Estrogen's Bone-Protective Effects May Involve Differential IL-1 Receptor Regulation in Human Osteoclast-Like Cells

J Clin Invest. 1999 May 15;103(10):1409-18. doi: 10.1172/JCI4682.


Declining estrogen levels during the first postmenopausal decade lead to rapid bone loss and increased fracture risk that can be reversed by estrogen replacement therapy. The bone-protective effects of estrogen may involve suppression of inflammatory cytokines that promote osteoclastogenesis and bone resorption, such as IL-1, TNF-alpha, and IL-6. We investigated whether estrogen modulates IL-1 actions on human osteoclasts (OCs) and other bone cell types. Isolated human OCs and primary bone marrow-derived OC-like cells expressed both the signaling (IL-1RI) and decoy (IL-1RII) IL-1 receptors, whereas only IL-1RI was detected in osteoblasts. IL-1RII/IL-1RI mRNA ratios and release of soluble IL-1RII (sIL-1RII) were lower in OC-like cells derived from women in the late postmenopausal period compared with younger women, but were unrelated to male donor age, suggesting that estrogen might play a role in regulating IL-1 receptor levels in vivo. Estrogen directly reduced in vitro OC-like cell IL-1RI mRNA levels while increasing IL-1RII mRNA levels and sIL-1RII release. These estrogenic events were associated with inhibited IL-1-mediated cytokine (IL-8) mRNA induction and cell survival, i.e., increased apoptosis. In contrast, estrogen did not alter IL-1R levels or IL-1 responsiveness in primary human osteoblasts or bone marrow stromal cells. We conclude that one novel mechanism by which estrogen exerts bone-protective effects may include a selective modulation of IL-1R isoform levels in OC or OC-like cells, thereby reducing their IL-1 responsiveness and cell survival. Conversely, this restraint on IL-1 actions may be lost as estrogen levels decline in aging women, contributing to an enhanced OC-mediated postmenopausal bone loss.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Base Sequence
  • Cells, Cultured
  • DNA Primers / genetics
  • Estradiol / pharmacology
  • Estrogen Replacement Therapy
  • Estrogens / physiology*
  • Female
  • Humans
  • Interleukin-1 / pharmacology
  • Male
  • Middle Aged
  • Osteoclasts / drug effects
  • Osteoclasts / immunology*
  • Osteoclasts / physiology*
  • Osteoporosis, Postmenopausal / etiology
  • Osteoporosis, Postmenopausal / immunology
  • Osteoporosis, Postmenopausal / physiopathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / physiology*
  • Receptors, Interleukin-1 Type I
  • Receptors, Interleukin-1 Type II
  • Signal Transduction


  • DNA Primers
  • Estrogens
  • Interleukin-1
  • RNA, Messenger
  • Receptors, Interleukin-1
  • Receptors, Interleukin-1 Type I
  • Receptors, Interleukin-1 Type II
  • Estradiol