Pathological changes of frozen shoulder in rat model and the therapeutic effect of PPAR‐γ agonist

Abstract

Frozen shoulder is a common shoulder disorder characterized by a gradual increase of pain and a limited range of motion. However, its pathophysiologic mechanisms remain unclear and there is no consensus as to the most effective treatment. The purpose of the study was to investigate the effect of transforming growth factor-β (TGF-β) on fibrosis and inflammatory response of the shoulder joint of rat models and to explore the therapeutic effect of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist. In the study, the effect of PPAR-γ agonist CDDO-IM treatment on cell proliferation, migration, and extracellular matrix proteins synthesis (vimentin, α-smooth muscle actin, collagen I, and collagen III) were tested by cell proliferation test, scratches test, real-time quantitative polymerase chain reaction, and Western blot analysis. The frozen shoulder was also established on the rat model by injecting adenovirus-TGF-β1 into rats' shoulder capsule. Pathological changes of the frozen shoulder tissue of the experimental group and PPAR-γ agonist treatment group were evaluated. The stiffness of joints of the three groups was tested. Inflammatory mediators' expression including cyclooxygenase-1, interleukin-1β, and tumor necrosis factor-α of the shoulder was tested by enzyme-linked immunosorbent assay, and the expression of extracellular matrix proteins was evaluated by hematoxylin and eosin staining and immunohistochemistry. The results showed that pathological changes of the frozen shoulder in the rat model include an abnormal proliferation of fibroblasts, infiltration of inflammatory cells, and disorder of fibrous structure, while rosiglitazone reduced the severity of the frozen shoulder in the treatment group. Clinically, PPAR-γ agonists may be a promising target for the treatment of the frozen shoulder.

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

“…Similar to these data, we demonstrate that IL-17A can directly promote a number of profibrotic mechanisms, including fibroblast survival and enhanced gene expression of proteins associated with matrix deposition. These profibrotic characteristics have previously been attributed to the elevated levels of the cytokine TGF-β in frozen shoulder ( 12 , 14 , 56 ). However, our data suggest the presence of IL-17A can also encourage the fibrotic hallmarks of frozen shoulder.…”

“…Although a number of animal models have been used to study cytokine-driven fibrotic pathogenesis, there is no well-described in vivo model available for frozen shoulder. Those that have described in vivo models have tended to inject TGF-β ( 56 ) into the joint or use joint immobilization ( 61 ) to directly explore the fibrotic pathways more so than the inflammatory mechanisms of disease, which may result in fibrosis. Additionally, in the current study, we primarily measure gene expression of matrix proteins rather than the physical proteins following IL-17A exposure.…”

Human bone marrow mesenchymal stem cell-derived extracellular vesicles inhibit shoulder stiffness via let-7a/Tgfbr1 axis

“…As aforementioned, driven by inflammation, a large number of fibroblasts are recruited in the shoulder capsule, and then secrete a large amount of collagen, leading to stiffness [ 10 , 12 , 13 ]. Therefore, promoting collagen degradation or inhibiting the secretion of collagen by fibroblasts has become the focus of anti-fibrosis for SS.…”

“…Triggered by inflammation, SS is characterized by thickening, stiffening, and fibrosis of joint capsule [ 9 , 10 ]. Numerous treatments were proposed against inflammation [ [11] , [12] , [13] ]. For example, Sun et al reported that steroid injection was effective against SS in inflammatory stage [ 14 , 15 ].…”

Cytokines' Role in the Pathogenesis and Their Targeting for the Prevention of Frozen Shoulder: A Narrative Review

“…Vimentin, TNF‐α, IL‐1β collagen 1 (COL1), and collagen 3 (COL3) are key effectors of FS pathogenesis and development. The peroxisome proliferator-activated receptor gamma (PPAR‐γ) agonist rosiglitazone was recently demonstrated to alleviate FS pathogenesis through these cytokines down regulation of [ 19 ]. Salmon calcitonin (sCT), a new candidate drug through its high ability to stimulate calcitonin receptor, activates protein kinase C (PKC) and protein kinase A (PKA) that are responsible for the down-regulation of fibrosis‐related molecules such as collagen 1, collagen 3, TGF‐β1, and interleukin-1α [ 20 ].…”