Translational research addressing the burden of joint disease
Joint soft tissues, including the synovium, capsule, tendon and entheses, are predominantly composed of mesenchymal stromal cells including fibroblasts, tissue-resident macrophages and blood and lymphatic vascular endothelial cells. The Dakin Group focuses on understanding the disease mechanisms underpinning chronic inflammation in soft tissue disease of the joint. We have developed access to well-phenotyped patient cohorts and refined biopsy procedures, providing a platform to investigate the cellular basis of human soft tissue joint disease. Accessing patient tissues was a pivotal factor in the acceptance of a paradigm shift towards inflammation in the onset and progression of tendinopathy, catalysing a step-change in disease understanding. This research highlighted that tissue inflammation signatures change with disease stage, identifying macrophage plasticity, fibroblast activation and memory as important pathological processes sustaining inflammation. These studies reveal that tissue-resident stromal cells including macrophages and fibroblasts are pivotal populations driving persistent inflammation in soft tissue joint disease. Stromal cells therefore represent untapped therapeutic targets in the treatment of common joint diseases.
Potentiating resolution of inflammatory joint disease
New therapeutic approaches are required that target stromal cells and promote resolution of soft tissue inflammation. Resolution pharmacology provides a new therapeutic approach to harness the capacity of proresolving lipid mediators and their receptors to drive chronic inflammation down a proresolving pathway.
We identified inflammation-resolving mediators including 15-epi-LipoxinA4(15-epi-LXA4), Maresin-1 (MaR1), Lipoxin B4(LXB4) and Resolvin E1 (RvE1) as potential therapeutics regulating inflammatory processes in stromal cells isolated from patients with tendon disease. Current therapies to treat joint disease do not address stromal-mediated inflammatory responses. Given the limited regenerative capacity of joint tissues and their low turnover rates, there are significant challenges associated with curbing tissue damage, fibrosis and pain, which might be accomplished through preventing or moderating chronic inflammation. New therapies based on proresolving mediators have the potential to target stromal cells driving inflammatory soft tissue joint diseases and hence to promote their resolution.
Aims and objectives
- Discover the cellular basis for chronic inflammatory diseases of joint soft tissues
- Identify new therapies to promote resolution of inflammatory soft tissue joint disease
- Identify the cellular basis of diseases affecting tendons (tendinopathy, tendon tears) and the shoulder joint capsule (frozen shoulder)
- Identify new therapeutic strategies to promote resolution of inflammation in tendinopathy and frozen shoulder