A link between central kynurenine metabolism and bone strength in rats with chronic kidney disease

Kałaska, Bartłomiej; Pawlak, Krystyna; Oksztulska-Kolanek, Ewa; Domaniewski, Tomasz; Znorko, Beata; Karbowska, Małgorzata; Citkowska, Aleksandra; Rogalska, Joanna; Roszczenko, Alicja; Brzóska, Małgorzata M.; Pawlak, Dariusz

doi:10.7717/peerj.3199

Cited by 7 publications

(11 citation statements)

References 53 publications

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“…These alterations may be associated with the pathological changes in bone structure. In contrast to the central kynurenines (Kalaska et al, 2017 ), we observed the negative relationships between serum level of kynurenine and bone biomechanical as well as geometrical parameters. These associations may suggest unfavorable effects of peripheral kynurenine pathway metabolites on bone structure and may develop new strategies for the treatment, prevention, and diagnosis of osteoporosis in CKD patients.…”

Section: Discussioncontrasting

confidence: 95%

“…Before biomechanical testing, left tibias were thoroughly thawed to room temperature. The biomechanical properties of left tibias were determined using the three-point-bending test as described previously (Brzoska et al, 2005 ; Kalaska et al, 2017 ). The testing was performed with a testing machine Zwick Roell Z.2.5 (Germany) using testXpert II software.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we observed the positive effect of central kynurenine on bone strength in rats with CKD (Kalaska et al, 2017 ). In the current study, we investigated the role of peripheral TRP catabolism, aryl hydrocarbon receptor (AhR) as a physiological receptor for KYN and AhR-dependent cytochrome P450 1A1 (CYP1A1) in the development of osteoporosis in CKD.…”

Section: Introductionmentioning

confidence: 93%

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Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

et al. 2017

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The diagnosis and treatment of bone disorders in patients with chronic kidney disease (CKD) represent a clinical challenge. CKD leads to mineral and bone complications starting early in the course of renal failure. Recently, we have observed the positive relationship between intensified central kynurenine turnover and bone strength in rats with subtotal 5/6 nephrectomy (5/6 Nx)-induced CKD. The aim of the present study was to determine the association between peripheral kynurenine pathway metabolites and bone strength in rats with 5/6 Nx-induced CKD. The animals were sacrificed 1 and 3 months after 5/6 Nx or sham operation. Nephrectomized rats presented higher concentrations of serum creatinine, urea nitrogen, and parathyroid hormone both 1 and 3 months after nephrectomy. These animals revealed higher concentrations of kynurenine and 3-hydroxykynurenine in the serum and higher gene expression of aryl hydrocarbon receptor (AhR) as a physiological receptor for kynurenine and AhR-dependent cytochrome in the bone tissue. Furthermore, nephrectomy significantly increased the number of osteoclasts in the bone without affecting their resorptive activity measured in serum. These changes were particularly evident in rats 1 month after 5/6 Nx. The main bone biomechanical parameters of the tibia were unchanged between nephrectomized and sham-operated rats but were significantly increased in older compared to younger animals. A similar trend was observed for geometrical parameters measured with calipers, bone mineral density based on Archimedes' method and image of bone microarchitecture obtained from micro-computed tomography analyses of tibial cortical bone. In nephrectomized animals, peripheral kynurenine levels correlated negatively with the main parameters of bone biomechanics, bone geometry, and bone mineral density values. In conclusion, our data suggest that CKD-induced elevated levels of peripheral kynurenine cause pathological changes in bone structure via AhR pathway. This finding opens new opportunities for the treatment/prevention of osteoporosis in CKD.

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Section: Discussioncontrasting

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

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“…There was also significant upregulation of expression of the AhR gene, presumably the mediator of KYN effects. In contrast to peripheral effects, central kynurenine metabolism (similarly to serotonin) may have a beneficial impact on bone parameters in the setting of renal insufficiency [73]. Rats undergoing partial nephrectomy were found to have a significant elevation in KYN with a decrease in tryptophan levels in brain areas examined (cerebellum, brainstem, frontal cortex, hypothalamus and striatum) and an increase in tibial cross-sectional area and wall thickness.…”

Section: The Dual Role Of Serotonin In Bone Homeostasismentioning

confidence: 99%

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

Anaya

Bollag

Hamrick

et al. 2020

IJMS

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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.

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“…42,191,192 Evidence for the accumulation of the metabolites of the kynurenine pathway in the course of chronic renal insufficiency and their impact on bone tissue, prompted some researchers, including our team, to deal with the topic of connections between the CKD, changes in kynurenine system activation and bone metabolism. 31,35,98,187,[192][193][194] In vitro studies have proven, that the accumulation of KYN and 3-HKYN in bone marrow stromal cells (BMSCs) have been associated with a decrease in cell proliferation and differentiation, though the mechanism which is directly mediated by their pro-oxidative properties. Microarray analysis identified 50 upregulated, and 36 downregulated micro RNAs (miRNAs) in KYN-treated BMSCs.…”

Section: Associations Between the Increased Activity Of The Kynureninmentioning

confidence: 99%

Kynurenine Pathway in Chronic Kidney Disease: What’s Old, What’s New, and What’s Next?

Mor

Kałaska

Pawlak

2020

Int J�Tryptophan�Res

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Impaired kidney function and increased inflammatory process occurring in the course of Chronic Kidney Disease (CKD) contribute to the development of complex amino-acid alterations. The essential amino-acid tryptophan (TRP) undergoes extensive metabolism along several pathways, resulting in the production of many biologically active compounds. The results of many studies have shown that its metabolism via the kynurenine pathway is potently increased in the course of CKD. Metabolites of this pathway exhibit differential, sometimes opposite, roles in several biological processes. Their accumulation in the course of CKD may induce oxidative cell damage which stimulates inflammatory processes. They can also modulate the activity of numerous cellular signaling pathways through activation of the aryl hydrocarbon receptor, leading to the disruption of homeostasis of various organs. As a result, they can contribute to the development of the systemic disorders accompanying the course of chronic renal failure. This review gathers and systematizes reports concerning the knowledge connecting the kynurenine pathway metabolites to systemic disorders accompanying the development of CKD.

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A link between central kynurenine metabolism and bone strength in rats with chronic kidney disease

Cited by 7 publications

References 53 publications

Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

Elevated Levels of Peripheral Kynurenine Decrease Bone Strength in Rats with Chronic Kidney Disease

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

Kynurenine Pathway in Chronic Kidney Disease: What’s Old, What’s New, and What’s Next?

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