Interferon gamma (IFN-γ)-mediated inflammation and the kynurenine pathway in relation to risk of hip fractures: the Hordaland Health Study

• Published in: Osteoporosis international Vol. 25; no. 8; pp. 2067 - 2075
• Main Authors: Apalset, E. M., Gjesdal, C. G., Ueland, P. M., Øyen, J., Meyer, K., Midttun, Ø., Eide, G. E., Tell, G. S.
• Format: Journal Article
• Language: English
• Published: London Springer London 01.08.2014; Springer Nature B.V
• Subjects: Aged; Biomarkers; Biomarkers - blood; C-Reactive Protein - metabolism; Endocrinology; Female; Follow-Up Studies; Fractures; Hip Fractures - blood; Hip Fractures - epidemiology; Hip joint; Humans; Immunology; Inflammation Mediators - blood; Inflammatory diseases; Interferon-gamma - blood; Kaplan-Meier Estimate; Kynurenine - blood; Male; Medicine; Medicine & Public Health; Neopterin - blood; Norway - epidemiology; Original; Original Article; Orthopedics; Osteoporosis; Rheumatology; Risk Assessment - methods; Risk factors; Signal Transduction - physiology; Norway; Osteoporosis; Osteoimmunology; Hip fracture; Inflammation; Neopterin; Kynurenine pathway
• ISSN: 0937-941X; 1433-2965; 1433-2965
• DOI: 10.1007/s00198-014-2720-7

Summary 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. Introduction 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 to74 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.