Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis

Abstract

Mechanical stimuli have fundamental roles in articular cartilage during health and disease. Chondrocytes respond to the physical properties of the cartilage extracellular matrix (ECM) and the mechanical forces exerted on them during joint loading. In osteoarthritis (OA), catabolic processes degrade the functional ECM and the composition and viscoelastic properties of the ECM produced by chondrocytes are altered. The abnormal loading environment created by these alterations propagates cell dysfunction and inflammation. Chondrocytes sense their physical environment via an array of mechanosensitive receptors and channels that activate a complex network of downstream signalling pathways to regulate several cell processes central to OA pathology. Advances in understanding the complex roles of specific mechanosignalling mechanisms in healthy and OA cartilage have highlighted molecular processes that can be therapeutically targeted to interrupt pathological feedback loops. The potential for combining these mechanosignalling targets with the rapidly expanding field of smart mechanoresponsive biomaterials and delivery systems is an emerging paradigm in OA treatment. The continued advances in this field have the potential to enable restoration of healthy mechanical microenvironments and signalling through the development of precision therapeutics, mechanoregulated biomaterials and drug systems in the near future. The pathways involved in sensing and responding to mechanical stimuli have important roles in maintaining cartilage health, and can contribute to disease when dysregulated. This Review discusses cartilage mechanosignalling pathways and how they can be targeted to treat osteoarthritis. Mechanical forces are a critical environmental factor for maintaining joint homeostasis, determining cell phenotype, inflammatory responses and the tightly regulated anabolic–catabolic signalling axis essential for cartilage homeostasis. Chondrocytes sense their mechanical environment through numerous direct and indirect mechanisms that regulate cell function in health and degenerative diseases, such as osteoarthritis. Targeted inhibition of mechanoinflammatory signalling pathways or restoration of functional chondroprotective extracellular matrix environments in osteoarthritis could prevent extracellular matrix degradation and promote reparative anabolic processes. Development of self-regulating and mechanically responsive biomaterials and drug delivery systems offer advanced ‘on-demand’ therapeutic approaches for the treatment of osteoarthritis.