Title: Elucidating the role of inflammatory mediators in Frozen Shoulder
Funder: Dunhill Medical Trust

Abstract: Frozen Shoulder is a common disabling joint disease affecting middle aged and elderly patients (Hand et al. 2007). Affected patients experience pain and restricted shoulder motion due to inflammation and fibrosis of the shoulder joint capsule. Frozen Shoulder is often self-limiting, although patients are profoundly symptomatic for up to 3 years prior to the condition resolving. The biological processes regulating inflammation, fibrosis and resolution in Frozen Shoulder remain understudied, hindering development of effective new therapies for symptomatic patients. Alarmins are danger-associated molecular pattern molecules released at inflammatory sites, activating pattern recognition receptors in multiple body tissues (Boteanu, et al., 2017; Kurien, et al., 2006). Alarmins including S100 proteins, IL-33, and High mobility group box 1 (HMGB1) were recently identified in tissues from Frozen Shoulder patients (Cher et al 2017). However, the mechanisms by which these alarmins regulate inflammation, fibrosis and resolution in Frozen Shoulder are unknown. HMGB1 exhibits diverse cellular functions regulating tissue health and disease. Importantly the redox status governs the biological actions of this molecule. The fully reduced form of HMGB1 (fr-HMGB1) is chemotactic, whereas the disulphide form (ds-HMGB1) is pro-inflammatory (Venereau, et al., 2012, Janko, et al., 2014). HMGB1 may therefore play a pivotal role in regulating inflammation and resolution processes in common joint diseases. This project will investigate the biological roles of alarmins in Frozen Shoulder, with particular focus on how these molecules mediate inflammation, fibrosis and resolution of disease. The project will build upon existing knowledge, identifying alarmins and their respective receptors in tissue samples collected from symptomatic Frozen Shoulder patients. Importantly this work will identify the distinct stromal cell types mediating Frozen Shoulder alarmin responses, to advance understanding of how alarmins facilitate cross-talk between stromal cell populations. Finally, the project will identify the redox status of HMGB1, to discern the biologically active forms governing inflammation and resolution in Frozen Shoulder patient tissue samples. Diseased capsular tissues will be compared with non-diseased matched tissues and where possible, biopsies from patients with resolved Frozen Shoulder will also be collected for analysis. The findings from this research will advance understanding of the biological mechanisms by which alarmins mediate inflammation, fibrosis and resolution in Frozen Shoulder. This will inform development of new treatments for FS patients during the symptomatic stage of the disease. Lastly, understanding of how FS resolves can inform our ability to promote successful resolution of inflammation in other chronic inflammatory musculoskeletal diseases.

Lay abstract: Inflammatory joint disease is a global health burden, causing pain, disability and negatively impacting upon healthy ageing. Frozen Shoulder is a common inflammatory joint disease, causing significant shoulder pain and stiffness in patients over 50 years of age. Frozen Shoulder affects activities of daily living and affected elderly patients can become increasingly dependent on others. Whilst Frozen Shoulder is usually self-limiting, patients can experience severe symptoms for up to 3 years prior to the condition resolving. Current therapies to treat Frozen Shoulder include physiotherapy, pain killers, injections and surgery, however these treatments are frequently ineffective and do not directly target the cells driving disease. The biological processes responsible for inflammation, pain and scarring which restrict joint movement are not fully understood in Frozen Shoulder. This hampers the development of successful treatments for affected patients. Studying Frozen Shoulder presents a unique opportunity to understand the biological processes that underpin the inflammatory and stiffening phases of disease and will help determine why the condition ultimately resolves. This 3-year project will provide funding for a Junior Doctor to study for a PhD at Oxford University. The project will collect tissue samples from patients undergoing surgery to treat Frozen Shoulder. Shoulder joint tissue collected from patients undergoing surgery for shoulder dislocation or fracture will be compared to those from Frozen Shoulder patients. These tissues will be analysed in a laboratory to improve understanding of how cells behave during inflammatory joint disease. Specifically, the project will investigate how molecules called alarmins act as ‘danger signals’ and cause inflammation and joint stiffness in patients with Frozen Shoulder. The project will identify the cell types involved in alarmin responses to understand how alarmins influence communication between cells. Finally, the project will identify if a particular alarmin called HMGB1 is an important molecule determining whether inflammation either persists or resolves. Determining the role of alarmins in Frozen Shoulder will improve understanding of how these molecules control inflammation and scar tissue formation in common joint diseases. The findings will help identify new treatments for symptomatic Frozen Shoulder patients. This research has broader implications and the potential to inform new strategies to treat other common inflammatory diseases affecting older patients.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL