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Shen, P.* ; Serve, S.* ; Wu, P.* ; Liu, X.* ; Dai, Y.* ; Durán-Hernández, N.* ; Nguyen, D.T.M.* ; Fuchs, M.* ; Maleitzke, T.* ; Reisener, M.J.* ; Dzamukova, M.* ; Nussbaumer, K.* ; Brunner, T.M.* ; Li, Y.* ; Holecska, V.* ; Heinz, G.* ; Heinrich, F.* ; Durek, P.* ; Katsoula, G. ; Gwinner, C.* ; Jung, T.* ; Zeggini, E. ; Winkler, T.* ; Mashreghi, M.F.* ; Pumberger, M.* ; Perka, C.* ; Löhning, M.*

NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis.

Proc. Natl. Acad. Sci. U.S.A. 120:e2207993120 (2023)

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Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 (NOS2) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2^-/- mice were protected from age-related OA development. Taken together, the TLR2-NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Toll-like Receptors ; Cartilage-anabolic And Catabolic Activities ; Chondrocytes ; Nitric Oxide Synthase ; Osteoarthritis; Toll-like Receptors; Nitric-oxide Synthase; Double-blind; Selective-inhibition; Knee; Progression; Gene; Mice; Differentiation; Chondrogenesis

ISSN (print) / ISBN 0027-8424

e-ISSN 1091-6490

Journal Proceedings of the National Academy of Sciences of the United States of America

Quellenangaben Volume: 120, Issue: 29, Article Number: e2207993120

Publisher National Academy of Sciences

Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Translational Genomics (ITG)

Grants WethankAdrian Madrigal
China Scholarship Council
state of Berlin
European Regional Development Fund (ERDF)
National Natural Science Foundation of China
German Federal Ministry of Education and Research (BMBF)
German Research Foundation (DFG)
Einstein Center for Regenerative Therapies
Dr. Rolf M. Schwiete Foundation
Willy Robert Pitzer Foundation (Pitzer Laboratory of Osteoarthritis Research)