Oxidation of dietary amino acids disrupts their anabolic effects on bone marrow-derived mesenchymal stem cells

Abstract

Age-dependent bone loss has been ''ell documented in both human and animal models. Since it has been proposed that aging is associated '' ith an increase in the generation of damaging reactive oxygen species (ROS), our hypothesis was that the oxidi1ed products of dietary amino acids could play a role in age-induced bone loss by altering osteoprogenitor cell differentiation and function or activating osteoclastic activit). We first examined the effects of the oxidi;rcd nutrients on the bone marrowderived mesenchymal stem cells and our data sho\ved a decrease in the protein and gene expression of osteogenic markers normally stimulated by nutrients Aromatic amino acids acti\ ated stgnaling path\\ays imoh ed in protein S) nthesis in vitro. and thus, in contrast, the O\.idt/ed metabolites of these aromatic amino actds had no effect on the activation of these anabolic path,,ays. We then examined the bone marro'' concentration of the O\.idi1ed aromatic amino acids in mature ( 12 months) \S. aged (24 months) C57BL/6 mice and found that kynurenine, the oxidi1ed product of the aromatic amino acid tryptophan, was found in the highest concentration in 12 months mice. Thus, we tested the effects of kynurenine, fed as a dietary supplement, on the bone mass of twelvemonth- old C57BU6 mice compared to a nom1al protein diet to sec if the O\.idized amino acid would induce a pattern conststent \vith age-related bone loss. Tv.elve-month-old, male C57BL 6 mice \\ere fed one of four diets; 18% protein dtet (normal protein diet); 8% protein diet tr}ptophan; 8°/o protem diet J..ynurentne (50 ~t\-l} and 8°/o protein diet + kynurenine (I 00 J.LM) for 8 \\ ks. Bone densitometry and mtcro-CT analyses demonstrated bone loss folio'' ing the k} mtrcnine diet. II istological and histomorphomctric studies showed a decreased bone !ormation and an increased osteoclastic acti\ity in the kynurenine groups; these animals also e'hibited an increase in serum pyridinolinc, a marker of bone breakdO\\n. Thus, these data demonstrate that feeding an O"\idi7cd product of an essential amino acid induces bone loss in a pattern consistent with accelerated aging, and we propose that one of the mechanisms involved in age-induced bone loss may be from alterations of dietary nutrients by the increased generation of ROS associated "" ith aging.