A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss.
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.
Goswami
Jaya
J
Department of Microbiology and Immunology, University at Buffalo, SUNY, Buffalo, NY, USA.
Hernández-Santos
Nydiaris
N
Zuniga
Luis A
LA
Gaffen
Sarah L
SL
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D015519:Bone Density / Q000235:genetics; D016207:Cytokines / Q000097:blood; D015536:Down-Regulation / Q000187:drug effects; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D020381:Interleukin-17 / Q000494:pharmacology; D020738:Leptin / Q000097:blood / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010024:Osteoporosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D010052:Ovariectomy / Q000009:adverse effects*; D053722:Receptors, Interleukin-17 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013131:Spine / Q000737:chemistry / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015430:Weight Gain / Q000235:genetics
D016207:Cytokines; D004967:Estrogens; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D020738:Leptin; D053722:Receptors, Interleukin-17; D014409:Tumor Necrosis Factor-alpha