Central IL-1 receptor signaling regulates bone growth and mass

Alon Bajayo, Inbal Goshen, Sharon Feldman, Valer Csernus, Kerstin Iverfeldt, Esther Shohami, Raz Yirmiya, Itai Bab*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

The proinflammatory cytokine IL-1, acting via the hypothalamic IL-1 receptor type 1 (IL-1RI), activates pathways known to suppress bone formation such as the hypothalamo pituitary-adrenocortical axis and the sympathetic nervous system. In addition, peripheral IL-1 has been implicated as a mediator of the bone loss induced by sex hormone depletion and TNF. Here, we report an unexpected low bone mass (LBM) phenotype, including impairment of bone growth, in IL-1RI-deficient mice (IL-1rKO mice). Targeted overexpression of human IL-1 receptor antagonist to the central nervous system using the murine glial fibrillary acidic protein promoter (IL-1raTG mice) resulted in a similar phenotype, implying that central IL-1RI silencing is the causative process in the LBM induction. Analysis of bone remodeling indicates that the process leading to the LBM in both IL-1rKO and IL-1raTG is characterized mainly by doubling the osteoclast number. Either genetic modification does not decrease testosterone or increase corticosterone serum levels, suggesting that systems other than the gonads and hypothalamo pituitary-adrenocortical axis mediate the central IL-1RI effect on bone. We further demonstrate that WT mice express mouse IL-1ra in bone but not in the hypothalamus. Because low levels of IL-1 are present in both tissues, it is suggested that skeletal IL-1 activity is normally suppressed, whereas central IL-1 produces a constant physiologic stimulation of IL-1RI signaling. Although the pathway connecting the central IL-1RI signaling to bone remodeling remains unknown, the outburst of osteoclastogenesis in its absence suggests that normally it controls bone growth and mass by tonically restraining bone resorption.

Original languageAmerican English
Pages (from-to)12956-12961
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number36
DOIs
StatePublished - 6 Sep 2005

Keywords

  • Bone remodeling
  • Bone resorption
  • Brain
  • Central regulation
  • IL-1 receptor antagonist

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