The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

Abstract

Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress.

The relationship between uremic toxins and symptoms in older men and women with advanced chronic kidney disease

“…Our results did not confirm the associations between uremic toxins and symptoms described previously in preclinical studies and in CKD cohorts [ 7–9 , 11 , 12 ]. This discrepancy may be partly due to the differences in the study population (e.g.…”

“…In a rat model, accumulation of IS led to behavioral alterations, including apathetic behavior, increased stress sensitivity and reduced locomotor and exploratory activity [ 10 ]. Moreover, the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes and bone breakdown and in interfering with stem cell function and osteogenesis; kynurenine might lead to detrimental effects in bone, with a lower bone mineral density and an elevated fracture risk [ 11 , 12 ]. Several studies have demonstrated that trimethylamine N -oxide (TMAO) can promote atherosclerosis, thrombosis, heart failure, insulin resistance and kidney disease via tissue or cell type–specific reprogramming [ 13 ].…”

Bioinformatics-Guided Analysis Uncovers AOX1 as an Osteogenic Differentiation-Relevant Gene of Human Mesenchymal Stem Cells

“…AOX1 is one of the key enzymes of tryptophan catabolism and loss of AOX1 may lead to the accumulation of kynurenine and NADP ( Vantaku et al, 2020 ). Meanwhile, kynurenine impacts MSCs and causes age-related bone loss ( Anaya et al, 2020 ). AOX1 also contributes to ATRA biosynthesis ( Zhong et al, 2021 ).…”

The microbiota-gut-bone axis and bone health

“…Compounds produced in the KYN pathway including kynurenic acid (KYNA), 3hydroxykynurenine (3-HKYN), and anthranilic acid (AA) contribute key effects in the promotion of bone-aging phenotypes. 73,74 KYN itself has been found influencing the proliferation process of bone marrow mesenchymal stem cells into osteoblastic cell lineage 75,76 ; elevated peripheral KYN level leads to the destruction in bone structure via aryl hydrocarbon receptor pathway. 77 KYNA has been demonstrated inhibiting the differentiation of osteoblasts and RANKLinduced osteoclastogenesis, 192 and meanwhile 3-HKYN has been observed reducing the viability of osteoblast-like cells due to its prooxidative nature.…”