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  • Review Article
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TLR4 signalling in osteoarthritis—finding targets for candidate DMOADs

Nature Reviews Rheumatology volume 11, pages 159–170 (2015)Cite this article

Subjects

Key Points

  • Inflammation and inflammation-induced catabolism (for example, involving activation of matrix metalloproteinases) are tightly controlled by Toll-like-receptor-mediated innate immune responses

  • Toll-like-receptor 4 (TLR4) binds a number of different agonists, some of which (so-called damage-associated molecular patterns) are released when tissues are damaged

  • The expression of TLR4 in cartilage is increased throughout the development of osteoarthritis (OA)

  • Many TLR4 agonists that have been identified in the joints of patients with OA can induce inflammatory responses in ex vivo tissue samples fromthese patients

  • Several pathways modulate TLR4 signalling in joint tissues, and a number of TLR4 blockers might be candidate disease-modifying OA drugs (DMOADs)

Abstract

Osteoarthritis (OA), the most common rheumatic disease, is characterized by joint-space narrowing due to progressive cartilage degradation and alterations in subchondral bone and the synovial membrane. These articular disturbances can have severe consequences, including pain, disability and loss of joint architectural integrity. Although the aetiology of OA is not understood, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by damage-associated molecules are thought to be involved. In this Review, we examine the relationship between Toll-like receptor 4 (TLR4) and OA in cartilage as well as in other OA-affected tissues, such as subchondral bone and synovium. We also discuss the different TLR4 agonists associated with OA and their effects in joint tissues. Finally, we describe existing and novel strategies that might be used to develop TLR4-specific disease-modifying OA drugs (DMOADs).

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Figure 1: TLR4 structure.
Figure 2: TLR4 signalling.
Figure 3: TLR4 signalling in chondrocytes.
Figure 4: Trafficking of TLR4 agonists and signalling in the joint.
Figure 5: Different strategies to target TLR4 in joint tissues.

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Acknowledgements

The authors' research is supported by research grants from Fondo de Investigación Sanitaria (PI12/00144 and PI13/00570). R.G. was funded by the Instituto de Salud Carlos III through a Sara Borrell programme. A.V. is the recipient of a fellowship from the Fundación Conchita Rábago. R.L. and O.G. were funded by the Instituto de Salud Carlos III through a research staff stabilization programme.

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Authors and Affiliations

  1. Musculoskeletal Research Group, Institute of Cellular Medicine, 4th Floor, Catherine Cookson Building, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

    Rodolfo Gómez

  2. Bone and Joint Research Unit, Instituto de Investigación, Fundación Jiménez Díaz, Universidad Autónoma de Madrid (UAM), Avenida Reyes Católicos, Madrid, Spain

    Amanda Villalvilla, Raquel Largo & Gabriel Herrero-Beaumont

  3. Servicio Galego de Saude (SERGAS), Santiago University Clinical Hospital, Neuroendocrine Interaction in Rheumatology and Inflammatory Diseases (NEIRID) Research Laboratory 9, Institute of Medical Research (IDIS), Building C, Level 2, Trav. Choupana s/n, 15706, Santiago de Compostela, Spain

    Oreste Gualillo

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R.G. researched data for the article and wrote the manuscript. R.G., A.V., R.L., O.G. and G.H.-B. substantially contributed to discussion of content and reviewing and editing the manuscript before submission.

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Correspondence to Rodolfo Gómez.

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Gómez, R., Villalvilla, A., Largo, R. et al. TLR4 signalling in osteoarthritis—finding targets for candidate DMOADs. Nat Rev Rheumatol 11, 159–170 (2015). https://doi.org/10.1038/nrrheum.2014.209

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