Three-dimensional, in-vitro approaches for modelling soft-tissue joint diseases.

Diseases affecting the soft tissues of the joint represent a considerable global health burden, causing pain and disability and increasing the likelihood of developing metabolic comorbidities. Current approaches to investigating the cellular basis of joint diseases, including osteoarthritis, rheumatoid arthritis, tendinopathy, and arthrofibrosis, involve well phenotyped human tissues, animal disease models, and in-vitro tissue culture models. Inherent challenges in preclinical drug discovery have driven the development of state-of-the-art, in-vitro human tissue models to rapidly advance therapeutic target discovery. The clinical potential of such models has been substantiated through successful recapitulation of the pathobiology of cancers, generating accurate predictions of patient responses to therapeutics and providing a basis for equivalent musculoskeletal models. In this Review, we discuss the requirement to develop physiologically relevant three-dimensional (3D) culture systems that could advance understanding of the cellular and molecular basis of diseases that affect the soft tissues of the joint. We discuss the practicalities and challenges associated with modelling the complex extracellular matrix of joint tissues-including cartilage, synovium, tendon, and ligament-highlighting the importance of considering the joint as a whole organ to encompass crosstalk across tissues and between diverse cell types. The design of bespoke in-vitro models for soft-tissue joint diseases has the potential to inform functional studies of the cellular and molecular mechanisms underlying disease onset, progression, and resolution. Use of these models could inform precision therapeutic targeting and advance the field towards personalised medicine for patients with common musculoskeletal diseases.