A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss

Eur J Immunol. 2009 Oct;39(10):2831-9. doi: 10.1002/eji.200939670.


Post-menopausal osteoporosis is considered to be an inflammatory process, in which numerous pro-inflammatory and T-cell-derived cytokines play a bone-destructive role. IL-17A is the signature cytokine of the pro-inflammatory Th17 population and plays dichotomous roles in diseases that affect bone turnover. Although IL-17A promotes bone loss in rheumatoid arthritis, it is protective against pathogen-induced bone destruction in a periodontal disease model. We used a model of ovariectomy-induced osteoporosis (OVX) in IL-17 receptor (IL-17RA)(-/-) mice to evaluate the role of the IL-17A in bone loss caused by estrogen deficiency. Unexpectedly, IL-17RA(-/-) mice were consistently and markedly more susceptible to OVX-induced bone loss than controls. There were no changes in prototypical Th1, Th2 or Th17 cytokines in serum that could account for increased bone loss. However, IL-17RA(-/-) mice exhibited constitutively elevated leptin, which further increased following OVX. Consistently, IL-17A and IL-17F treatment of 3T3-L1 pre-adipocytes inhibited adipogenesis, leading to reduced production of leptin. In addition to its role in regulating metabolism and satiety, leptin can regulate bone turnover. Accordingly, these data show that IL-17A negatively regulates adipogenesis and subsequent leptin expression, which correlates with increased bone destruction during OVX.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipogenesis / drug effects
  • Animals
  • Bone Density / genetics
  • Cytokines / blood
  • Down-Regulation / drug effects
  • Estrogens / deficiency*
  • Female
  • Interleukin-17 / pharmacology
  • Leptin / blood
  • Leptin / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Osteoporosis / blood
  • Osteoporosis / etiology*
  • Osteoporosis / pathology
  • Ovariectomy / adverse effects*
  • Receptors, Interleukin-17 / metabolism*
  • Signal Transduction / physiology*
  • Spine / chemistry
  • Spine / pathology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Weight Gain / genetics


  • Cytokines
  • Estrogens
  • Il17ra protein, mouse
  • Interleukin-17
  • Leptin
  • Receptors, Interleukin-17
  • Tumor Necrosis Factor-alpha