Increased serum calpain activity is associated with HMGB1 levels in systemic sclerosis

Abstract

Background: Systemic sclerosis (SSc) or scleroderma is an intractable autoimmune disorder that affects multiple organs. The objectives were to investigate clinical correlations of serum calpain activity and high mobility group box 1 (HMGB1) levels with immunological and clinical traits. Methods: A total of 31 patients with SSc, 20 age-and gender-matched healthy control subjects (HC), and 10 patients with other connective tissue diseases (CTD) were recruited in the study. We measured serum calpain activity and HMGB1 levels and analyzed the datasets (GSE40839, GSE48149, GSE76808, GSE81292, GSE33463, and GSE58095) from Gene Expression Omnibus (GEO) database to explore the potential mechanism by which calpain exerts its function through bioinformatics methods. Results: Serum calpain activity was significantly increased in patients with SSc compared with those in HC and in patients with CTD and was correlated with serum HMGB1 levels, modified Rodnan skin score, erythrocyte sedimentation rate, mean platelet volume, and plateletcrit. Notably, serum calpain activity and HMGB1 levels in SSc patients with interstitial lung disease (ILD) were significantly higher than those in SSc patients without ILD. Serum calpain activity and HMGB1 levels could be the independent risk factors for SSc-ILD and novel biomarkers in patients with SSc. Conclusion: This is the first study that reports increased serum calpain activity and the correlation between calpain and HMGB1 in patients with SSc or SSc-ILD. The serum calpain activity and HMGB1 levels may serve as measures of ILD in patients with SSc. Also, calpain and HMGB1 could be potential therapeutic targets for patients with SSc or SSc-ILD in the future.

Prevalence and risk factors of systemic sclerosis‐associated interstitial lung disease in East Asia: A systematic review and meta‐analysis

“…The pooled SSc‐ILD prevalence was 56% (95% CI 49‐63) (Figure 2), which was stable in the sensitivity analysis (Figure 3). 11‐37 Heterogeneity across studies was high ( I 2 = 96.1%). There were significant differences in the prevalence of SSc‐ILD for subgroups stratified by region, study quality, SSc classification criteria, and publication year (Table 2).…”

“…The following 15 risk factors appearing in more than one study were selected in the meta‐analysis: disease duration, dSSc, anti‐topoisomerase I antibody (ATA), anti‐centromere body antibody (ACA), anti‐U3 ribonucleoprotein (RNP) antibody, digital ulcer, age, male sex, antinuclear antibody (ANA), anti‐U1 RNP antibody, anti‐Th/To antibody, Raynaud phenomenon, erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), and anti‐ribonucleic acid polymerases (RNAP). SSc‐ILD patients had a longer disease duration than SSc patients without ILD (WMD = 1.97, 95% CI 0.55‐3.38) 12,21,23 . Diffuse SSc (OR = 2.84, 95% CI 1.91‐4.21), 12,20,21,23,30 positive ATA (OR = 4.92, 95% CI 2.74‐8.84), 12,17,20,21,23,24,30,31,37,40 positive ACA (OR = 0.14, 95% CI 0.08‐0.25), 12,17,20,21,23,24,30,31,37 positive anti‐U3 RNP antibody (OR = 0.17, 95% CI 0.04‐0.66), 23,37 and higher ESR (WMD = 6.62, 95% CI 1.19‐12.05) 12,21,23 were associated with ILD in SSc patients (Figure 4A‐F).…”

“…There was no publication bias among studies about dSSc by Egger test ( t = 0.29, P = 0.79), about ATA by Egger test ( t = 1.39, P = 0.20), or about ACA by Egger test ( t = 1.45, P = 0.19) (Figure B‐D). However, age (WMD = 3.39, 95% CI −1.54 to 8.31), 12,20,21,23,30 male sex (OR = 1.31, 95% CI 0.83‐2.06), 12,20,21,23,30 Raynaud phenomenon (OR = 0.68, 95% CI 0.30‐1.54), 12,21,23,30 digital ulcer (OR = 1.79, 95% CI 1.00‐3.20), 12,29 CRP (WMD = 0.98, 95% CI 0.00‐1.95), 12,23 positive ANA (OR = 1.6, 95% CI 0.62‐4.17), 12,20,21 positive anti‐U1 RNP antibody (OR = 0.98, 95% CI 0.69‐1.40), 17,21,23,24,30,31,37 positive anti‐Th/To antibody (OR = 0.35, 95% CI 0.09‐1.31), 23,37 and positive anti‐RNAP (OR = 0.49, 95% CI 0.23‐1.03) 17,23,31,37 were not associated with ILD in SSc patients (Figure A‐I). There was no publication bias in the studies about age by the Egger's test ( t = −0.43, P = 0.70), about male sex by the Egger's test ( t = 1.55, P = 0.33), and about anti‐U1 RNP by the Egger's test ( t = 1.35, P = 0.24) (Figure A‐C).…”

Myeloid cell-specific deletion of Capns1 prevents macrophage polarization toward the M1 phenotype and reduces interstitial lung disease in systemic sclerosis

“…Calpain has been implicated in pulmonary arterial hypertension [12]. Also, our lab recently reported an increase in serum calpain activity, which correlated with elevation of HMGB1 in patients with SSc or SSc-ILD [31]. The serum calpain activity and HMGB1 levels may serve as measures of ILD in patients with SSc [31].…”

“…Also, our lab recently reported an increase in serum calpain activity, which correlated with elevation of HMGB1 in patients with SSc or SSc-ILD [31]. The serum calpain activity and HMGB1 levels may serve as measures of ILD in patients with SSc [31]. However, a mechanistic role of calpain in SSc-ILD has never been reported.…”