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  • Review Article
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Emerging regulators of the inflammatory process in osteoarthritis

Key Points

  • Multiple danger-associated molecular patterns, including activators of complement, are increased within joints affected by osteoarthritis (OA), and complement activation is a major factor in progression of experimental knee OA

  • Biomechanical cartilage injury and joint inflammation compromise chondrocyte viability and reprogram viable chondrocytes to procatabolic differentiation using transcriptional 'go signals', including NFκB and possibly HIF-2α and MTF1

  • Oxidative stress and dysregulated chondrocyte mitochondrial function contribute not only to impaired matrix synthetic function and viability, but also to molecular inflammatory processes and matrix catabolism in OA

  • Biomechanical injury, oxidative stress and inflammatory mediators modulate proteostasis responses, including autophagy and the unfolded protein response to endoplasmic reticulum stress

  • Chondrocyte bioenergy sensors including AMPK and SIRT1 can modulate deleterious chondrocyte responses to oxidative stress and inflammatory mediators, potentially providing therapeutic 'entry points' for limiting OA progression

Abstract

Chronic, low-grade inflammation in osteoarthritis (OA) contributes to symptoms and disease progression. Effective disease-modifying OA therapies are lacking, but better understanding inflammatory pathophysiology in OA could lead to transformative therapy. Networks of diverse innate inflammatory danger signals, including complement and alarmins, are activated in OA. Through inflammatory mediators, biomechanical injury and oxidative stress compromise the viability of chondrocytes, reprogramming them to hypertrophic differentiation and proinflammatory and pro-catabolic responses. Integral to this reprogramming are 'switching' pathways in transcriptional networks, other than the well-characterized effects of NFκB and mitogen-activated protein kinase signalling; HIF-2α transcriptional signalling and ZIP8-mediated Zn2+ uptake, with downstream MTF1 transcriptional signalling, have been implicated but further validation is required. Permissive factors, including impaired bioenergetics via altered mitochondrial function and decreased activity of bioenergy sensors, interact with molecular inflammatory responses and proteostasis mechanisms such as the unfolded protein response and autophagy. Bioenergy-sensing by AMPK and SIRT1 provides 'stop signals' for oxidative stress, inflammatory, and matrix catabolic processes in chondrocytes. The complexity of molecular inflammatory processes in OA and the involvement of multiple inflammatory mediators in tissue repair responses, raises daunting questions about how to therapeutically target inflammatory processes and macroscopic inflammation in OA. Bioenergy sensing might provide a pragmatic 'entry point'.

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Figure 1: Relationships between inflammatory mediator networks in OA.
Figure 2: Functions of AMPK and SIRT1 in chondrocyte resistance to cell stress and inflammatory processes that promote matrix catabolism.
Figure 3: Modulation of inflammatory processes by the UPR in chondrocytes in OA.
Figure 4: Therapeutic modulation of AMPK and SIRT1 as an entry point for 'stop signals' for chondrocyte procatabolic reprogramming by inflammation, oxidative stress, and altered UPR and autophagy.

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Acknowledgements

The authors' work is supported by funding from the VA Research Service, Arthritis Foundation, and NIH (PAG07996, AI81881).

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Both authors contributed equally to researching the data for the article, providing a substantial contribution to discussions of the content, writing the article and review and/or editing of the manuscript before submission.

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Correspondence to Robert Terkeltaub.

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R.T. declares he serves as a scientific advisory board member for Cardax. R.L. B. declares no competing interests

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Liu-Bryan, R., Terkeltaub, R. Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol 11, 35–44 (2015). https://doi.org/10.1038/nrrheum.2014.162

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