Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis.

Frozen shoulder is a common fibroproliferative disease characterized by the insidious onset of pain and restricted range of shoulder movement with a significant socioeconomic impact. The pathophysiological mechanisms responsible for chronic inflammation and matrix remodeling in this prevalent fibrotic disorder remain unclear; however, increasing evidence implicates dysregulated immunobiology. IL-17A is a key cytokine associated with inflammation and tissue remodeling in numerous musculoskeletal diseases, and thus, we sought to determine the role of IL-17A in the immunopathogenesis of frozen shoulder. We demonstrate an immune cell landscape that switches from a predominantly macrophage population in nondiseased tissue to a T cell-rich environment in disease. Furthermore, we observed a subpopulation of IL-17A-producing T cells capable of inducing profibrotic and inflammatory responses in diseased fibroblasts through enhanced expression of the signaling receptor IL-17RA, rendering diseased cells more sensitive to IL-17A. We further established that the effects of IL-17A on diseased fibroblasts was TRAF-6/NF-κB dependent and could be inhibited by treatment with an IKKß inhibitor or anti-IL-17A antibody. Accordingly, targeting of the IL-17A pathway may provide future therapeutic approaches to the management of this common, debilitating disease.

Fibroblast activation and inflammation in frozen shoulder.

INTRODUCTION: Frozen shoulder is a common, fibro-proliferative disease characterised by the insidious onset of pain and progressively restricted range of shoulder movement. Despite the prevalence of this disease, there is limited understanding of the molecular mechanisms underpinning the pathogenesis of this debilitating disease. Previous studies have identified increased myofibroblast differentiation and proliferation, immune cell influx and dysregulated cytokine production. We hypothesised that subpopulations within the fibroblast compartment may take on an activated phenotype, thus initiating the inflammatory processes observed in frozen shoulder. Therefore, we sought to evaluate the presence and possible pathogenic role of known stromal activation proteins in Frozen shoulder. METHODS: Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients undergoing shoulder stabilisation surgery. Fibroblast activation marker expression (CD248, CD146, VCAM and PDPN, FAP) was quantified using immunohistochemistry. Control and diseased fibroblasts were cultured for in vitro studies from capsule biopsies from instability and frozen shoulder surgeries, respectively. The inflammatory profile and effects of IL-1ß upon diseased and control fibroblasts was assessed using ELISA, immunohistochemistry and qPCR. RESULTS: Immunohistochemistry demonstrated increased expression of fibroblast activation markers CD248, CD146, VCAM and PDPN in the frozen shoulder group compared with control (p < 0.05). Fibroblasts cultured from diseased capsule produced elevated levels of inflammatory protein (IL-6, IL-8 & CCL-20) in comparison to control fibroblasts. Exposing control fibroblasts to an inflammatory stimuli, (IL-1ß) significantly increased stromal activation marker transcript and protein expression (CD248, PDPN and VCAM). CONCLUSIONS: These results show that fibroblasts have an activated phenotype in frozen shoulder and this is associated with inflammatory cytokine dysregulation. Furthermore, it supports the hypothesis that activated fibroblasts may be involved in regulating the inflammatory and fibrotic processes involved in this disease.

The epidemiology of acromioclavicular joint excision.

BACKGROUND: With the development of arthroscopic procedures such as subacromial decompression (ASAD) and rotator cuff repair (RCR), it is hypothesized that there may have been a similar rise in the performance of acromioclavicular joint excision (ACJE). The purpose of this study was to investigate the epidemiology of ACJE to examine incidence, surgical technique, age, gender of patients and associated procedures in an urban population. METHODS: A prospectively collected surgical database was retrospectively examined to identify patients undergoing ACJE. Associated procedures such as ASAD or RCR were determined from these records. The demographic details (age and gender) were also recorded. RESULTS: A total of 411 ACJEs were performed over the study period (n = 216 males, n = 195 female). The overall incidence increased from 9.3 per 100,000 in 2009, to a peak of 19.6 per 1,00,000 in 2013. In 349 patients, ACJE was undertaken as part of an arthroscopic procedure, of which 332 were ASAD+ACJE alone. The prevalence of arthroscopic ACJE in ASADs was 23.7% (349/1400). ACJE was performed as an open procedure in 62 (15%) cases. Those undergoing open ACJE were younger than those undergoing an arthroscopic procedure (mean difference 6.2 years, 95% CI 3.2-9.2, p < 0.001). CONCLUSIONS: We demonstrate an increasing incidence of ACJE in the general population. The groups of patients most likely to undergo ACJE are women aged between 45 and 54 years old, men aged 55-64 years and the most socioeconomically deprived. The higher incidence of ACJE in the most deprived socioeconomic quintile may have public health implications. Level of Evidence: II; retrospective design: prognosis study.