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Damage-associated molecular patterns in the pathogenesis of osteoarthritis: potentially novel therapeutic targets

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Abstract

Osteoarthritis (OA) is a chronic disease that degrades the joints and is often associated with increasing age and obesity. The two most common sites of OA in adults are the knee and hip joints. Increased mechanical stress on the joint from obesity can cause the articular cartilage to degrade and release damage-associated molecular patterns (DAMPs). These DAMPs are involved in various molecular pathways that interact with nuclear factor-kappa B and result in the transcription of inflammatory cytokines and activation of matrix metalloproteinases that progressively destroy cartilage. This review focuses on the interactions and contribution to the pathogenesis and progression of OA through the DAMPs: high-mobility group box 1 (HMGB-1), the receptor for advanced glycation end-products (RAGE), the alarmin proteins S100A8 and S100A9, and heparan sulfate. HMGB-1 is released from damaged or necrotic cells and interacts with toll-like receptors (TLRs) and RAGE to induce inflammatory signals, as well as behave as an inflammatory cytokine to activate innate immune cells. RAGE interacts with HMGB-1, advanced glycation end-products, and innate immune cells to increase local inflammation. The alarmin proteins are released following cell damage and interact through TLRs to increase local inflammation and cartilage degradation. Heparan sulfate has been shown to facilitate the binding of HMGB-1 to RAGE and could play a role in the progression of OA. Targeting these DAMPs may be the potential therapeutic strategies for the treatment of OA.

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Funding

This work was supported by research Grants R01 HL112597, R01 HL116042, and R01 HL120659 to DK Agrawal from the National Heart, Lung and Blood Institute, National Institutes of Health, USA. The content of this review article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Clinical and Translational Science, Creighton University School of Medicine, CRISS II Room 510, 2500 California Plaza, Omaha, NE, 68178, USA

    John H. Rosenberg, Vikrant Rai, Matthew F. Dilisio & Devendra K. Agrawal

  2. Department of Orthopedic Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA

    Matthew F. Dilisio

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  1. John H. Rosenberg
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Correspondence to Devendra K. Agrawal.

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As the corresponding author, I declare that this manuscript is original; that the article does not infringe upon any copyright or other proprietary right of any third party; that neither the text nor the data have been reported or published previously. All the authors have no conflict of interest and have read the journal’s authorship statement.

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Rosenberg, J.H., Rai, V., Dilisio, M.F. et al. Damage-associated molecular patterns in the pathogenesis of osteoarthritis: potentially novel therapeutic targets. Mol Cell Biochem 434, 171–179 (2017). https://doi.org/10.1007/s11010-017-3047-4

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