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Table 1 Biopsy studies; studies investigating the pathophysiology of frozen shoulder with glenohumeral capsular tissue samples

From: The puzzling pathophysiology of frozen shoulders – a scoping review

Author Year Study design Biopsy location n FS n Controls Analysis method Most relevant findings
Hannafin [5] 1994 case series anterior, inferior and posterior 15 histology Frozen shoulder starts with a hypervascular synovitis followed by diffuse fibroplasia with thickening and contracture of the capsule
Bunker [6] 1995 case series CHL + RI 12 immunohistochemistry Active fibroblastic proliferation with differentiation into myofibroblasts and the deposition of thick nodular bands of collagen
Rodeo [7] 1997 case control anterosuperior 19 21 immunohistochemistry Hypervascular synovial hyperplasia with fibroblasts, occasional T-cells, B-cells and newly synthesized collagen type I and III was found. TGF-β, PDGF, IL-1β and TNF-α are involved in an inflammatory and fibrotic process in frozen shoulders
Bunker [8] 2000 case serie RI 14 4 RT-PCR The presence of mRNA for a large number of cytokines and growth was demonstrated in frozen shoulder capsular tissue
Ryu [9] 2006 case control RI 11 5 immunohistochemistry, western blot Immunostaining for VEGF was stronger in frozen shoulders compared to controls
Hand [10] 2007 case series RI 22 immunohistochemistry Fibroblastic proliferation and an infiltrate of chronic inflammatory cells (mast cells, T cells, B cells and macrophages) was found
Kilian [11] 2007 case control RI 6 6 immunohistochemistry, RT-PCR Significant enhancement of α-1(I) mRNA transcription (mature collagen) was found
Uhthoff [12] 2007 case series 5 different locations 4 immunohistochemistry Fibroplasia together with type III collagen was present in the entire joint capsule. Contracture, (vimentin expression), was found only in the anterior joint capsule (rotator interval and CHL)
DePalma [13] 2008 case series capsule 32 histology Evidence of a low grade chronic inflammatory process with variable involvement of the biceps tendon sheath was found
Kanbe [14] 2009 case series RI 10 immunohistochemistry NF-κB, IL-6, MMP3, β1-integrin and VEGF were expressed in the synovial tissue of frozen shoulders
Li [15] 2009 case control RI 12 12 RT-PCR A higher expression of mRNA for TGF-β and several MMPs was found
Kabbabe [16] 2010 case control 4 different locations 13 10 qPCR Inflammatory (IL-6 and IL-8) and fibrogenic (MMP3) cytokines were expressed at a higher level in frozen shoulders compared to controls
Nago [17] 2010 case series + in vitro cell culture RI 7 histology, RT-PCR Treatment of cultured glenohumeral/synovial fibroblast from frozen shoulder patients with hyaluronan inhibited cell proliferation and expression of adhesion related procollagens and cytokines.
Hagiwara [18] 2012 case control RI + MGHL + IGHL 12 18 immunohistochemistry, qPCR, scanning acoustic microscopy A higher number of cells, stiffer capsular tissue and increased gene expression related to fibrosis (COL1A1, PDGF-B) inflammation (IL-1β) and chondrogenesis was found
Xu [19] 2012 case control RI 8 10 immunohistochemistry Increased expression of nerve growth factor receptor and new nerve fibers were found in frozen shoulder capsular tissue compared to controls
Kim [20] 2013 case series RI 17 9 immunohistochemistry, RT-PCR ICAM-1 was increased in capsular tissue, synovial fluid, and serum of frozen shoulder patients compared to controls
Lho [21] 2013 case control RI + subacromial bursa 14 7 immunohistochemistry, RT-PCR, ELISA IL-1α, IL-1β, TNF-α, COX-1 and COX-2 were expressed at higher levels in joint capsule of frozen shoulder patients compared to controls. In the subacromial bursa, IL-1α, TNF-α and COX-2 were expressed at higher levels
Raykha [22] 2014 case control + in vitro cell culture RI ? ? western blot, RT-PCR β-catenin and IGF-2 expression were found to be elevated in frozen shoulders compared to controls
Cho [23] 2015 case control capsule 18 18 immunohistochemistry, RT-PCR Upregulation of acid sensing ion channels (ACICs)was found in capsular tissue and synovial fluid of frozen shoulder patients
Cohen [24] 2016 case control anteroinferior capsule 9 8 RT-PCR Elevated expression of Tenascin C and Fibronectin 1 mRNA was found in capsular tissue of frozen shoulder patients.
Hettrich [25] 2016 case control anterior and posterior 20 14 immunohistochemistry Intra articular corticosteroid injection reduces fibrosis, vascular hyperplasia and myofibroblast differentiation
Hwang [26] 2016 case control RI 8 14 immunohistochemistry Immunoreactivity of AGEs was stronger in frozen shoulder capsules compared to controls
Cui [27] 2017 case control capsule + bursa + synovium 5 2 RNA sequencing 147 genes were upregulated and 24 downregulated in capsular tissue of frozen shoulder patients compared to controls
Cher [28] 2018 case control RI 10 10 immunohistochemistry Immunoreactivity of alarmins was stronger in frozen shoulder patients. The expression of the alarmin HMGB1 correlated with the severity of pain
Hagiwara [29] 2018 case control RI + MGHL + IGHL 12 7 shotgun proteome analysis The pathophysiology might differ between the upper and lower parts of the joint capsule. In the RI and MGHL samples, different proteins were higher expressed compared to the IGHL samples
Akbar [30] 2019 case control + in vitro cell culture RI 10 10 immunohistochemistry, qPCR, ELISA Fibroblasts in FS have activated phenotype with an increased expression of fibroblast activation markers. Cultured FS fibroblasts produced elevated levels of inflammatory proteins (IL-6, IL-8, CCL-20)
Cho [31] 2019 case control + animal (rat) study capsule 21 13 immunohistochemistry Overexpression of IL-6, MMP-2 and MMP-9 may be associated with frozen shoulder
Kamal [32] 2020 case control anterior 22 26 RT-PCR Inflammation and ECM remodelling were the most signifant and highly enriched processes in frozen shoulder. MMP13 expression was increased and TNF-α expression was reduced in frozen shoulders
Yang [33] 2020 case control + in vitro cell culture RI 9 10 immunohistochemistry, RT-PCR, flow cytometry COL1A1, COL3A1, TGF-β1, and IL-6 were expressed at increased levels in the frozen shoulder group compared to controls. The presence of calcitonin receptors in shoulder capsular tissue was confirmed. Treatment with salmon calcitonin decreased the expression of COL1A1, COL3A1, fibronectin 1, laminin 1, TGF-β1 and IL-1α
Yano [34] 2020 case control CHL + IGHL 33 25 immunohistochemistry, RT-PCR, high performance liquid chromatography AGEs and HMGB1 might play important roles in the pathogenesis of frozen shoulder. Gene expression levels of RAGE, HMGB1, TLR2, TLR4 and NF-κB were significantly greater in frozen shoulders compared to controls
  1. CHL coracohumeral ligament, RI rotator interval, MGHL middle glenohumeral ligament, IGHL inferior glenohumeral ligament, RT-PCR real time polymerase chain reaction, ELISA enzyme linked immune sorbent assay, TGF-β transforming growth factor beta, AGE advanced glycation end product, MMP matrix metalloproteinase, TIMP tissue Inhibitor of Metallo Proteinases, TSH thyroid stimulating hormone, IGF insulin like growth factor, ICAM intercellular adhesion molecule-1, ECM extracellular matrix, TNF-α tumor necrosis factor alfa, VEGF vascular endothelial growth factor