Frozen Shoulder (FS) is a debilitating musculoskeletal condition with an uncertain aetiology and poorly understood pathogenic mechanism. This study aimed to investigate the pathology of FS. We hypothesised that an altered expression of cytokines may disrupt the normal tissue remodeling process, leading to FS, which would be apparent histologically.

Patients undergoing arthroscopic treatment of FS were prospectively recruited, along with control patients being treated for subacromial impingement. Synovial biopsies were taken from all subjects. Synovial RNA levels were analysed using quantitative Polymerase Chain Reaction (qPCR). Inflammatory cytokines and growth factors thought to play a role in the pathogenesis of FS were assessed. These included metalloproteases (MMP, ADAMTS) involved in tissue remodeling and fibrosis, inflammatory cytokines such as interleukins (IL), and growth factors such as colony stimulating factors (MCSF, GMCSF, CSF1R). Samples underwent histological analysis, to assess inflammation and fibrosis.

Thirteen patients with FS and ten control patients with subacromial impingement were recruited. Arthroscopic inspection revealed greater levels of synovitis (2.63+ vs 0.40+, p< 0.01) and papillary proliferation (50% vs 10%, p=0.02) in FS patients compared with the control group, confirming the initial clinical diagnosis of FS. Histological analysis of the synovium revealed samples from the FS group were more likely to demonstrate a fibrotic, focally nodular collagen morphology (53.8% vs 10%, p=0.03). There were similar levels of chronic inflammatory cells present in those with FS and control patients (53.8% vs 30%, p=0.25). There was no evidence of acute inflammation in any of the samples. Immunohistochemical staining revealed a high level of AGEs present in the synovium and smooth muscle tissue in all samples. There was no observed difference between diabetic and non-diabetic samples. Cytogenetic analysis using qPCR revealed fibrogenic factors MMP3 (p=0.068), and ADAMTS4 (p=0.083) to be elevated in FS cases, as were inflammatory cytokines IL6 (p=0.062) and IL8 (p=0.075)

We have quantified the level of inflammatory cytokines and growth factors in FS, demonstrating that these factors are elevated in FS. This indicates that altered levels of inflammatory cytokines may be associated with the pathogenesis of inflammation evolving into fibrosis, the characteristic feature of FS. We have also shown the histology of this fibrosis to be different to that observed in normal synovium.