OBJECTIVE: To detect the expression of plasma exosomal microRNA (miRNA) in systemic sclerosis (SSc), and to investigate its clinical significance. METHODS: A total of 20 patients who were initially diagnosed with SSc and did not receive medication in Department of Rheumatology and Immunology of Meizhou People' s Hospital from January 2020 to January 2022 were recruited, as well as 15 healthy individuals whose gender and age matched with those of the SSc patients. Plasma exosomes were isolated using ultracentrifugation method. The expression levels of exosomal miR-34-5p, miR-92-3p and miR-142-3p were detected by quantative real-time polymerase chain reaction (qRT-PCR). Correlations between the expression levels of exosomal miRNAs and clinical characteristic were analyzed by Spearman's rank correlation coefficient test. RESULTS: The mean age of 20 patients with SSc was (52.6±12.6) years, including 7 males and 13 females. Among the 20 SSc patients, 13 cases were diagnosed as limited cutaneous systemic sclerosis (lcSSc) and 7 cases were diagnosed as diffuse cutaneous systemic sclerosis (dcSSc) according to the extent of skin involvement. According to the findings of high resolution chest CT, 7 of 20 SSc patients were diagnosed with interstitial lung disease (ILD) and 13 SSc patients were diagnosed with non-ILD. The expression levels of exosomal miR-34-5p, miR-92-3p and miR-142-3p were significantly elevated in the SSc patients compared with those in the healthy controls group (P=0.003, P=0.000 1, and P=0.016, respectively). Compared with the SSc patients without ILD, the expression levels of miR-34-5p and miR-142-3p were significantly lower in the SSc patients with ILD (P=0.037 and P=0.015, respectively). The expression levels of exosomal miR-34-5p and miR-142-3p showed negative correlation with ILD (r=-0.48, P=0.031 and r=-0.55, P=0.011, respectively), and arthritis (r=-0.46, P=0.040 and r=-0.48, P=0.032, respectively). The expression levels of exosomal miR-142-3p showed a negative correlation with erythrocyte sedimentation rate (ESR) (r=-0.55, P=0.012). CONCLUSION Plasma exosomal miR-34-5p, miR-92-3p and miR-142-3p were dysregulated in SSc. The dyregulation of exosomal miR-34-5p and miR-142-3p showed correlation with SSc associated ILD (SSc-ILD).
Male ; Female ; Humans ; Young Adult ; Adult ; Clinical Relevance ; MicroRNAs/genetics* ; Scleroderma, Systemic/genetics* ; Lung Diseases, Interstitial

miRNAs are important post-transcriptional regulators. The aberrant expression of miRNAs is strongly associated with the initiation and progression of pathophysiologic processes in a wide range of human diseases. Scleroderma (systemic sclerosis; SSc) is a highly heterogeneous autoimmune disease that includes the progressive fibrotic replacement of normal tissue architecture in multiple organs. Our previous studies have suggested that SSc skin tissues display a different miRNA expression signature than that found in normal controls. miRNAs with pro- or antifibrotic properties are found to be dysregulated in SSc skin fibrosis. Serum miRNA levels are associated with SSc activity and severity. miRNAs have the potential to be therapeutic targets and serve as biomarkers for SSc diagnosis and assessment of disease state and severity. This review summarizes the SSc miRNA expression signature and the roles of dysregulation of miRNAs in SSc tissues and serum and examines the future therapeutic potential of targeting miRNAs in the management of SSc patients.
Animals ; Biological Markers/metabolism ; Fibrosis/etiology/metabolism ; Humans ; MicroRNAs/*genetics/metabolism ; Scleroderma, Systemic/diagnosis/etiology/genetics/*metabolism

Systemic sclerosis (SSc) is a connective tissue disease characterized by extensive fibrosis, vasculopathy, and activation of the immune system. Its pathogenesis and mechanisms have not been identified. Studies have shown that environmental and genetic factors are involved in the pathogenesis and development of SSc. Although the concordance for the disease among identical twins is low, concordance for antoantibodies associated with SSc and for fibroblast gene expression profiles is higher. However, the candidate-gene approach has not established clear associations between polymorphisms and SSc. Based on the involvement of SSc, the candidate gene can be screened from three groups: fibrosis, immune response, and vascular disease. This article summarizes the recent advances in these three aspects.
Fibrillins ; Genetic Predisposition to Disease ; Humans ; Microfilament Proteins ; genetics ; Polymorphism, Genetic ; Protein Tyrosine Phosphatases ; genetics ; Scleroderma, Systemic ; genetics ; Tumor Necrosis Factor-alpha ; genetics

To determine whether angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is associated with the development and clinical features of systemic sclerosis (SSc) in Korean, we studied seventy two Korean patients with SSc fulfilling the ACR preliminary classification criteria. The controls were 114 healthy, disease free Koreans. ACE I/D genotypes were determined by PCR method using oligonucleotides. Sixty eight patients (94.4%) were women and age at diagnosis was 43.5+/-12.6 yr old (mean+/-SD). Thirty nine patients (54.2%) had a diffuse type of SSc. There were no statistical differences in the frequencies of all ACE I/D genotypes and D allele between patients and controls, and neither between diffuse and limited types of SSc. ACE I/D gene polymorphism was not associated with the development of SSc in Korea. The investigation for the pathogenesis of SSc requires more studies about the role of other candidate genes such as endothelin, TGF-beta, nitric oxide, or angiotensin II receptor in addition to the ACE genes.
Scleroderma, Systemic/*enzymology/*genetics ; *Polymorphism, Genetic ; Peptidyl-Dipeptidase A/*genetics ; Middle Aged ; Male ; Korea ; Humans ; Genotype ; Gene Frequency ; Female ; DNA/genetics ; Case-Control Studies ; Base Sequence ; Alleles ; Adult

Uncontrolled fibrosis of skin and internal organs is the main characteristic of scleroderma, and collagen is a major extracellular matrix protein that deposits in the fibrotic organs. As the chaperone of collagen, heat shock protein 47 (HSP47) is closely related with the development of fibrosis. To explore the potential function of HSP47 in the pathogenesis of scleroderma, the clinical, in vivo and in vitro studies were performed. In clinical, the increased mRNA level of HSP47 was observed in the skin fibroblasts and PBMC from scleroderma patients, and the enhanced protein level of HSP47 was also detected in the skin biopsy and plasma of the above patients. Unexpectedly, the enhanced levels of HSP47 were positively correlated with the presence of anti-centromere antibody in scleroderma patients. Moreover, a high expression of HSP47 was found in the skin lesion of BLM-induced scleroderma mouse model. Further in vitro studies demonstrated that HSP47 knockdown could block the intracellular and extracellular collagen over-productions induced by exogenous TGF-β. Therefore, the results in this study provide direct evidence that HSP47 is involved in the pathogenesis of scleroderma. The high expression of HSP47 can be detected in the circulatory system of scleroderma patients, indicating that HSP47 may become a pathological marker to assess the progression of scleroderma, and also explain the systemic fibrosis of scleroderma. Meanwhile, collagen over-expression is blocked by HSP47 knockdown, suggesting the possibility that HSP47 can be a potential therapeutic target for scleroderma.
Adolescent ; Adult ; Animals ; Biopsy ; Blotting, Western ; Cells, Cultured ; Collagen ; metabolism ; Female ; Fibroblasts ; drug effects ; metabolism ; Fibrosis ; HSP47 Heat-Shock Proteins ; blood ; genetics ; metabolism ; Humans ; Leukocytes, Mononuclear ; metabolism ; Male ; Mice ; Mice, Inbred C3H ; Middle Aged ; NIH 3T3 Cells ; Protein Binding ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Scleroderma, Systemic ; blood ; genetics ; metabolism ; Skin ; metabolism ; pathology ; Transforming Growth Factor beta ; pharmacology ; Young Adult