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Advanced glycation end products promote meniscal calcification by activating the mTOR-ATF4 positive feedback loop.
- Source :
-
Experimental & molecular medicine [Exp Mol Med] 2024 Mar; Vol. 56 (3), pp. 630-645. Date of Electronic Publication: 2024 Mar 01. - Publication Year :
- 2024
-
Abstract
- The meniscus is vital for maintaining knee homeostasis and function. Meniscal calcification is one of the earliest radiological indicators of knee osteoarthritis (KOA), and meniscal calcification is associated with alterations in biomechanical properties. Meniscal calcification originates from a biochemical process similar to vascular calcification. Advanced glycation end products (AGEs) and their receptors (RAGEs) reportedly play critical roles in vascular calcification. Herein, we investigated whether targeting AGE-RAGE is a potential treatment for meniscal calcification. In our study, we demonstrated that AGE-RAGE promotes the osteogenesis of meniscal cells and exacerbates meniscal calcification. Mechanistically, AGE-RAGE activates mTOR and simultaneously promotes ATF4 accumulation, thereby facilitating the ATF4-mTOR positive feedback loop that enhances the osteogenic capacity of meniscal cells. In this regard, mTOR inhibits ATF4 degradation by reducing its ubiquitination, while ATF4 activates mTOR by increasing arginine uptake. Our findings substantiate the unique role of AGE-RAGE in the meniscus and reveal the role of the ATF4-mTOR positive feedback loop during the osteogenesis of meniscal cells; these results provide potential therapeutic targets for KOA.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Activating Transcription Factor 4 genetics
Activating Transcription Factor 4 metabolism
Feedback
Glycation End Products, Advanced metabolism
Receptor for Advanced Glycation End Products metabolism
TOR Serine-Threonine Kinases
Meniscus metabolism
Osteoarthritis, Knee
Vascular Calcification metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2092-6413
- Volume :
- 56
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Experimental & molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 38424194
- Full Text :
- https://doi.org/10.1038/s12276-024-01190-6