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Review
. 2022 May;38(2):193-219.
doi: 10.1016/j.cger.2021.11.015.

Osteoarthritis Pathophysiology: Therapeutic Target Discovery may Require a Multifaceted Approach

Tonia L Vincent  1 , Tamara Alliston  2 , Mohit Kapoor  3 , Richard F Loeser  4 , Linda Troeberg  5 , Christopher B Little  6
Affiliations
Review

Osteoarthritis Pathophysiology: Therapeutic Target Discovery may Require a Multifaceted Approach

Tonia L Vincent et al. Clin Geriatr Med. 2022 May.

Abstract

Molecular understanding of osteoarthritis (OA) has greatly increased through careful analysis of tissue samples, preclinical models, and large-scale agnostic "-omic" studies. There is broad acceptance that systemic and biomechanical signals affect multiple tissues of the joint, each of which could potentially be targeted to improve patient outcomes. In this review six experts in different aspects of OA pathogenesis provide their independent view on what they believe to be good tractable approaches to OA target discovery. We conclude that molecular discovery has been high but future transformative studies require a multidisciplinary holistic approach to develop therapeutic strategies with high clinical efficacy.

Keywords: Aging; Bone; Cartilage; Fibrosis; Inflammation; Osteoarthritis; Pathophysiology; Treatment targets.

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Conflict of interest statement

Competing interests: The authors have no potential or apparent conflicts of interest with regard to this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Figures

Figure 1:
Figure 1:. MMPs and ADAMTSs metalloproteases cleave type II collagen and aggrecan in the OA cartilage extracellular matrix.
Chondrocytes secrete metalloproteases that degrade the cartilage extracellular matrix in OA. Studies on transgenic mice suggest that MMP13 is the key collagenase in cartilage, while ADAMTS5 is the main ‘aggrecanase’.
Figure 2:
Figure 2:
Schematic image depicting the key inflammatory cells and soluble mediators and pathways implicated in osteoarthritis pathogenesis.
Figure 3:
Figure 3:
Fibroblast like synoviocytes (FLS) and macrophages are key cell types present in the synovium. FLS exhibit increased proliferation and migration, and also acquire a myofibroblast like phenotype, resulting in the excessive ECM deposition in the synovium during osteoarthritis.
Figure 4.
Figure 4.. Balance of pro-regenerative and mechano-inflammatory responses in articular cartilage with abnormal mechanical load.
Compressive load leads to sodium dependent release of pericellular matrix growth factors, which drive repair and chondroprotection through a variety of intracellular signalling pathways. Surface shear stress (perpendicular to compressive load) leads to activation of TGFβ-activated kinase 1 (TAK1) dependent inflammatory signalling and results in nerve growth factor regulation (driving pain) and matrix degradation.
Figure 5:
Figure 5:
Factors that promote stress-induced senescence
See this image and copyright information in PMC

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