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