The effects of tissue-specific proteinase activated receptor-2 (PAR-2) ablation on remodelling events found in bone and cartilage, using a murine destabilisation of the medical meniscus (DMM) model

Abstract

Osteoarthritis (OA) is a common musculoskeletal disease, associated with significant cost to the National Health Service (NHS) and physical consequences to the sufferer. It is known that cartilage degradation and subchondral sclerosis are hallmark features of OA. However, it is not known in which tissue pathological changes occur first. By identifying this, future therapeutics could be guided more accurately to maximise their benefit. This study has highlighted significant problems in generating a reliable and reproducible human‐derived model of cartilage catabolism using human mesenchymal stem cells (hMSCs). Generating such a model is important, as it will allow assessment of potential therapies in a physiologically relevant human model, and further work is needed in this area. However, one significant finding from this work was that the addition of matriptase to a cytokine stimulus enhanced proteoglycan and collagen degradation from cartilage discs and macro‐pellets. Matriptase is a serine proteinase, and is involved in cartilage catabolism through activation of pro‐MMPs and signaling via PAR‐2. These findings therefore support the role of matriptase in OA pathogenesis, specifically cartilage catabolism. Proteinase‐activated receptor‐2 (PAR‐2) is known to be involved in OA pathogenesis, with global ablation of this receptor preventing abnormal remodelling events in the cartilage and subchondral bone. In this study, tissue‐specific ablation of PAR‐2 revealed that loss of PAR‐2 conferred its primary beneficial effect in the bone by preventing subchondral sclerosis. The debate about whether cartilage or bone changes occur first in OA remains controversial, but it was apparent from various time‐course studies that bone changes occurred first, followed by cartilage catabolism during OA progression. However, in this study it was also evident that cartilage damage could occur independently of subchondral sclerosis, which is in opposition to the long standing view that subchondral sclerosis is a prerequisite for cartilage damage to occur. Thus, this study highlights that targeting either the cartilage or bone may be beneficial for therapies, although for ease of use, targeting the bone may be more clinically useful. Furthermore the importance of PAR‐2 expressed on chondrocytes in the development and maturation of osteophytes was evident in this study.