Fibrosis in frozen shoulder: Activation of IL-6 through PI3K-Akt signaling pathway in synovial fibroblast

Tang, Yiyong; Hou, Jingyi; Yu, Menglei; Yi, Long; Alike, Yamuhanmode; Li, Qingyue; Li, Fangqi; Zhang, Yuanhao; Warsame, Maslah; Zhang, Congda; Shen, Huiyong

doi:10.1016/j.molimm.2022.07.007

Cited by 17 publications

(24 citation statements)

References 36 publications

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“…The pathological features of FS have been reported to involve leukocyte and myeloid infiltration, increased vascularity, fibroblast proliferation, and chronic inflammation. 3,4,49 Nonetheless, the specific inflammatory pathways remain to be identified and may illuminate why this condition eventually resolves spontaneously.…”

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confidence: 99%

Increased Expression of Adipokines in Patients With Frozen Shoulder

Qiao,

Yao,

Zhao

et al. 2023

Am J Sports Med

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Background: Adipokines represent a spectrum of bioactive molecules that could modulate fibroblastic and inflammatory processes. The role of adipokines in the pathogenesis of frozen shoulder (FS), a common musculoskeletal disorder characterized by chronic inflammation, remains obscure. Purpose: To evaluate whether adipokines contribute to the pathogenic mechanisms of FS and to evaluate any potential correlation of adipokines with patients’ symptoms. Study Design: Controlled laboratory study. Methods: Shoulder capsule specimens were obtained from 10 patients with FS and 10 patients with shoulder instability (control group). The specimens were dyed using hematoxylin and eosin and immunohistochemically assessed with antibodies targeting adipokines, collagen I, collagen III, and tumor necrosis factor α. Immunoreactivity was graded from “no” to “strong” in a blinded manner. Reverse transcription–quantitative real-time polymerase chain reaction (RT-qPCR) analysis was conducted. Before the surgery, patient-reported frequency of pain, severity of pain, stiffness, and shoulder range of motion were documented. Results: In comparison with the control group, patients with FS had significantly greater pain frequency, pain severity, and stiffness and more limited shoulder range of motion ( P < .001). Hematoxylin and eosin- and Masson trichrome–stained samples from the FS group displayed hypercellularity and increased collagen fibers. Immunohistochemistry and RT-qPCR analyses indicated that expression of adipokines was significantly increased in FS capsules compared with the control group. The expression of collagen I, collagen III, and tumor necrosis factor α was also increased in FS capsules. No significant correlation was noted between adipokine expression and patient-reported outcomes in the control group, whereas in patients with FS, adiponectin expression was correlated with pain frequency ( r = 0.78; P = .01) and stiffness ( r = 0.73; P = .02). Visfatin was also correlated with pain frequency ( r = 0.70; P = .02). Conclusion/Clinical Relevance: This study indicated a potential role for adipokines in the pathogenesis of FS and demonstrated a correlation between adipokine expression and patients’ pain and stiffness.

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confidence: 99%

Increased Expression of Adipokines in Patients With Frozen Shoulder

Qiao,

Yao,

Zhao

et al. 2023

Am J Sports Med

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“…Previous research showed that IL-6 promotes AKT phosphorylation, activates PI3-AKT signal pathway, increases the expression of COL-1 and COL-3, and results in the deposition of ECM and brosis in FS 31 .…”

Section: Discussionmentioning

confidence: 98%

Proteomics and Phosphoproteomics reveal Mechanism of Tuina in the Treatment of Frozen Shoulder：A research report based on rats

Qiao,

Wang,

Zheng

et al. 2023

Preprint

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Frozen shoulder (FS) is a common disorder often treated with tuina, but the mechanisms involved remain unknown. We established proteomics and phosphoproteomics to investigate the mechanisms associated with the treatment of capsule fibrosis in FS rats. We used a method consisting of three weeks of cast immobilisation to establish a model of FS. We then administered Tuina once daily for 14 days, evaluated histological changes and screened for differentially expressed proteins (DEPs) using proteomics and phosphoproteomics. This study showed that Tuina could inhibit capsule fibrosis in FS rats. Proteomics revealed proteins regulated by Tuina belonging to the PI3K-AKT and ECM receptor interaction signaling pathways. Thbs1, Vtn and Tnn were significantly enriched in these pathways and highly expressed in the model rat. Tuina resulted in suppressed expression of these proteins. Phosphoproteomics detected differentially expressed proteins regulated by Tuina were enriched in MAPK, endocrine resistance, FoxO and central carbon metabolism in cancer pathways. The combination of proteomics and phosphoproteomics for PPI network analysis revealed that the phosphorylation of Myh3 and Srsf1 have an important regulatory effect. Our results demonstrated the mechanisms behind the inhibition of FS capsule fibrosis following Tuina, a scientific medical therapy for FS patients.

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“…KEGG pathway analysis demonstrated signi cant enrichment in pathways such as protein digestion and absorption, ECM-receptor interaction, relaxin signaling pathway, focal adhesion, PI3K-Akt signaling pathway, and IL-17 signaling pathway. Yang et al reported that IL6 promoted brosis in FS through the PI3K-Akt signaling pathway in broblasts, as observed in synovial tissue of FS patients [20]. Moeed et al found that interleukin-17, produced by T-cell subsets in joint capsule tissue of FS patients, induced brosis and in ammatory responses in broblasts by increasing the expression of its signal receptors [21].…”

Section: Discussionmentioning

confidence: 99%

Collagen synthesis-associated pivotal biomarkers identification and ceRNA networks construction in frozen shoulder by comprehensive bioinformatics and machine learning strategies

wen,

Zhao,

Wang

et al. 2023

Preprint

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Background Frozen shoulder is characterized by aberrant collagen synthesis and fibrosis. Long non-coding RNAs (lncRNAs) have been implicated in collagen production and fibrosis development. However, the specific alterations in lncRNA expression in frozen shoulder patients remain poorly understood. Therefore, this study aimed to identify collagen synthesis-related genes and provide a competitive endogenous RNA (ceRNA) networks for frozen shoulder. Methods We acquired dataset GSE140731 from the Gene Expression Omnibus (GEO) database and used the 'limma' R software package to identify differentially expressed lncRNAs (DELs) and mRNAs (DEGs). These DEGs were intersected with collagen synthesis-related genes to obtain collagen synthesis-related DEGs (CS-DEGs). Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted using the 'ClusterProfiler' package in R. Machine learning algorithms were employed to select candidate core genes based on CS-DEGs, which were then validated using an external dataset (GSE190023). This validation process led to identifying two core genes, COL11A1 and ADAMTS14. TargetScan, miRTarBase, and miRDB databases were utilized to predict target microRNAs for these core genes, while ENCORI was employed to predict target lncRNAs for these microRNAs. The intersection of predicted lncRNAs with DELs yielded core lncRNAs. Lastly, the 'ggalluvial' package in R was used to construct the lncRNA-miRNA-mRNA ceRNA networks. The ceRNA networks was further validated using quantitative real-time polymerase chain reaction (RT-qPCR). Result A total of 427 DELs and 549 DEGs were identified. Combined with the Molecular Signatures Database (Msigdb), we discovered 23 upregulated and 1 downregulated CS-DEGs. These genes were primarily associated with collagen synthesis regulation. Using three machine learning algorithms, we selected three candidate core genes, and after validation with an external dataset, two core genes (COL11A1 and ADAMTS14) were identified. By cross-predicting miRNAs and establishing lncRNA-miRNA interactions, we constructed a ceRNA networks of 2 lncRNAs, 9 miRNAs, and 2 mRNAs. Histological staining revealed increased collagen fibres and fibroblast cell numbers in frozen shoulder synovial tissues using H&E staining, and significantly higher fibrosis was observed in frozen shoulder patients compared to the control group using Masson's trichrome staining. RT-qPCR results were consistent with the sequencing data. Conclusion This study represents the first attempt to construct a ceRNA networks related to collagen synthesis in frozen shoulder using a combination of bioinformatics approaches and experimental validation. The identified ceRNA networks has the potential to regulate the development and progression of fibrosis in frozen shoulder, thereby presenting promising biomarkers and therapeutic targets for the diagnosis and treatment of frozen shoulder and associated joint stiffness.

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Fibrosis in frozen shoulder: Activation of IL-6 through PI3K-Akt signaling pathway in synovial fibroblast

Cited by 17 publications

References 36 publications

Increased Expression of Adipokines in Patients With Frozen Shoulder

Increased Expression of Adipokines in Patients With Frozen Shoulder

Proteomics and Phosphoproteomics reveal Mechanism of Tuina in the Treatment of Frozen Shoulder：A research report based on rats

Collagen synthesis-associated pivotal biomarkers identification and ceRNA networks construction in frozen shoulder by comprehensive bioinformatics and machine learning strategies

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