Evaluation of Tryptophan/Kynurenine Pathway Relevance With Immune System Biomarkers of Low Energy Trauma Hip Fractures in Osteoporotic Patients

Abstract

Objectives: This study aims to evaluate tryptophan degradation and clarify whether altered levels of kynurenine and tryptophan (Kyn/Trp) ratio could be correlated to osteoporotic hip fractures via immune system. Patients and methods:The study included 60 patients with osteoporotic hip fracture (20 males, 40 females, mean age 76.6±6.9 years; range 59 to 95 years). Patients were divided into two as patients with collum femoris fractures (group 1; n=23) and intertrochanteric fractures (group 2; n=37). Fifteen healthy subjects without any fracture were selected as control group (group 3; 3 males, 12 females; mean age 69.7±8.4; range 60 to 86 years). All fractures were simple falls due to low energy trauma. Bone mineral density measurements were performed with Lunar dual energy X-ray absorptiometry. Kyn/Trp levels were measured by high performance liquid chromatography. Interleukin (IL)-6 and IL-1 beta levels were measured with solid-phase sandwich enzyme-linked immunosorbent assay. Results: All bone mineral density values were in agreement for osteoporosis and there was no significant difference between the two groups. Higher Kyn/Trp ratios were observed in groups 1 and 2 compared to group 3. This difference was more significant in group 1 (p=0.0001) than that in group 2 (p=0.048). Also, group 1 had significantly higher Kyn/Trp ratio than group 2 (p=0.011). There were significantly higher IL-6 and lower IL-1 beta levels both in groups 1 and 2 compared to group 3 (p=0.0001). There was no significant difference between group 1 and group 2 in terms of IL-6 and IL-1 beta levels. There was positive correlation with Kyn/Trp ratio (r=0.581, p=0.004) in group 2. Also, significant correlation was detected between IL-6 and IL-1 beta levels in the same group (r=0.665, p=0.036). Conclusion: Both increased degradation of tryptophan and ratio of Kyn/Trp indicate the relationship of immune activation with bone healing.

IDO activation, inflammation and musculoskeletal disease

“…Some role of inflammation would certainly be suggested by the association between increased levels of kynurenine or its catabolites and the progress and degree of bone dysfunction, since the first enzyme of the kynurenine pathway, IDO, is induced and activated by several inflammatory stimuli such as interferon-γ, LPS and TNFα. This activation of the kynurenine pathway has been demonstrated in human mesenchymal stem cells with a strong positive correlation between kynurenine pathway activity and osteoblast formation 57,59 . Correspondingly, inhibition of the kynurenine pathway using an inhibitor of IDO produced a reduction of osteoblastogenesis and genetic deletion of IDO resulted in the loss of bone structure and strength with fewer osteoblasts and a higher proportion of osteoclasts than wild-type animals.…”

Chronic dietary supplementation with kynurenic acid, a neuroactive metabolite of tryptophan, decreased body weight without negative influence on densitometry and mandibular bone biomechanical endurance in young rats

“…However, neither kynurenine nor KYNA content was altered [56]. Similarly, Dinçel et al [59] observed reduced tryptophan content and unaltered levels of kynurenine in the plasma of humans with osteoporotic hip fractures. Furthermore, reduced levels of erythrocyte tryptophan were found in male idiopathic osteoporotic patients.…”

Metabolomics in Bone Research

“…Linolenate, a precursor of arachidonate (an inflammatory mediator), was found to be increased, much like corticosterone and cortisol, which are inhibitors in the proinflammatory pathway [ 67 ]. Kynurenine, a metabolite of tryptophan, was elevated in the post-reaming plasma, while tryptophan itself declined, pointing towards an upregulated activity of the kynurenine pathway [ 68 , 69 ]. It should be pointed out that the increase in the kynurenine/tryptophan ratio has been considered a marker for indoleamine 2,3-dioxygenase (IDO) activity [ 69 ].…”