Evidence map›Paper›PMID 41580082›Full record

ArticleThe Journal of biological chemistry2026

Tryptophan metabolites 3-hydroxykynurenine (3HK) and 3-hydroxyanthranilic acid (3HAA) increase oxidative stress and impair osteoblastic bone formation.

Dima W Alhamad, Husam Bensreti, Kehong Ding, Shabiha Sultana, Christopher L Yearwood, Ashley Ellingwood, Joseph Shaver, Kyle Burkhart, Alok Tripathi, Jennifer Dorn and 19 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of biological chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

29 authors.

Dima W AlhamadDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Husam BensretiDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Kehong DingDepartment of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
Shabiha SultanaDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Christopher L YearwoodDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Ashley EllingwoodDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Joseph ShaverDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Kyle BurkhartDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Alok TripathiDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Jennifer DornDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Michaela CushingDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Hima NesbitDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Caihong DaiDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Eric MoreyDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Colby GrossDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Miar AlhamadDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Dylan TaylorDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Alena CherezovaDepartment of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
Daria V IlatovskayaDepartment of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
Wenbo ZhiCenter for Biotechnology and Genomic Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Marion A CooleyDepartment of Oral Biology & Diagnostic Sciences, Dental College of Georgia, Augusta, Georgia, USA.
Roger ZhongDepartment of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Maribeth H JohnsonDepartment of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Wendy B BollagDepartment of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA; Charlie Norwood VA Medical Center, Augusta, Georgia, USA.
Mark W HamrickDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Sadanand FulzeleDepartment of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA; Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
William D HillDepartment of Pathology, Medical University of South Carolina, Charleston, South Carolina, USA.
Carlos M IsalesDepartment of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA; Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Meghan E McGee-LawrenceDepartment of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA. Electronic address: mmcgeelawrence@augusta.edu.

Funding

Novel mechanisms of muscle and bone loss with HIV infection, antiretroviral therapy, and aging.R01AR082307 · NIAMS · AUGUSTA UNIVERSITY · PI Eric J Belin de Chantemele, Meghan E. McGee-Lawrence · 2023 to 2026
$2.5M
Mechanisms of HIV-associated HypertensionR01HL175471 · NHLBI · AUGUSTA UNIVERSITY · PI Eric J Belin de Chantemele · 2024 to 2026
$2.0M
NHLBI NIH HHS R01 HL175471NIAMS NIH HHS R01 AR082307
6 · The paper itself

Abstract

The aryl hydrocarbon receptor (AhR) is activated by kynurenine (Kyn), a tryptophan metabolite that accumulates with age, and this process drives osteoblast dysfunction. However, Kyn can be further metabolized, and the extent to which downstream metabolite molecules activate AhR in mesenchymal lineage cells and impact bone formation activity was unclear from previous studies. We hypothesized that Kyn metabolites activate AhR signaling and impair bone formation to drive bone loss. In the current study, tryptophan, Kyn, and 3-hydroxy-kynurenine (3HK) dose-dependently activated AhR in mesenchymal stem cell models, with 3HK being the most potent activator. Treating mesenchymal stem cells with 3HK and 3-hydroxyanthranilic acid (3HAA) dose-dependently induced DNA damage that at lower concentrations induced senescence and at higher concentrations promoted apoptotic cell death. This cell death was rescued upon scavenging reactive oxygen species with N-acetylcysteine, suggesting a mechanism of apoptosis related to increased oxidative stress. With regards to bone formation activity, the differentiation of primary bone marrow stromal cells into matrix-producing osteoblasts was blunted upon the introduction of Kyn, 3HK or 3HAA into osteogenic differentiation media, with 3HK and 3HAA inducing the greatest deficits in mineralized matrix production. In vivo administration of 3HAA to C57BL/6 mice was detrimental to whole-body bone mineral density and cortical bone mass, although trabecular bone was largely unaffected. Together, our results suggest that several intermediate metabolites in the tryptophan-Kyn pathway activate AhR and impede the differentiation of osteoblasts by inducing DNA damage, senescence and oxidative stress, which may have negative consequences for cortical bone in vivo.

Indexed as

3-Hydroxyanthranilic AcidKynurenineOsteoblastsOsteogenesisOxidative StressTryptophanAnimalsApoptosisCells, CulturedDNA DamageMesenchymal Stem CellsMiceMice, Inbred C57BLReactive Oxygen SpeciesReceptors, Aryl Hydrocarbon3-Hydroxyanthranilic Acid3-hydroxykynurenineKynurenineReactive Oxygen SpeciesReceptors, Aryl HydrocarbonTryptophanagingaryl hydrocarbon receptorbonekynurenineosteoblastreactive oxygen species (ROS)

Identifiers

PMID41580082
PMCPMC13018973

What Socratic holds

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LicenceCC BY
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.