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Article ; Online: The Role of the Kynurenine Pathway in the Pathophysiology of Frailty, Sarcopenia, and Osteoporosis.

Ballesteros, Juan / Rivas, Daniel / Duque, Gustavo

2023 Volume 15, Issue 14

Abstract: ... significant effects on aging and musculoskeletal health. The kynurenine pathway, essential in tryptophan ... increased levels of inflammatory factors. Due to the disruption of the kynurenine pathway by chronic ... collected, kynurenines could have a promising role as biomarkers for osteoporosis sarcopenia ...

Abstract	Tryptophan is an essential nutrient required to generate vitamin B3 (niacin), which is mainly involved in energy metabolism and DNA production. Alterations in tryptophan metabolism could have significant effects on aging and musculoskeletal health. The kynurenine pathway, essential in tryptophan catabolism, is modulated by inflammatory factors that are increased in older persons, a process known as inflammaging. Osteoporosis, sarcopenia, osteosarcopenia, and frailty have also been linked with chronically increased levels of inflammatory factors. Due to the disruption of the kynurenine pathway by chronic inflammation and/or changes in the gut microbiota, serum levels of toxic metabolites are increased and are associated with the pathophysiology of those conditions. In contrast, anabolic products of this pathway, such as picolinic acid, have demonstrated a positive effect on skeletal muscle and bone. In addition, physical activity can modulate this pathway by promoting the secretion of anabolic kynurenines. According to the evidence collected, kynurenines could have a promising role as biomarkers for osteoporosis sarcopenia, osteosarcopenia, and frailty in older persons. In addition, some of these metabolites could become important targets for developing new pharmacological treatments for these conditions.
MeSH term(s)	Humans ; Aged ; Aged, 80 and over ; Kynurenine/metabolism ; Tryptophan/metabolism ; Sarcopenia ; Frailty ; Osteoporosis
Chemical Substances	Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX)
Language	English
Publishing date	2023-07-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu15143132
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Article: Kynurenine pathway metabolism in patients with osteoporosis after 2 years of drug treatment.

Forrest, Caroline M / Mackay, Gillian M / Oxford, Lynn / Stoy, Nicholas / Stone, Trevor W / Darlington, L Gail

Clinical and experimental pharmacology & physiology

2006 Volume 33, Issue 11, Page(s) 1078–1087

Abstract: ... measured the concentrations of kynurenine pathway metabolites in the plasma of patients with osteoporosis ... 1. Metabolism of tryptophan along the oxidative pathway via kynurenine results in the production ... thus, to progress of the disease. The oxidative metabolism of tryptophan (the kynurenine pathway) could represent a novel target ...

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.
MeSH term(s)	3-Hydroxyanthranilic Acid/chemistry ; 3-Hydroxyanthranilic Acid/metabolism ; Aged ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Female ; Humans ; Indomethacin/therapeutic use ; Kynurenic Acid/chemistry ; Kynurenic Acid/metabolism ; Kynurenine/blood ; Kynurenine/chemistry ; Kynurenine/metabolism ; Lipid Peroxidation ; Male ; Middle Aged ; Molecular Structure ; Neopterin/blood ; Osteoporosis/drug therapy ; Osteoporosis/metabolism ; Sodium Salicylate/therapeutic use ; Tryptophan/chemistry ; Tryptophan/metabolism ; ortho-Aminobenzoates/chemistry ; ortho-Aminobenzoates/metabolism
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; ortho-Aminobenzoates ; anthranilic acid (0YS975XI6W) ; 3-Hydroxyanthranilic Acid (1UQB1BT4OT) ; Kynurenine (343-65-7) ; Neopterin (670-65-5) ; Tryptophan (8DUH1N11BX) ; Kynurenic Acid (H030S2S85J) ; Sodium Salicylate (WIQ1H85SYP) ; Indomethacin (XXE1CET956)
Language	English
Publishing date	2006-11
Publishing country	Australia
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	189277-0
ISSN	1440-1681 ; 0305-1870 ; 0143-9294
ISSN (online)	1440-1681
ISSN	0305-1870 ; 0143-9294
DOI	10.1111/j.1440-1681.2006.04490.x
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Article: Exercised accelerated the production of muscle-derived kynurenic acid in skeletal muscle and alleviated the postmenopausal osteoporosis through the Gpr35/NFκB p65 pathway.

Shi, Tianshu / Shi, Yong / Gao, Hongliang / Ma, Yuze / Wang, Qianjin / Shen, Siyu / Shao, Xiaoyan / Gong, Wang / Chen, Xiang / Qin, Jian / Wu, Jing / Jiang, Qing / Xue, Bin

Journal of orthopaedic translation

2022 Volume 35, Page(s) 1–12

Abstract: ... The expression levels of kynurenine aminotransferases (Kats) were detected by RT-PCR and Western Blot ... model mice, accompanied by a decreased level of kynurenine aminotransferases (Kats) in the gastrocnemius ... the impact of exercise on myokine secretion in the postmenopausal osteoporosis (PMOP) process.: Methods ...

Abstract	Background: Reduced serum estrogen levels in postmenopausal patients not only aggravate bone loss but also impact myokine secretion. Emerging evidence has revealed the importance of myokines in bone metabolism, and exercise can interfere with the secretion of myokines. However, few studies have explored the impact of exercise on myokine secretion in the postmenopausal osteoporosis (PMOP) process. Methods: Ten-weeks-old C57B/L6 female mice were used for constructing the postmenopausal osteoporosis model. The expression levels of kynurenine aminotransferases (Kats) were detected by RT-PCR and Western Blot. The concentration of serum kynurenic acid (Kyna) was detected by HPLC-MS. Micro-CT analysis was used for determine the changes of bone mineral density and the microstructure. The primary osteoblast and osteoclast were isolated from mice to determine the effect and mechanism of Kyna on the bone formation and resorption. Results: In our research, we found a lower serum level of muscle-derived kynurenic acid (Kyna) in PMOP model mice, accompanied by a decreased level of kynurenine aminotransferases (Kats) in the gastrocnemius muscle. Moreover, treadmill-running exercise upregulated the muscle levels of KATs and increased the serum concentration of Kyna, which was positively correlated with the alleviation of bone loss. Furthermore, we found that exogenous Kyna treatment alleviated bone mineral loss and microstructure destruction in PMOP mice by inhibiting osteoclast maturation and increasing osteoblast viability. Mechanistically, we observed that Kyna reduced the NFκB p65 phosphorylation level by activating the Gpr35 receptor, which inhibited NFATc1 expression in osteoclasts and upregulated Runx2 expression in osteoblasts. Conclusion: Our results revealed that the muscle levels of Kats and serum level of Kyna were negatively correlated with the severity of PMOP. Exercise intervention and exogenous Kyna treatment alleviated the impairment of bone microstructure through the Gpr35 receptor, paving the way for a novel therapeutic intervention in PMOP. The translational potential of this article: This study provides evidences that Kyna could increase the osteoblastgenesis and inhibit the osteoclastgenesis, which could be a novel therapeutic approach for osteoporosis treatment.
Language	English
Publishing date	2022-04-04
Publishing country	Singapore
Document type	Journal Article
ZDB-ID	2747531-1
ISSN	2214-031X
ISSN	2214-031X
DOI	10.1016/j.jot.2022.03.003
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Article: Kynurenine and neopterin levels in patients with rheumatoid arthritis and osteoporosis during drug treatment.

Forrest, Caroline M / Kennedy, Alan / Stone, Trevor W / Stoy, Nicholas / Darlington, L Gail

Advances in experimental medicine and biology

2003 Volume 527, Page(s) 287–295

Abstract: The kynurenine pathway from tryptophan generates compounds which can act on glutamate receptors ... with drugs and then at monthly intervals for 6 months during treatment. Kynurenine analysis was performed ... of tryptophan, 3-hydroxykynurenine and 3-hydroxyanthranilic acid and increased levels of kynurenine and ...

Abstract	The kynurenine pathway from tryptophan generates compounds which can act on glutamate receptors in peripheral tissues or modulate free radical activity. We have measured the concentrations of several of these compounds in the plasma of patients with rheumatoid arthritis (RA) and osteoporosis (OP) before treatment with drugs and then at monthly intervals for 6 months during treatment. Kynurenine analysis was performed by HPLC. Compared with healthy controls, RA patients showed significantly decreased baseline levels of tryptophan, 3-hydroxykynurenine and 3-hydroxyanthranilic acid and increased levels of kynurenine and xanthurenic acid, while kynurenic acid concentrations were normal. Different results were recorded from patients with OP with only a significant reduction in tryptophan and 3-hydroxyanthranilic acid when compared with healthy controls. During 6 months of treating the RA patients with prednisolone or methotrexate, and the OP patients with raloxifene or etidronate and calcium there were significant therapeutic responses and a significant trend towards a reduction in levels of neopterin in RA patients receiving methotrexate but no changes in the profiles of tryptophan metabolites. The results are consistent with the induction of indoleamine-2,3-dioxygenase (IDO) in both RA and OP but with far greater activation of the pathway in the much more inflammatory condition, i.e. RA. It is concluded that there are changes in the kynurenine pathway, which may modify the activation of tissue glutamate receptors, in RA and OP, but that these are not affected by the drug treatments studied.
MeSH term(s)	Arthritis, Rheumatoid/blood ; Arthritis, Rheumatoid/drug therapy ; Case-Control Studies ; Etidronic Acid/therapeutic use ; Female ; Humans ; Kynurenine/blood ; Methotrexate/therapeutic use ; Neopterin/blood ; Osteoporosis/blood ; Osteoporosis/drug therapy ; Prednisolone/therapeutic use ; Raloxifene Hydrochloride/therapeutic use ; Receptors, Glutamate/metabolism ; Tryptophan/blood
Chemical Substances	Receptors, Glutamate ; Kynurenine (343-65-7) ; Raloxifene Hydrochloride (4F86W47BR6) ; Neopterin (670-65-5) ; Tryptophan (8DUH1N11BX) ; Prednisolone (9PHQ9Y1OLM) ; Etidronic Acid (M2F465ROXU) ; Methotrexate (YL5FZ2Y5U1)
Language	English
Publishing date	2003
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4615-0135-0_32
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Article ; Online: The Tryptophan and Kynurenine Pathway Involved in the Development of Immune-Related Diseases.

Tsuji, Ai / Ikeda, Yuka / Yoshikawa, Sayuri / Taniguchi, Kurumi / Sawamura, Haruka / Morikawa, Sae / Nakashima, Moeka / Asai, Tomoko / Matsuda, Satoru

International journal of molecular sciences

2023 Volume 24, Issue 6

Abstract: ... such as inflammatory bowel disease, cardiovascular disease, osteoporosis, and/or polycystic ovary syndrome. Interestingly, kynurenine ... The tryptophan and kynurenine pathway is well-known to play an important role in nervous, endocrine ... that some kynurenine metabolites are considered to have anti-oxidative, anti-inflammatory, and/or neuroprotective ...

Abstract	The tryptophan and kynurenine pathway is well-known to play an important role in nervous, endocrine, and immune systems, as well as in the development of inflammatory diseases. It has been documented that some kynurenine metabolites are considered to have anti-oxidative, anti-inflammatory, and/or neuroprotective properties. Importantly, many of these kynurenine metabolites may possess immune-regulatory properties that could alleviate the inflammation response. The abnormal activation of the tryptophan and kynurenine pathway might be involved in the pathophysiological process of various immune-related diseases, such as inflammatory bowel disease, cardiovascular disease, osteoporosis, and/or polycystic ovary syndrome. Interestingly, kynurenine metabolites may be involved in the brain memory system and/or intricate immunity via the modulation of glial function. In the further deliberation of this concept with engram, the roles of gut microbiota could lead to the development of remarkable treatments for the prevention of and/or the therapeutics for various intractable immune-related diseases.
MeSH term(s)	Female ; Humans ; Tryptophan/metabolism ; Kynurenine/metabolism ; Brain/metabolism ; Gastrointestinal Microbiome ; Immune System Diseases/metabolism
Chemical Substances	Tryptophan (8DUH1N11BX) ; Kynurenine (343-65-7)
Language	English
Publishing date	2023-03-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24065742
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Article ; Online: The Tryptophan and Kynurenine Pathway Involved in the Development of Immune-Related Diseases

Ai Tsuji / Yuka Ikeda / Sayuri Yoshikawa / Kurumi Taniguchi / Haruka Sawamura / Sae Morikawa / Moeka Nakashima / Tomoko Asai / Satoru Matsuda

International Journal of Molecular Sciences, Vol 24, Iss 5742, p

2023 Volume 5742

Abstract	The tryptophan and kynurenine pathway is well-known to play an important role in nervous, endocrine, and immune systems, as well as in the development of inflammatory diseases. It has been documented that some kynurenine metabolites are considered to have anti-oxidative, anti-inflammatory, and/or neuroprotective properties. Importantly, many of these kynurenine metabolites may possess immune-regulatory properties that could alleviate the inflammation response. The abnormal activation of the tryptophan and kynurenine pathway might be involved in the pathophysiological process of various immune-related diseases, such as inflammatory bowel disease, cardiovascular disease, osteoporosis, and/or polycystic ovary syndrome. Interestingly, kynurenine metabolites may be involved in the brain memory system and/or intricate immunity via the modulation of glial function. In the further deliberation of this concept with engram, the roles of gut microbiota could lead to the development of remarkable treatments for the prevention of and/or the therapeutics for various intractable immune-related diseases.
Keywords	tryptophan ; kynurenine ; immune-related disease ; engram ; gut–brain axis ; gut microbiota ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The kynurenine pathway in HIV, frailty and inflammaging.

Sultana, Shabiha / Elengickal, Anthony / Bensreti, Husam / Belin de Chantemèle, Eric / McGee-Lawrence, Meghan E / Hamrick, Mark W

Frontiers in immunology

2023 Volume 14, Page(s) 1244622

Abstract: Kynurenine (Kyn) is a circulating tryptophan (Trp) catabolite generated by enzymes including IDO1 ... with age and Kyn is implicated in several age-related disorders including neurodegeneration, osteoporosis ...

Abstract	Kynurenine (Kyn) is a circulating tryptophan (Trp) catabolite generated by enzymes including IDO1 that are induced by inflammatory cytokines such as interferon-gamma. Kyn levels in circulation increase with age and Kyn is implicated in several age-related disorders including neurodegeneration, osteoporosis, and sarcopenia. Importantly, Kyn increases with progressive disease in HIV patients, and antiretroviral therapy does not normalize IDO1 activity in these subjects. Kyn is now recognized as an endogenous agonist of the aryl hydrocarbon receptor, and AhR activation itself has been found to induce muscle atrophy, increase the activity of bone-resorbing osteoclasts, decrease matrix formation by osteoblasts, and lead to senescence of bone marrow stem cells. Several IDO1 and AhR inhibitors are now in clinical trials as potential cancer therapies. We propose that some of these drugs may be repurposed to improve musculoskeletal health in older adults living with HIV.
MeSH term(s)	Humans ; Aged ; Kynurenine ; Frailty ; HIV Infections/drug therapy ; Tryptophan ; Cytokines
Chemical Substances	Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX) ; Cytokines
Language	English
Publishing date	2023-09-08
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1244622
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Article ; Online: Kynurenine suppresses osteoblastic cell energetics in vitro and osteoblast numbers in vivo.

Pierce, Jessica L / Roberts, Rachel L / Yu, Kanglun / Kendall, Riley K / Kaiser, Helen / Davis, Colleen / Johnson, Maribeth H / Hill, William D / Isales, Carlos M / Bollag, Wendy B / Hamrick, Mark W / McGee-Lawrence, Meghan E

Experimental gerontology

2019 Volume 130, Page(s) 110818

Abstract: Aging is a progressive process associated with declining tissue function over time. Kynurenine ... the pathways involved in the harmful effects of kynurenine on bone. In this study, we sought to investigate ... the effects of controlled kynurenine administration on osteoblast bioenergetics, in vivo osteoblast abundance ...

Abstract	Aging is a progressive process associated with declining tissue function over time. Kynurenine, an oxidized metabolite of the essential amino acid tryptophan that increases in abundance with age, drives cellular processes of aging and dysfunction in many tissues, and recent work has focused on understanding the pathways involved in the harmful effects of kynurenine on bone. In this study, we sought to investigate the effects of controlled kynurenine administration on osteoblast bioenergetics, in vivo osteoblast abundance, and marrow fat accumulation. Additionally, as an extension of earlier studies with dietary administration of kynurenine, we investigated the effects of kynurenine on Hdac3 and NCoR1 expression and enzymatic deacetylase activity as potential mechanistic contributors to the effects of kynurenine on osteoblasts. Kynurenine administration suppressed cellular metabolism in osteoblasts at least in part through impaired mitochondrial respiration, and suppressed osteoblastic numbers in vivo with no concurrent effects on marrow adiposity. Deleterious effects of kynurenine treatment on osteoblasts were more pronounced in female models as compared to males. However, kynurenine treatment did not inhibit Hdac3's enzymatic deacetylase activity nor its repression of downstream glucocorticoid signaling. As such, future work will be necessary to determine the mechanisms by which increased kynurenine contributes to aging bone bioenergetics. The current study provides novel further support for the idea that kynurenine contributes to impaired osteoblastic function, and suggests that impaired matrix production by kynurenine-affected osteoblasts is attributed in part to impaired osteoblastic bioenergetics. As circulating kynurenine levels in increase with age, and human bone density inversely correlates with the serum kynurenine to tryptophan ratio, these mechanisms may have important relevance in the etiology and pathogenesis of osteoporosis in humans.
MeSH term(s)	Aging/metabolism ; Animals ; Bone Density ; Bone and Bones/metabolism ; Cell Differentiation/drug effects ; Female ; Histone Deacetylases ; Kynurenine/metabolism ; Male ; Mice ; Osteoblasts/metabolism ; Osteoporosis/metabolism ; Sex Characteristics ; Tryptophan
Chemical Substances	Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX) ; Histone Deacetylases (EC 3.5.1.98) ; histone deacetylase 3 (EC 3.5.1.98)
Language	English
Publishing date	2019-12-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	390992-x
ISSN	1873-6815 ; 0531-5565
ISSN (online)	1873-6815
ISSN	0531-5565
DOI	10.1016/j.exger.2019.110818
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Article ; Online: Kynurenine induces an age-related phenotype in bone marrow stromal cells.

Patel, Dhara / Potter, Matthew / Anaya, Jordan Marcano / McGee-Lawrence, Meghan E / Hamrick, Mark W / Hill, William D / Isales, Carlos M / Fulzele, Sadanand

Mechanisms of ageing and development

2021 Volume 195, Page(s) 111464

Abstract: ... such as Kynurenine (KYN). With age, Kynurenine accumulates and suppresses osteogenic differentiation, impairs ... studies have shown that Kynurenine negatively impacts bone marrow stromal cells (BMSCs) and, consequently ... Therefore, in this article, we review Kynurenine and how it plays a vital role in BMSC dysfunction and bone loss with age. ...

Abstract	Advanced age is one of the important contributing factors for musculoskeletal deterioration. Although the exact mechanism behind this degeneration is unknown, it has been previously established that nutritional signaling plays a vital role in musculoskeletal pathophysiology. Our group established the vital role of the essential amino acid, tryptophan, in aging musculoskeletal health. With advanced age, inflammatory factors activate indoleamine 2,3-dioxygenase (IDO1) and accumulate excessive intermediate tryptophan metabolites such as Kynurenine (KYN). With age, Kynurenine accumulates and suppresses osteogenic differentiation, impairs autophagy, promotes early senescence, and alters cellular bioenergetics of bone marrow stem cells. Recent studies have shown that Kynurenine negatively impacts bone marrow stromal cells (BMSCs) and, consequently, promotes bone loss. Overall, understanding the mechanism behind BMSCs losing their ability for osteogenic differentiation can provide insight into the prevention of osteoporosis and the development of targeted therapies. Therefore, in this article, we review Kynurenine and how it plays a vital role in BMSC dysfunction and bone loss with age.
MeSH term(s)	Autophagy ; Bone Marrow Cells/physiology ; Cellular Senescence ; Humans ; Kynurenine/metabolism ; Musculoskeletal Physiological Phenomena ; Osteogenesis/physiology ; Osteoporosis/metabolism ; Osteoporosis/prevention & control ; Signal Transduction ; Stromal Cells/physiology ; Tryptophan/metabolism
Chemical Substances	Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX)
Language	English
Publishing date	2021-02-22
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	183915-9
ISSN	1872-6216 ; 0047-6374
ISSN (online)	1872-6216
ISSN	0047-6374
DOI	10.1016/j.mad.2021.111464
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Article ; Online: Kynurenine inhibits autophagy and promotes senescence in aged bone marrow mesenchymal stem cells through the aryl hydrocarbon receptor pathway.

Kondrikov, Dmitry / Elmansi, Ahmed / Bragg, Robert Tailor / Mobley, Tanner / Barrett, Thomas / Eisa, Nada / Kondrikova, Galina / Schoeinlein, Patricia / Aguilar-Perez, Alexandra / Shi, Xing-Ming / Fulzele, Sadanand / Lawrence, Meghan McGee / Hamrick, Mark / Isales, Carlos / Hill, William

Experimental gerontology

2019 Volume 130, Page(s) 110805

Abstract: ... of osteogenic pathways with age is kynurenine, a tryptophan metabolite and an endogenous ... species and in different tissues. We previously found that kynurenine accumulates with age in the plasma ... In the present study, we investigated the effect of kynurenine on BMSCs, with a focus on autophagy and senescence ...

Abstract	Osteoporosis is an age-related deterioration in bone health that is, at least in part, a stem cell disease. The different mechanisms and signaling pathways that change with age and contribute to the development of osteoporosis are being identified. One key upstream mechanism that appears to target a number of osteogenic pathways with age is kynurenine, a tryptophan metabolite and an endogenous Aryl hydrocarbon receptor (AhR) agonist. The AhR signaling pathway has been reported to promote aging phenotypes across species and in different tissues. We previously found that kynurenine accumulates with age in the plasma and various tissues including bone and induces bone loss and osteoporosis in mice. Bone marrow mesenchymal stem cells (BMSCs) are responsible for osteogenesis, adipogenesis, and overall bone regeneration. In the present study, we investigated the effect of kynurenine on BMSCs, with a focus on autophagy and senescence as two cellular processes that control BMSCs proliferation and differentiation capacity. We found that physiological levels of kynurenine (10 and 100 μM) disrupted autophagic flux as evidenced by the reduction of LC3B-II, and autophagolysosomal production, as well as a significant increase of p62 protein level. Additionally, kynurenine also induced a senescent phenotype in BMSCs as shown by the increased expression of several senescence markers including senescence associated β-galactosidase in BMSCs. Additionally, western blotting reveals that levels of p21, another marker of senescence, also increased in kynurenine-treated BMSCs, while senescent-associated aggregation of nuclear H3K9me3 also showed a significant increase in response to kynurenine treatment. To validate that these effects are in fact due to AhR signaling pathway, we utilized two known AhR antagonists: CH-223191, and 3',4'-dimethoxyflavone to try to block AhR signaling and rescue kynurenine /AhR mediated effects. Indeed, AhR inhibition restored kynurenine-suppressed autophagy levels as shown by levels of LC3B-II, p62 and autophagolysosomal formation demonstrating a rescuing of autophagic flux. Furthermore, inhibition of AhR signaling prevented the kynurenine-induced increase in senescence associated β-galactosidase and p21 levels, as well as blocking aggregation of nuclear H3K9me3. Taken together, our results suggest that kynurenine inhibits autophagy and induces senescence in BMSCs via AhR signaling, and that this may be a novel target to prevent or reduce age-associated bone loss and osteoporosis.
MeSH term(s)	Animals ; Autophagy/drug effects ; Basic Helix-Loop-Helix Transcription Factors ; Bone Marrow Cells/drug effects ; Cell Differentiation/drug effects ; Cellular Senescence/drug effects ; Kynurenine/pharmacology ; Mesenchymal Stem Cells/drug effects ; Mice ; Osteogenesis/drug effects ; Osteoporosis ; Receptors, Aryl Hydrocarbon/metabolism ; Signal Transduction ; beta-Galactosidase/drug effects
Chemical Substances	AHR protein, human ; Basic Helix-Loop-Helix Transcription Factors ; Receptors, Aryl Hydrocarbon ; Kynurenine (343-65-7) ; beta-Galactosidase (EC 3.2.1.23)
Language	English
Publishing date	2019-12-05
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	390992-x
ISSN	1873-6815 ; 0531-5565
ISSN (online)	1873-6815
ISSN	0531-5565
DOI	10.1016/j.exger.2019.110805
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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito