Defining the extracellular matrix in non-cartilage soft tissues in osteoarthritis – a systematic review

Objective Osteoarthritis (OA) is increasingly seen as a disease of global joint dysfunction, affecting not only cartilage but also the other joint tissues. Extracellular matrix (ECM) is a critical determinant of tissue mechanobiology, but ECM is poorly understood in osteoarthritic joint tissues beyond cartilage in human OA and animal models of OA. Therefore, we aimed to define the structural composition and architecture of non-cartilage soft joint tissue ECM in human OA, and to compare the ECM changes observed in humans to those seen in animal models of OA. Design A systematic search strategy, devised using relevant matrix, tissue, and disease nomenclature, was run through the MEDLINE, EMBASE, and Scopus databases. Demographic, clinical, and biological data were extracted from eligible studies. Bias analysis was performed. Results 142 studies were included, which covered capsule, ligaments, meniscus, skeletal muscle, synovium, and tendon in both humans and animals, and fat pad and intervertebral disc in humans only. Overall, included studies show that the expression of structural ECM components changes in disease within an ECM that becomes disorganised with increasing joint degeneration. Conclusions This systematic review consolidates existing knowledge of a poorly defined aspect of OA pathophysiology. Changes in ECM composition and architecture occur across soft joint tissues in OA, but most of these remain poorly defined due to the low number of studies and lack of healthy comparator groups. Further research to better understand the context within which cartilage is damaged in OA may enable a better understanding of OA and its potential treatments. Key messages What is already known on this topic Extracellular matrix (ECM) is a critical determinant of tissue mechanobiology and cell behaviour, but it is poorly described in osteoarthritic joint tissues beyond cartilage. What this study adds Our study highlights the global nature of ECM dysregulation across the osteoarthritic joint. In addition, this study describes practical and methodological challenges that should be addressed to improve the contribution of future studies to define the role of ECM in non-cartilage soft tissues in osteoarthritis. How this study might affect research, practice or policy A better understanding of ECM changes and their underlying mechanisms throughout the osteoarthritic joint may assist with disease classification and patient stratification and also holds promise for the development of ECM-targeting treatments which could modify the pathogenic cell behaviour that may drive osteoarthritis progression.