Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation.

Autor:	Liu H; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA.; Ohio Musculoskeletal and Neurological Institute (OMNI), Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA., Binoy A; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA.; Ohio Musculoskeletal and Neurological Institute (OMNI), Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA., Ren S; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA.; Ohio Musculoskeletal and Neurological Institute (OMNI), Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA., Martino TC; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA.; Ohio Musculoskeletal and Neurological Institute (OMNI), Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA., Miller AE; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA.; Ohio Musculoskeletal and Neurological Institute (OMNI), Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA., Willis CRG; School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford, BD7 1DP, UK., Veerabhadraiah SR; Department of Orthopaedics, University of Utah, Salt Lake City, Utah, 84108 USA., Sukul A; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA.; Ohio Musculoskeletal and Neurological Institute (OMNI), Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA., Bons J; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA., Rose JP; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA., Schilling B; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA., Jurynec MJ; Department of Orthopaedics, University of Utah, Salt Lake City, Utah, 84108 USA., Zhu S; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA.; Ohio Musculoskeletal and Neurological Institute (OMNI), Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA.; Diabetes Institute (DI), Heritage College of Osteopathic Medicine (HCOM), Ohio University, Athens, OH, 45701, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 06. Date of Electronic Publication: 2024 Aug 06.
DOI:	10.1101/2024.07.23.604872
Abstrakt:	Objectives: Chondrocyte metabolic dysfunction plays an important role in osteoarthritis (OA) development during aging and obesity. Protein post-translational modifications (PTMs) have recently emerged as an important regulator of cellular metabolism. We aim to study one type of PTM, lysine malonylation (MaK) and its regulator Sirt5 in OA development. Methods: Human and mouse cartilage tissues were used to measure SIRT5 and MaK levels. Both systemic and cartilage-specific conditional knockout mouse models were subject to high-fat diet (HFD) treatment to induce obesity and OA. Proteomics analysis was performed in Sirt5 -/- and WT chondrocytes. SIRT5 mutation was identified in the Utah Population Database (UPDB). Results: We found that SIRT5 decreases while MAK increases in the cartilage during aging. A combination of Sirt5 deficiency and obesity exacerbates joint degeneration in a sex dependent manner in mice. We further delineate the malonylome in chondrocytes, pinpointing MaK's predominant impact on various metabolic pathways such as carbon metabolism and glycolysis. Lastly, we identified a rare coding mutation in SIRT5 that dominantly segregates in a family with OA. The mutation results in substitution of an evolutionally invariant phenylalanine (Phe-F) to leucine (Leu-L) (F101L) in the catalytic domain. The mutant protein results in higher MaK level and decreased expression of cartilage ECM genes and upregulation of inflammation associated genes. Conclusions: We found that Sirt5 mediated MaK is an important regulator of chondrocyte cellular metabolism and dysregulation of Sirt5-MaK could be an important mechanism underlying aging and obesity associated OA development.
Databáze:	MEDLINE
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