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Cited by 17Bone Metabolism and DiseasesTryptophan and brain disordersOsteoarthritis Treatment and Mechanisms

Aberrant Tryptophan Metabolism Manipulates Osteochondral Homeostasis

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Xiang, Tingwen, Yang, Chuan, Xie, Langlang, Xiao, Shiyu, Tang, Yong, Huang, Gang, Sun, Dong, Chen, Yueqi +1 more·2025·Research
DOI 10.34133/research.0728PMC PMC12150400
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Abstract

Tryptophan (Trp), an essential amino acid, performs as a precursor for synthesizing various bioactive molecules primarily metabolized through the kynurenine (Kyn), serotonin, and indole pathways. The diverse metabolites were deeply implicated in multiple physiological processes. Emerging research has revealed the multifaceted contribution of Trp in skeletal health and pathophysiology of bone-related disease with the involvement of specific receptors including aryl hydrocarbon receptor (AhR), which modulated the downstream signaling pathways to manage the expression of pivotal genes and thereby altered cellular biological processes, such as proliferation and differentiation. Accompanied by distinct alterations in immune function, inflammatory responses, endocrine balance, and other physiological aspects, their impact and efficacy in osteochondrogenic disorders have also been well documented. Nevertheless, a thorough understanding of Trp metabolism within bone biology is currently lacking. In this review, we elucidate the complexities of Trp metabolic pathway and several metabolites, delineating their versatile modulatory roles in the physiology and pathology of osteoblasts (OBs), osteoclasts (OCs), chondrocytes, and intercellular coupling effects, as well as in the progression of osteochondral disorder. Moreover, we comprehensively delineate the regulatory mechanisms by which gut microbiota-generated indole derivatives mediate bidirectional crosstalk along the gut–bone axis. The establishment of an elaborate governing network about bone homeostasis provides a novel insight on therapeutic interventions.

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  • Microbial conversion of dietary tryptophan generates indoles, kynurenines, and tryptamine, each capable of shaping mucosal and systemic immunity.

    “Microbial conversion of dietary tryptophan generates indoles, kynurenines, and tryptamine, each capable of shaping mucosal and systemic immunity [57]”

    From Interorgan Communications in Skeletal Pathophysiology: From Molecular Pathways to Multidisciplinary Therapies (2026) · cites this paper as [57]

    The Introduction (page not specified) says tryptophan is obtained through diet and distinguishes endogenous enzyme-catalyzed kynurenine from gut microbiota-generated indoles and tryptamine. It also describes effects on intestinal homeostasis and immune phenotypes. The claim is unsupported in attributing kynurenine production to microbial conversion. (LLM, conf=0.89)

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  • Indole derivatives engage AhR, enabling intestinal signals to alter macrophage and dendritic-cell behavior and recalibrate the Th17/Treg axis; these immune shifts converge on the RANKL/OPG pathway, influencing osteoclast and osteoblast dynamics.

    “Indole derivatives engage the aryl hydrocarbon receptor (AhR), enabling intestinal signals to alter macrophage and dendritic-cell behavior and to recalibrate the T helper 17 (Th17)/regulatory T cell (Treg) axis. These immune shifts converge on the RANKL/OPG pathway, thereby influencing osteoclast and osteoblast dynamics.”

    From Interorgan Communications in Skeletal Pathophysiology: From Molecular Pathways to Multidisciplinary Therapies (2026) · cites this paper as [57]

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Authors
Xiang, T., Yang, C., Xie, L., Xiao, S., Tang, Y., Huang, G., Sun, D., Chen, Y., & Luo, F.
Affiliations
Army Medical University (CN)
Corresponding author
  • Huang, Gang
  • Sun, Dong
  • Chen, Yueqi
  • Luo, Fei
ORCID
Venue
Research
Publisher
American Association for the Advancement of Science (AAAS)
Published
2025-01
Volume
8
Pages
0728-0728
ISSN
2639-5274 (ISSN-L)
DOI
10.34133/research.0728
PMC
PMC12150400
OpenAlex
W4410426106
Cited by
17
References
7
Citations by year
2026: 16 · 2025: 1
FWCI
1.50
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation Regional Innovation and Development Joint Fund (U23A20413)
  • National Natural Science Foundation of China (82103778, 82172448, 82272515, 82471836)
  • Key Clinical Cultivation Discipline Construction Project of PLA (145AHQ141009000X)
  • Key Clinical Specialty of PLA (51561Z23711)
  • Science and Technology Research Program of Chongqing Municipal Education Commission (KJZD-K202212801)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
Keywords
tryptophan metabolism, kynurenine pathway, serotonin pathway, indole pathway, aryl hydrocarbon receptor, osteoblasts, osteoclasts, chondrocytes, gut microbiota, indole derivatives, gut-bone axis, bone homeostasis

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