Kynurenine Promotes RANKL-Induced Osteoclastogenesis In Vitro by Activating the Aryl Hydrocarbon Receptor Pathway
Open accessAbstract
There is increasing evidence of the involvement of the tryptophan metabolite kynurenine (KYN) in disrupting osteogenesis and contributing to aging-related bone loss. Here, we show that KYN has an effect on bone resorption by increasing osteoclastogenesis. We have previously reported that in vivo treatment with KYN significantly increased osteoclast number lining bone surfaces. Here, we report the direct effect of KYN on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis in Raw 264.7 macrophage cells, and we propose a potential mechanism for these KYN-mediated effects. We show that KYN/RANKL treatment results in enhancement of RANKL-induced osteoclast differentiation. KYN drives upregulation and activation of the key osteoclast transcription factors, c-fos and NFATc1 resulting in an increase in the number of multinucleated TRAP+ osteoclasts, and in hydroxyapatite bone resorptive activity. Mechanistically, the KYN receptor, aryl hydrocarbon receptor (AhR), plays an important role in the induction of osteoclastogenesis. We show that blocking AhR signaling using an AhR antagonist, or AhR siRNA, downregulates the KYN/RANKL-mediated increase in c-fos and NFATc1 and inhibits the formation of multinucleated TRAP + osteoclasts. Altogether, this work highlights that the novelty of the KYN and AhR pathways might have a potential role in helping to regulate osteoclast function with age and supports pursuing additional research to determine if they are potential therapeutic targets for the prevention or treatment of osteoporosis.
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AhR activation in bone marrow macrophages leads to significant upregulation of c-Fos and NFATc1 expression, thereby initiating osteoclastic differentiation.
“Consistently, the AhR activation in BMMs was also found to lead to significant upregulation of c-Fos and NFATc1 expression, thereby initiating osteoclastic differentiation [113].”
From An Overlooked Bone Metabolic Disorder: Cigarette Smoking-Induced Osteoporosis (2022) · cites this paper as [113]
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- Authors
- Eisa, N. H., Reddy, S. V., Elmansi, A. M., Kondrikova, G., Kondrikov, D., Shi, X.-M., Novince, C. M., Hamrick, M. W., McGee-Lawrence, M. E., Isales, C. M., Fulzele, S., & Hill, W. D.
- Affiliations
- Medical University of South Carolina (US)
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Augusta University (US)
- Department of Orthopaedic Surgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Corresponding author
- Hill, William D.
- ORCID
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2020-10-26
- Volume
- 21
- Issue
- 21
- Pages
- 7931
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC7662708
- OpenAlex
- W3096743526
- Cited by
- 55
- References
- 56
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 8 · 2023: 8 · 2022: 14 · 2021: 9
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (R01 AG067510-01A1, P01 AG036675)
- U.S. Department of Veterans Affairs (Merit Award 1I01CX000930-01)
- 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 › Rheumatoid Arthritis Research and Therapies
- Keywords
- kynurenine, aryl hydrocarbon receptor, osteoclastogenesis, RANKL, bone resorption, tryptophan metabolism, c-fos, NFATc1, osteoporosis, RAW 264.7 macrophages
- MeSH terms
- RAW 264.7 Cells, Animals, Cell Differentiation, Gene Expression Regulation, Kynurenine, Osteogenesis, Signal Transduction, Proto-Oncogene Proteins c-fos, Receptors, Glutamate, Receptors, Aryl Hydrocarbon, Cell Proliferation, NFATC Transcription Factors, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, RANK Ligand
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