Article ; Online: Kynurenine inhibits autophagy and promotes senescence in aged bone marrow mesenchymal stem cells through the aryl hydrocarbon receptor pathway.
2019 Volume 130, Page(s) 110805
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 ... ...
| 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 | |||||
| Shelf mark |
|
|||||
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 579: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.