxmeyer, Hal ; Dalrymple, Stacie A. ; Murray, Richard ; Manolagas, Stavros C. / Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens : The role of the androgen receptor. In: Journal of Clinical Investigation. 1995 ; Vol. 95, No. 6. pp. 2886-2895.
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