Batshon G, Elayyan J, Qiq O, et al. Serum NT/CT SIRT1 ratio reflects early osteoarthritis and chondrosenescence. Annals of the Rheumatic Diseases 2020; 79: 1370-1380. https://doi.org/10.1136/annrheumdis-2020-217072
Serum NT/CT SIRT1 ratio reflects early osteoarthritis and chondrosenescence
|Author:||Batshon, George1; Elayyan, Jinan1; Qiq, Omar1;|
1Institute of Dental Sciences, Hebrew University of Jerusalem, Jerusalem, Israel
2Joint Replacement and Reconstructive Surgery Unit, Orthopaedic Surgery Complex, Hadassah Mount Scopus Hospital, Jerusalem, Israel
3Laboratory for Experimental Orthopaedics, Dept. of Orthopaedics, Justus Liebig University Giessen, Gießen, Germany
4Developmental Biology Research Affinity Group, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
5Translational Tissue Engineering Center, Wilmer Eye Institute and the Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA
6Bone and Cartilage Research Unit, Arthropole Liège, Institute of Pathology, University of Liège, Liege, Belgium
7Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 9.5 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2020103088829
|Publish Date:|| 2020-10-30
Objective: Previous work has established that the deacetylase sirtuin-1 (SIRT1) is cleaved by cathepsin B in chondrocytes subjected to proinflammatory stress, yielding a stable but inactive N-terminal (NT) polypeptide (75SIRT1) and a C-terminal (CT) fragment. The present work examined if chondrocyte-derived NT-SIRT1 is detected in serum and may serve as an investigative and exploratory biomarker of osteoarthritis (OA).
Methods: We developed a novel ELISA assay to measure the ratio of NT to CT of SIRT1 in the serum of human individuals and mice subjected to post-traumatic OA (PTOA) or age-dependent OA (ADOA). We additionally monitored NT/CT SIRT1 in mice subject to ADOA/PTOA followed by senolytic clearance. Human chondrosenescent and non-senescent chondrocytes were exposed to cytokines and analysed for apoptosis and NT/CT SIRT1 ratio in conditioned medium.
Results: Wild-type mice with PTOA or ADOA of moderate severity exhibited increased serum NT/CT SIRT1 ratio. In contrast, this ratio remained low in cartilage-specific Sirt1 knockout mice despite similar or increased PTOA and ADOA severity. Local clearance of senescent chondrocytes from old mice with post-traumatic injury resulted in a lower NT/CT ratio and reduced OA severity. While primary chondrocytes exhibited NT/CT ratio increased in conditioned media after prolonged cytokine stimulation, this increase was not evident in cytokine-stimulated chondrosenescent cells. Finally, serum NT/CT ratio was elevated in humans with early-stage OA.
Conclusions: Increased levels of serum NT/CT SIRT1 ratio correlated with moderate OA in both mice and humans, stemming at least in part from non-senescent chondrocyte apoptosis, possibly a result of prolonged inflammatory insult.
Annals of the rheumatic diseases
|Pages:||1370 - 1380|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This work was funded by European Commission Framework 7 programme (EU FP7; HEALTH.2012.2.4.5-2, project number 305815, Novel Diagnostics and Biomarkers for Early Identification of Chronic Inflammatory Joint Diseases); Israel Science Foundation (grant no. 121/12, 370/17), US- Israeli Binational foundation Grant 2013145 (to Vl and MDG) and Rosetrees Trust (grant no. a770).
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.