Kynurenine Pathway Metabolism in Patients With Osteoporosis After 2 Years of Drug Treatment

Abstract

1. Metabolism of tryptophan along the oxidative pathway via kynurenine results in the production of quinolinic acid and kynurenic acid, which can act on glutamate receptors in peripheral tissues. We have now measured the concentrations of kynurenine pathway metabolites in the plasma of patients with osteoporosis before treatment with drugs, throughout and after 2 years of treatment with the drugs raloxifene or etidronate. Oxidative stress was assessed by measuring levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal. Kynurenines were analysed by HPLC. Bone density was measured using dual-energy X-ray absorptiometry scans. 2. Patients with osteoporosis showed significantly lower baseline levels of 3-hydroxyanthranilic acid compared with healthy controls, but significantly higher levels of anthranilic acid and lipid peroxidation products. After 2 years treatment with etidronate and calcium, we observed significant therapeutic responses quantified by bone densitometric scanning. Significant improvements were not seen in patients treated with raloxifene. 3. In parallel, the levels of 3-hydroxyanthranilic acid, anthranilic acid and lipid peroxidation products were restored to control values by both drug treatments studied and tryptophan levels were increased significantly compared with baseline values. 4. The results suggest that tryptophan metabolism is altered in osteoporosis in a manner that could contribute to the oxidative stress and, thus, to progress of the disease. The oxidative metabolism of tryptophan (the kynurenine pathway) could represent a novel target for the development of new drugs for the treatment of osteoporosis. In addition, we noted that etidronate is a more effective drug than raloxifene, but that the simultaneous use of non-steroidal anti-inflammatory drugs may reduce the efficacy of etidronate.

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

“…58,59 These results might be pointing to a possible beneficial role of 3-HAA in humans and the presence of a clinically important alternative KP pathway for 3-HAA generation (Figure 1). The notion that 3-HAA per se is not necessarily toxic is supported by our mouse injection studies, which showed no evidence of cell death beyond what was evident in vehicle-injected brains ( Figure 8C; see also Supplemental Figure S1 at http://ajp.amjpathol.org).…”

Grape seed proanthocyanidins inhibit H₂O₂-induced osteoblastic MC3T3-E1 cell apoptosis via ameliorating H₂O₂-induced mitochondrial dysfunction

“…Oxidative stress, resulting from excessive levels of reactive oxygen species (ROS), represents a major cause of cellular damage and death in pathological conditions including osteoporosis, in which oxidative stress is associated with increased bone resorption and low bone mass (Forrest et al, 2006;Baek et al, 2010;Yilmaz and Eren, 2009;Sanchez-Rodriguez et al, 2007a;Varanasi et al, 1999). It was reported that blood 8-hydroxy-2'-deoxyguanosine (8-OH-dG), a marker of oxidative stress, was associated with osteoporosis in postmenopausal women (Baek et al, 2010).…”

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

“…This is associated with distinct increases in blood levels of oxidative stress markers (4)(5)(6). The main oxygen species responsible for oxidative stress are hydrogen peroxide (H 2 O 2 ), the free radical superoxide anion (O 2 -) and the hydroxyl radical (OH -).…”