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Cathepsins and their endogenous inhibitors cystatins: expression and modulation in multiple sclerosis.

Haves-Zburof D, Paperna T, Gour-Lavie A, Mandel I, Glass-Marmor L, Miller A - J. Cell. Mol. Med. (2011)

Bottom Line: In the serum, only cathepsin S levels were reduced by IFN-β (16%, P = 0.006, n = 25).Interestingly, pre-treatment serum cathepsin S/cystatin C ratio was higher in 'good responders' to IFN-β therapy compared to patients without a good response (by 94%, P = 0.003).These results suggest that cathepsin S and cystatin C may contribute to disease activity in MS, specifically in a subgroup of patients that are responsive to IFN-β therapy, and that these proteins should be further evaluated as biomarkers in MS.

View Article: PubMed Central - PubMed

Affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

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Related in: MedlinePlus

Response phenotype to IFN-β treatment and cathepsin S and cystatin C expression levels. IFN-β treated MS patients were stratified according to their response phenotype. (A) CTSS and CSTC pre-treatment levels relative RNA levels depicted as 2−ΔCT values, compared between ‘good responders’ (blue circles, n= 12) and ‘others’ patient groups (red triangles, n= 11). (B) Serum cathepsin S and cystatin C pre-treatment levels assessed by ELISA in ‘good responders’ (n= 14) and the ‘others’ patient groups (n= 10). (C) Serum cathepsin S to cystatin C ratios in ‘good responders’ (n= 14) and ‘others’ patient groups (n= 10); values prior to IFN-β therapy and 3–6 months after therapy initiation are connected by lines.
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fig04: Response phenotype to IFN-β treatment and cathepsin S and cystatin C expression levels. IFN-β treated MS patients were stratified according to their response phenotype. (A) CTSS and CSTC pre-treatment levels relative RNA levels depicted as 2−ΔCT values, compared between ‘good responders’ (blue circles, n= 12) and ‘others’ patient groups (red triangles, n= 11). (B) Serum cathepsin S and cystatin C pre-treatment levels assessed by ELISA in ‘good responders’ (n= 14) and the ‘others’ patient groups (n= 10). (C) Serum cathepsin S to cystatin C ratios in ‘good responders’ (n= 14) and ‘others’ patient groups (n= 10); values prior to IFN-β therapy and 3–6 months after therapy initiation are connected by lines.

Mentions: Following the pharmacogenetics study which reported association of the CTSS gene with IFN-β response in MS [31], and our observation that IFN-β seems to reduce cathepsin S serum protein levels (above), we assessed cathepsin S and its inhibitors’ expression with respect to the IFN-β treatment response phenotype in the patient cohort. Pre-treatment levels of cathepsin S were higher in RNA from PBLs of patients classified as ‘good responders’ (n= 12) compared to the ‘others’ group (n= 11), shown in Figure 4A; however, this trend did not reach statistical significance. Differences for CTSB, CSTB (not shown) and CSTC (Fig. 4A), or any of the ratios of the proteases to their inhibitors, were not significant. Interestingly, the pre-treatment serum protein levels of the inhibitor cystatin C were correlated with response status, and were significantly lower in the ‘good responders’ group (64% higher levels in the ‘others group versus the ‘good responder’ group, n= 10 and n= 14, respectively, P= 0.004, Fig. 4B). The sensitivity and specificity for detecting a good responder was 71% and 90%, respectively, using 809 ng/ml as a cut-off value [Area under curve (AUC) = 0.850 ± 0.079, P= 0.004]. The protein ratio cathepsin S/cystatin C in the serum, reflecting the balance of the proteolytic activity for cathepsin S, was significantly higher in ‘good responders’ prior to treatment initiation (by 94%, P= 0.003) (Fig. 4C).


Cathepsins and their endogenous inhibitors cystatins: expression and modulation in multiple sclerosis.

Haves-Zburof D, Paperna T, Gour-Lavie A, Mandel I, Glass-Marmor L, Miller A - J. Cell. Mol. Med. (2011)

Response phenotype to IFN-β treatment and cathepsin S and cystatin C expression levels. IFN-β treated MS patients were stratified according to their response phenotype. (A) CTSS and CSTC pre-treatment levels relative RNA levels depicted as 2−ΔCT values, compared between ‘good responders’ (blue circles, n= 12) and ‘others’ patient groups (red triangles, n= 11). (B) Serum cathepsin S and cystatin C pre-treatment levels assessed by ELISA in ‘good responders’ (n= 14) and the ‘others’ patient groups (n= 10). (C) Serum cathepsin S to cystatin C ratios in ‘good responders’ (n= 14) and ‘others’ patient groups (n= 10); values prior to IFN-β therapy and 3–6 months after therapy initiation are connected by lines.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822953&req=5

fig04: Response phenotype to IFN-β treatment and cathepsin S and cystatin C expression levels. IFN-β treated MS patients were stratified according to their response phenotype. (A) CTSS and CSTC pre-treatment levels relative RNA levels depicted as 2−ΔCT values, compared between ‘good responders’ (blue circles, n= 12) and ‘others’ patient groups (red triangles, n= 11). (B) Serum cathepsin S and cystatin C pre-treatment levels assessed by ELISA in ‘good responders’ (n= 14) and the ‘others’ patient groups (n= 10). (C) Serum cathepsin S to cystatin C ratios in ‘good responders’ (n= 14) and ‘others’ patient groups (n= 10); values prior to IFN-β therapy and 3–6 months after therapy initiation are connected by lines.
Mentions: Following the pharmacogenetics study which reported association of the CTSS gene with IFN-β response in MS [31], and our observation that IFN-β seems to reduce cathepsin S serum protein levels (above), we assessed cathepsin S and its inhibitors’ expression with respect to the IFN-β treatment response phenotype in the patient cohort. Pre-treatment levels of cathepsin S were higher in RNA from PBLs of patients classified as ‘good responders’ (n= 12) compared to the ‘others’ group (n= 11), shown in Figure 4A; however, this trend did not reach statistical significance. Differences for CTSB, CSTB (not shown) and CSTC (Fig. 4A), or any of the ratios of the proteases to their inhibitors, were not significant. Interestingly, the pre-treatment serum protein levels of the inhibitor cystatin C were correlated with response status, and were significantly lower in the ‘good responders’ group (64% higher levels in the ‘others group versus the ‘good responder’ group, n= 10 and n= 14, respectively, P= 0.004, Fig. 4B). The sensitivity and specificity for detecting a good responder was 71% and 90%, respectively, using 809 ng/ml as a cut-off value [Area under curve (AUC) = 0.850 ± 0.079, P= 0.004]. The protein ratio cathepsin S/cystatin C in the serum, reflecting the balance of the proteolytic activity for cathepsin S, was significantly higher in ‘good responders’ prior to treatment initiation (by 94%, P= 0.003) (Fig. 4C).

Bottom Line: In the serum, only cathepsin S levels were reduced by IFN-β (16%, P = 0.006, n = 25).Interestingly, pre-treatment serum cathepsin S/cystatin C ratio was higher in 'good responders' to IFN-β therapy compared to patients without a good response (by 94%, P = 0.003).These results suggest that cathepsin S and cystatin C may contribute to disease activity in MS, specifically in a subgroup of patients that are responsive to IFN-β therapy, and that these proteins should be further evaluated as biomarkers in MS.

View Article: PubMed Central - PubMed

Affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Show MeSH
Related in: MedlinePlus