title: Interferon gamma (IFN-γ)-mediated inflammation and the kynurenine pathway in relation to risk of hip fractures: the Hordaland Health Study.
abstract: The cytokine interferon gamma (IFN-γ) stimulates neopterin release and tryptophan degradation into kynurenines through the kynurenine pathway. High levels of neopterin were associated with increased hip fracture risk, as were some of the kynurenines, suggesting a role of IFN-γ-mediated inflammation in the processes leading to hip fracture.
  
  
  BACKGROUND
  Low-grade systemic inflammation has been associated with bone loss and risk of fractures. Interferon gamma (IFN-γ) initiates macrophage release of neopterin and also stimulates degradation of tryptophan along the kynurenine pathway as part of cell-mediated immune activation. Plasma neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Risk of hip fracture was investigated in relation to markers of inflammation and metabolites in the kynurenine pathway (kynurenines).
  
  
  METHODS
  Participants (71 to 74 years, N = 3,311) in the community-based Hordaland Health Study (HUSK) were followed for hip fractures from enrolment (1998-2000) until 31 December 2009. Plasma C-reactive protein (CRP), neopterin, KTR, and six kynurenines were investigated as predictors of hip fracture, using Cox proportional hazards regression analyses.
  
  
  RESULTS
  A hazard ratio (HR) of 1.9 (95% confidence interval (CI) 1.3-2.7) for hip fracture was found in the highest compared to the lowest quartile of neopterin (p trend across quartiles <0.001). CRP and KTR were not related to hip fracture risk. Among the kynurenines, a higher risk of fracture was found in the highest compared to the lowest quartiles of anthranilic acid and 3-hydroxykynurenine. For subjects in the highest quartiles of neopterin, CRP, and KTR compared to those in no top quartiles, HR was 2.5 (95% CI 1.6-4.0).
  
  
  CONCLUSIONS
  This may indicate a role for low-grade immune activation in the pathogenic processes leading to hip fracture.
authors.affiliation: Department of Global Public Health and Primary Care, University of Bergen, Kalfarveien 31, 5018, Bergen, Norway, ellen.apalset@igs.uib.no.
authors.forename: E M
authors.initials: EM
authors.lastname: Apalset
authors.forename: C G
authors.initials: CG
authors.lastname: Gjesdal
authors.forename: P M
authors.initials: PM
authors.lastname: Ueland
authors.forename: J
authors.initials: J
authors.lastname: Øyen
authors.forename: K
authors.initials: K
authors.lastname: Meyer
authors.forename: Ø
authors.initials: Ø
authors.lastname: Midttun
authors.forename: G E
authors.initials: GE
authors.lastname: Eide
authors.forename: G S
authors.initials: GS
authors.lastname: Tell
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006620:Hip Fractures / Q000097:blood* / Q000453:epidemiology; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D007371:Interferon-gamma / Q000097:blood*; D053208:Kaplan-Meier Estimate; D007737:Kynurenine / Q000097:blood*; D008297:Male; D019798:Neopterin / Q000097:blood; D009664:Norway / Q000453:epidemiology; D018570:Risk Assessment / Q000379:methods; D015398:Signal Transduction / Q000502:physiology
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D007737:Kynurenine; D019798:Neopterin; D007371:Interferon-gamma; D002097:C-Reactive Protein