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Abstract Number: 1012

Role of High Glucose Environment on Chondrocyte Activation and Characterization of Diabetic Osteoarthritic Cartilage: Toward Pathophysiological Delineation of Diabetes Mellitus-Related Osteoarthritis

Marie-Charlotte Laiguillon1, Alice Courties1,2, Xavier Houard1, Martine Auclair1, Alain Sautet3, Bruno Fève1, Jacqueline Capeau1, Francis Berenbaum2 and Jérémie Sellam2, 1Sorbonne Universités, UPMC Univ Paris 06, UMRS 938 and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France, 2AP-HP, Saint-Antoine Hospital, Rheumatology Department and DHU i2B, Paris, France, 3AP-HP, Saint-Antoine Hospital, Orthopaedic Surgery Department, Paris, France

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: chondrocytes, diabetes and inflammatory cytokines, OA

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Session Information

Title: Biology and Pathology of Bone and Joint: Cartilage, Synovium and Osteoarthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Recent epidemiological studies have suggested an association between type 2 diabetes/hyperglycemia and osteoarthritis (OA) but experimental evidences are lacking (1). We aimed i) to decipher in vitro the impact of a high glucose environment on chondrocyte activation ii) to compare the production of pro-inflammatory mediators by OA cartilage explants derived from diabetic (db) or non-db patients.

Methods: Primary cultures of chondrocytes from new-born mice were stimulated for 24h and 72h with/without IL-1β (5 ng/mL) under a normal (5.5 mM) or a high (25 mM) glucose environment. Glucose uptake by cells was analyzed by incorporation of radioactive 2-deoxyglucose. Osmotic stress was assessed by adding mannitol. Gene expression and release of pro-inflammatory mediators (IL-6, COX2/PGE2) were analyzed by RT-qPCR, ELISA and EIA, respectively. Oxidative stress was assessed by the measurement of reactive oxygen species (ROS) by fluorescent DCFDA and production of NO by Griess reaction. To address the role of high glucose and oxidative stress on chondrocyte activation, cells were pretreated with cytochalasin B (1 µM), a glucose transporter inhibitor, or treated with a specific inhibitor of the polyol pathway (Epalrestat, 10 µM), a specific mitochondrial antioxidant (Mitotempo, 50 µM) or a NO synthase inhibitor (L-NAME, 5 mM). Ex vivo, pro-inflammatory mediators (IL-6, PGE2) release in 24h-conditioned media of IL-1b- stimulated OA cartilage from db and non-db patients was measured by ELISA/EIA.

Results : In vitro, at 72h, the expression and release of IL-6 and COX2/PGE2 were dramatically increased in the presence of IL-1β in high glucose as compared to normal glucose concentration  by 5.6- and 3- [IL-6 mRNA and protein, respectively], 8- [Cox2] and 3.6-fold [PGE2]) (n=5, p=0.03 for all analyzes).  Glucose uptake was also transiently increased by IL-1β at 72h (n=3). Mannitol experiments ruled out the hypothesis of an osmotic stress due to high glucose (n=3). High glucose environment under IL-1β stress increased ROS and NO production (2.1- and 1.9-fold, respectively; n=5, p=0.04 and p=0.03). Cytochalasin B significantly decreased the induction of IL-6 mRNA (-40%; n=6, p=0.02). L-NAME significantly decreased the release of IL-6 and PGE2 (-40% and -78%, respectively; n=5, p=0.04) as did Epalrestat (-49% for mRNA IL-6 and -55% for COX2; n=3), and as did Mitotempo (IL-6: -69% and COX2: -90%; n=2).

Conclusion : High glucose exposure sensitizes chondrocytes to IL-1b activation via increased glucose uptake, oxidative stress and polyol metabolic pathway leading to a sustained chondrocytic pro-inflammatory phenotype. Such results are in accordance with an increased sensitivity to inflammatory stress of OA cartilage of db patients. These results strengthen the hypothesis that diabetes could be a trigger for the initiation and/or the severity of OA.

References: Schett G et al. Diabetes Care. 2013


Disclosure:

M. C. Laiguillon,
None;

A. Courties,
None;

X. Houard,
None;

M. Auclair,
None;

A. Sautet,
None;

B. Fève,
None;

J. Capeau,
None;

F. Berenbaum,
None;

J. Sellam,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-high-glucose-environment-on-chondrocyte-activation-and-characterization-of-diabetic-osteoarthritic-cartilage-toward-pathophysiological-delineation-of-diabetes-mellitus-related-osteoarthritis/

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