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Serum levels of tissue inhibitors of metalloproteinase 2 in patients with systemic sclerosis with duration more than 2 years: correlation with cardiac and pulmonary abnormalities.
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PMID:  17392585     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study, we measured the serum concentration of TIMP-2 in patients with systemic sclerosis (SSc) and explored its possible correlation with cardiac and pulmonary lesions. We studied 42 patients with SSc, with duration equal to or more than 2 years. CT chest, ECG, echocardiography, and serum TIMP-2 concentration measurement using ELISA technique were performed in all patients and in 25 normal controls. The mean serum levels of TIMP-2 in patients was higher than in controls (P = .005). The mean CT score of dSSc patients with elevated TIMP-2 levels was significantly higher than dSSc patients with normal levels (P = .013). Four patients out of five with elevated TIMP-2 levels showed diastolic dysfunction (80%), compared to 2 out of 15 lSSc patients with normal levels (13.3%), with P = .014. Our research, though involving a small group of patients, points to the probable role of TIMP-2 in the development of pulmonary lesions in dSSc patients and cardiac lesions in lSSc patients with duration equal to or more than 2 years.
Authors:
Amira Shahin; Amani Elsawaf; Shahira Ramadan; Olfat Shaker; Mona Amin; Mohamed Taha
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Mediators of inflammation     Volume:  2006     ISSN:  0962-9351     ISO Abbreviation:  Mediators Inflamm.     Publication Date:  2006  
Date Detail:
Created Date:  2007-03-29     Completed Date:  2007-05-09     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  9209001     Medline TA:  Mediators Inflamm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38458     Citation Subset:  IM    
Affiliation:
Rheumatology and Rehabilitation Department, Faculty of Medicine, Cairo University, Egypt.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Case-Control Studies
Echocardiography, Doppler
Electrocardiography
Female
Heart Diseases / diagnosis,  etiology*,  metabolism
Humans
Lung Diseases / diagnosis,  etiology*,  metabolism,  pathology
Male
Middle Aged
Reference Values
Scleroderma, Systemic / blood*,  complications,  drug therapy
Time Factors
Tissue Inhibitor of Metalloproteinase-2 / blood*
Tomography, X-Ray Computed
Chemical
Reg. No./Substance:
127497-59-0/Tissue Inhibitor of Metalloproteinase-2
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Journal ID (nlm-ta): Mediators Inflamm
Journal ID (publisher-id): MI
ISSN: 0962-9351
Publisher: Hindawi Publishing Corporation
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Copyright © 2006 Amira Shahin et al.
open-access: This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received Day: 21 Month: 7 Year: 2006
Revision Received Day: 15 Month: 10 Year: 2006
Accepted Day: 15 Month: 10 Year: 2006
Print publication date: Year: 2006
Electronic publication date: Day: 20 Month: 12 Year: 2006
Volume: 2006 Issue: 6
E-location ID: 38458
ID: 1775032
PubMed Id: 17392585
DOI: 10.1155/MI/2006/38458

Serum Levels of Tissue Inhibitors of Metalloproteinase 2 in Patients With Systemic Sclerosis With Duration More Than 2 Years: Correlation With Cardiac and Pulmonary Abnormalities
Amira Shahin1*
Amani Elsawaf1
Shahira Ramadan2
Olfat Shaker3
Mona Amin4
Mohamed Taha5
1Rheumatology and Rehabilitation Department, Faculty of Medicine, Cairo University, Cairo, Egypt
2Dermatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
3Medical Biochemistry Department, Faculty of Medicine, Cairo University, Cairo, Egypt
4Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
5Medical Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Correspondence: *Amira Shahin: amirashahin@hotmail.com

BACKGROUND

Systemic sclerosis (SSc) is an autoimmunological multisystem disease affecting the skin, dermal blood vessels, and internal organs. It is characterized pathologically by the overproduction of connective tissue and fibrosis [1].

Fibrosis in the skin and internal organs in the course of systemic sclerosis is caused by the accumulation of an excessive quantity of collagen and other components of the extracellular matrix (ECM) in the affected area [2].

Fibroblasts play an important role in the metabolism of extracellular matrix and connective tissue within the skin. They produce matrix metalloproteinases (MMPs)—zinc-dependent endopeptidases—which can digest all matrix components. The fibroblast also produce the specific inhibitors of MMPs, known as tissue inhibitors of matrix metalloproteinases (TIMPs) [3]. The quantity of ECM components is thought to depend on the equilibrium between MMPs and their inhibitors [4].

The results of the research evaluating the production of collagen by the fibroblast of SSc patients have also been inconclusive. Some authors have demonstrated normal functioning in these cells, while others have found increased fibroblast production of collagen [5, 6].

The role of TIMP-1 in the pathogenesis of SSc has been well described in previous studies. Its levels in patients with diffuse SSc (dSSc) were suggested to correlate with the progressive course of dermal fibrosis seen in early disease [79].

TIMP-2 is an important member of the TIMPs. It was demonstrated that an increased concentration of TIMP-2 may play a certain role in the development of SSc [9]. It was also suggested that TIMP-2 may have a role in the pathogenesis of pulmonary fibrosis in SSc [10].

The fibrillar collagen matrix is an important constituent of the left ventricular myocardium. It contributes to the maintenance of left ventricular geometry and the structural alignment of adjoining myocytes. MMP activity is tightly controlled in normal myocardium by TIMPs. Increased myocardial MMP activity has been reported to occur in both clinical and experimental forms of dilated cardiomyopathy [1116]. Higher serum levels of TIMP-2 were observed in patients with SSc and cardiovascular changes [17].

The purpose of our research was to specify the dependence between the serum concentration of TIMP-2 in patients with SSc and the pulmonary and cardiac dysfunction as detected by CT, echocardiography, and ECG.


MATERIAL AND METHODS
Patients

Forty-two nonsmoking patients affected by SSc, with disease duration equal to or more than 2 years, attending the Rheumatology and Rehabilitation Department, Kasr Eleini Hospital, were recruited in the recent study (thirty-three women, mean age 42.2 ± 11.3, range 19–65 years, and mean disease duration 6.5 ± 5.2 with range 2–25 years).

Twenty-two patients had diffuse form (dSSc) (17 women, mean age 39.9 ± 11.7 with range 19–58 years, and mean duration 6.4 ± 4.6 with range 2–18 years), and 20 patients had limited form (lSSc) (16 women, mean age 44.7 ± 9.9 with range 19–65 years, and mean disease duration 6.6 ± 5.8 with range 2–25 years).

All patients met the American Rheumatism Association preliminary criteria for diagnosis and classification of SSc [18], and the LeRoy et al criteria for subclassification of SSc [19].

Twenty-five normal nonsmoking volunteers (eighteen women, mean age 42.9 ± 12.0, ranging from 21–61 years) were involved as controls.

All patients had complete clinical examination including evaluation for gastrointestinal, pulmonary, cardiac, renal and muscle involvement, in addition to the routine laboratory investigations.

Antinuclear antibodies (ANA) were identified by the indirect immunofluorescence method using HEp-2 cells as a substrate. Anti-Scl-70 antibodies were identified by using ELISA.

Drug treatment—during the period of observation and collection of serum samples for testing—included calcium channel blockers (26 patinets, 14 with dSSc), vasodilators (6 patients, 2 with dSSc), corticosteroids (20 patients,16 with dSSC, 10–40 mg/day), methotrexate (16 patients, 12 with dSSc, 12.5–15 mg/week), and cyclophosphamide (4 patient, 3 with dSSc, IV pulse/month).

Modified Rodnan skin thickness score was used to evaluate the skin involvement. The body was divided into 17 regions (face, anterior chest, abdomen, upper arms, forearms, hands, fingers, thighs, legs, and feet). The degree of skin involvement in each region was scored from 0 to 3 (0 = normal skin, and 3 = extreme thickening) and then summing the score of all the palpated sites [20].

Doppler echocardiography

A two-dimensional method and Doppler echocardiography technique were applied for all patients. Imaging was performed with a Sonos 1000 equipped with 2.5-mHz phased pulsed array transducers (Hewlett-Packard, USA).

High-resolution computed tomography

Pulmonary interstitial disease was assessed by high-resolution computed tomography (HRCT) using Somatom Plus-S (Siemens, Erlangen, Germany) CT units. The HRCT images were divided into upper, middle, and lower areas. For each area of the lung, the following scores were used and then summed for each patient: 0 = no interstitial changes; 1 = thickened septal lines, subpleural lines, parenchymal bands, and subpleural cysts; and 2 = honey combing. Any HRCT scoring above 0 was considered abnormal [21].

Serum levels of tissue inhibitor of metalloproteinases 2 (TIMP-2) was measured by using Biotrak TM TIMP-2 human ELISA system, supplied by Amersham Pharmacia Bioteck. The assay is based on a 2-site ELISA sandwich format. Peroxidase-labeled Fab antibody to TIMP-2 is added to standard sample and the mixture is incubated in microtitre wells precoated with anti-TIMP-2 antibody. The amount of peroxidase is determined by the addition of TMB substrate, and the concentration of TIMP-2 in a sample is determined by interpolation from a standard curve.

The cutoff value at and above which the level was considered abnormal (2 SD above the mean in the control subjects) for TIMP-2 was settled at 68.7 ng/mL (mean serum level in the controls was 39.1 ± 14.8 ng/mL).

Statistical analysis

The results were expressed as mean ± SD, and analyzed statistically by using the Mann-Witney test and Chi square with Fisher exact test when appropriate. P value less than .05 was regarded as statistically significant.


RESULTS

The serum levels of TIMP-2 in the patients ranged from 23–274 ng/mL, and the mean concentration was 78.3 ± 71.9 ng/mL, while in the controls it ranged from 23–73 ng/mL, and the mean concentration was 36.4 ± 10.5 ng/mL. The difference between the means of the patients and the controls was statistically significant (P = .005).

The mean concentration of TIMP-2 in patients with dSSc was 94.6 ± 79.8 ng/mL, with range 31–274 ng/mL, with significant difference when compared to controls (P = .0007). While the mean concentration in patients with lSSc was 61.3 ± 58.5 ng/mL with range 23–243 ng/mL, without significant difference when compared to the controls (P = .051). The difference between the mean concentrations of the dSSc patients and the lSSc patients was nonsignificant (P > .05).

Anticentromere antibodies were detected in 16 patients (38.1%); all of them had lSSc (80% of the patients with lSSc). While anti-Scl-70 antibodies were detected in 19 patients (45.2%), 18 patients had dSSc (81.8% of patients with dSSc), and 1 patient had lSSc (5% of patients with lSSc).

In patients with dSSc, a significant positive correlation was observed between the serum levels of TIMP-2 on the one hand and the age of patients (P = .02) and CT score (P = .05) on the other hand. In patients with lSSc, no significant correlation was observed between TIMP-2 levels and any of the other variables.

Fourteen patients showed elevated serum levels of TIMP-2 above the cutoff value (9 patients had dSSc).

TIMP-2 in patients with dSSc

Nine patients out of 22 with dSSc (40.9%) showed elevated serum levels above the cutoff value. Patients were divided into two groups: patients with elevated serum levels of TIMP-2 (group 1), and patients with normal levels (group 2).

The mean duration in group 1 was 5.3 ± 2.7 years (range 2–10 years). The mean duration of patients in group 2 was 7.2 ± 5.8 (range 2–18 years), and the difference between the two groups was nonsignificant (P > .05).

The mean Rodnan score of patients in group 1 was 22±11 (range 8–42), while in group 2 it was 17 ± 7.3 (range 6–30), and the difference was nonsignificant (P > .05).

For all dSSc patients, the mean HRCT score was 4.9 ± 4.9 (range 0–14). Six patients showed normal lungs by HRCT, and the remaining 16 patients showed different types of lung lesions.

The mean CT score of the patients in group 1 was 6.1±5.7 (range 0–14), and in group 2 it was 2.8±2.9 (range 0–10), and the difference between the two groups was significant (P = .013) (Figure 1).

The difference between the frequency of cardiac abnormalities in group 1 and group 2 was statistically nonsignificant (Table 1).

No statistically significant difference was found between the two groups concerning any of the other disease's parameters (Table 1).

TIMP-2 in patients with lSSc

Five lSSc patients showed elevated serum levels of TIMP-2 above the cutoff value. Patients with lSSc were further divided into two groups: patients with elevated serum levels of TIMP-2 (group 3), and patients with normal levels (group 4).

The duration of disease in 5 patients in group 3 was more than 4 years, and the mean duration was 12.4 ± 7.5 years (range 6–25 years). The mean duration of patients in group 4 was 4.6 ± 3.7 (range 2–12), and the difference between the two groups was significant (P = .014).

The mean Rodnan score of patients in group 3 was 10.6±2.1 (range 8–13), while in group 4 it was 11.3±4.2 (range 6–21), and the difference was nonsignificant (P > .05).

For all lSSc patients the mean HRCT score was 3.9 ± 3.3 (range 0–10). Six patients showed normal lungs by HRCT, and the remaining 14 patients showed different types of lung lesions.

The mean CT score of the patients in group 3 was 5.4±3.3 (range 0–8), and in group 4 it was 3.3 ± 3.3 (range 0–10), and the difference between the two groups was nonsignificant (P > .05) (Figure 2).

Diastolic dysfunction was the commonest echocardiographic finding found among patients with lSSc. Four patients out of five in group 3 showed diastolic dysfunction (80%), compared to1 out of 15 in group 4 (13.3%) with P = .014. The lSSc patient who had the highest TIMP-2 levels (243 ng/mL) had left atrial and left ventricular hypertrophy. One patient in group 3 had RBBB and LAHB.

No statistically significant difference was found between the two groups concerning any of the other disease's parameters (Table 2).


DISCUSSION

In the recent study, we investigated the relation between the serum levels of TIMP-2 and cardiac and pulmonary involvement in SSc patients with duration equal to or more than 2 years.

There are many factors that affect the development of fibrosis in scleroderma. Many studies pointed to the role of metalloproteinases and their inhibitors in this process [2225]. More than 20 human metalloproteinases have been described [26]. Among these metalloproteinases are collagenases, gelatinases, elastases, stromelisine, and membrane metalloproteinases [27].

The production of metalloproteinases is regulated by cytokines and growth factors. Their activity is also affected by TIMPs [28].

The quantity of ECM components is thought to depend on the equilibrium between MMPs and their inhibitors, the TIMPs. The disruption of this equilibrium is of essential significance both in the pathomechanism of physiological processes such as healing of wounds or involution of the uterus and in the process of angiogenesis as well as in certain diseases such as tumor growth and metastasis [4].

MMPs and TIMPs may play an important role in various rheumatic diseases. MMP-3 was suggested to be an important factor in the pathogenesis of systemic lupus erythematosus and rheumatoid arthritis. Serum MMP-9 activity in patients with diffuse cutaneous SSc was significantly decreased compared with that of limited cutaneous SSc or normal controls [8]. The role of TIMP-1 in the pathogenesis of SSc has been well described in previous studies. Increased levels of both MMP-1 and TIMP-1 were found to be correlated with the disease severity [7, 8]. TIMP-1 level was reported to be a useful indicator of disease activity, especially of lung fibrosis [29].

The previous studies reported contradictory results concerning the role of TIMP-2 in SSc patients. While Yazawa et al demonstrated that Serum TIMP-2 level could be a useful marker of the extent of skin sclerosis and disease activity and the balance of TIMP-2 and MMP-2 might play an important role in the pathogenesis of the disease [9]. Young-Min et al found no difference in serum levels of TIMP-2 between patients of SSc and controls [7].

The recent study showed a significant difference between patients and controls concerning the serum TIMP-2 levels (P = .005), and this difference was more significant when comparing patients with dSSc and controls (P = .0007).

TIMPs were accused for being responsible for acceleration of dermal fibrosis in early stages of the disease. Zurita-Salinas et al reported increased TIMP-1 levels in fibroblasts only from patients with early stages SSc [30]. Young-Min have demonstrated that TIMP-1 levels were significantly higher in early disease (< 2 years) than in late stage disease (> 4 years) in patients with diffuse form of SSc [7].

In the recent study, the duration of disease in all patients was equal to or more than 2 years to avoid considering skin involvement as an associated factor. No relation was reported between the skin scoring and the serum TIMP-2 levels in this study. The duration of disease was significantly longer in lSSc patients with elevated levels of TIMP-2 (group 3) compared to lSSc with normal levels (group 4) with P < .05.

No relation could be found between TIMP-2 levels and anti-Scl-70 (anti-topoisomerase 1) nor anticentromere antibodies. Kikuchi et al [8] found an association between TIMP-1 levels and anti-Scl-70. Young-Min et al [7] found no relation between TIMP-1, TIMP-2, or MMP-1 and anti-Scl-70 or anticentromere antibody.

MMPs and TIMPs have been shown to exist in various tissues, including myocardium, and to be involved in collagen remodeling [1316]. TIMP-2 and TIMP-3 were found to have important and unique roles in early cardiac development [31]. Changes in the balance between matrix deposition and matrix degradation by MMPs and their inhibitors TIMPs can lead to cardiac fibrosis [32]. It was suggested that MMPs could be responsible for induction of cardiac and pulmonary lesions in patients with sarcoidosis by causing damage to adjacent cardiac myocytes and pulmonary alveoli, leading to the interstitial fibrosis [33].

In the recent study, the mean lung CT score in dSSc patients with elevated TIMP-2 levels (group 1) was significantly more than in patients with normal levels (group 2) (P = .013). This finding supports the results of Dziankowska-Bartkowiak et al [10] who suggested a possible role of TIMP-2 in the development of pulmonary fibrosis.

Diastolic dysfunction was the most common echocardiographic finding found among lSSc patients. Eighty % of group 3 showed diastolic dysfunction compared to 13.3% of group 4 with P = .014. It has been suggested that left ventricular relaxation pattern is a feature of SSc [34, 35], and could be explained by myocardial fibrosis [36].

Cardiac involvement is not rare in SSc, and it may be primary or secondary to lung involvement [3740]. The recent findings suggest a probable role of TIMP-2 in the development of myocardial fibrosis in SSc patients. A higher serum TIMP-2 levels were observed in a previous study in SSc patients with cardiovascular changes [17].


CONCLUSION

This study, though involving a small group of patients, confirms the observations made by other authors regarding the probable role of TIMP-2 in inducing fibrosis in the course of SSc, and suggests a possible role of TIMP-2 in the development of pulmonary involvement in dSSc patients, and cardiac lesions in lSSc patients, with disease duration equal to or more than 2 years.


References
1. Mauch C,Eckes B,Hunzelmann N,Oono T,Kozlowska E,Krieg T. Control of fibrosis in systemic sclerodermaJournal of Investigative Dermatology 1993;100(1):92S–96S. [pmid: 8423407]
2. Varga J,Jimcncz SA. Clements PJ,Furst DEPathogenesis of scleroderma, cellular aspectsSystemic Sclerosis 1996Baltimore, Md: Williams and Wilkins; :304–321.
3. Mattila L,Airola K,Ahonen M,et al. Activation of tissue inhibitor of metalloproteinases-3 (TIMP-3) mRNA expression in scleroderma skin fibroblastsJournal of Investigative Dermatology 1998;110(4):416–421. [pmid: 9540985]
4. Baker T,Tickle S,Wasan H,Docherty A,Isenberg D,Waxman J. Serum metalloproteinases and their inhibitors: markers for malignant potentialBritish Journal of Cancer 1994;70(3):506–512. [pmid: 8080738]
5. Uitto J,Bauer EA,Eisen AZ. Scleroderma. Increased biosynthesis of triple-helical type I and type III procollagens associated with unaltered expression of collagenase by skin fibroblasts in cultureJournal of Clinical Investigation 1979;64(4):921–930. [pmid: 90059]
6. LeRoy EC. Increased collagen synthesis by scleroderma skin fibroblasts in vitro. A possible defect in the regulation or activation of the scleroderma fibroblastJournal of Clinical Investigation 1974;54(4):880–889. [pmid: 4430718]
7. Young-Min SA,Beeton C,Laughton R,et al. Serum TIMP-1, TIMP-2, and MMP-1 in patients with systemic sclerosis, primary Raynaud's phenomenon, and in normal controlsAnnals of the Rheumatic Diseases 2001;60(9):846–851. [pmid: 11502611]
8. Kikuchi K,Kubo M,Sato S,Fujimoto M,Tamaki K. Serum tissue inhibitor of metalloproteinases in patients with systemic sclerosisJournal of the American Academy of Dermatology 1995;33(6):973–978. [pmid: 7490368]
9. Yazawa N,Kikuchi K,Ihn H,et al. Serum levels of tissue inhibitor of metalloproteinases 2 in patients with systemic sclerosisJournal of the American Academy of Dermatology 2000;42(1 pt 1):70–75. [pmid: 10607322]
10. Dziankowska-Bartkowiak B,Waszczykowska E,Luczyńska M,Zalewska A,Sysa-Jędrzejowska A. Serum levels of tissue inhibitor of metalloproteinases 2 in systemic sclerosis: a preliminary studyMedical Science Monitor 2002;8(2):CR108–CR112. [pmid: 11859283]
11. Weber KT,Pick R,Janicki JS,Gadodia G,Lakier JB. Inadequate collagen tethers in dilated cardiopathyAmerican Heart Journal 1988;116(6 pt 1):1641–1646. [pmid: 3195449]
12. Gunja-Smith Z,Morales AR,Romanelli R,Woessner JF Jr. Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy: role of metalloproteinases and pyridinoline cross-linksAmerican Journal of Pathology 1996;148(5):1639–1648. [pmid: 8623931]
13. Werb Z,Alexander CM. Kelly WN,Harris ED,Ruddy S,Sledge CBProteinases and matrix degradationTextbook of Rheumatology 1993New York, NY: WB Saunders; :248–268.
14. Stetler-Stevenson WG. Dynamics of matrix turnover during pathologic remodeling of the extracellular matrixAmerican Journal of Pathology 1996;148(5):1345–1350. [pmid: 8623905]
15. Woessner JF Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodelingFASEB Journal 1991;5(8):2145–2154. [pmid: 1850705]
16. Tyagi SC,Kumar S,Voelker DJ,Reddy HK,Janicki JS,Curtis JJ. Differential gene expression of extracellular matrix components in dilated cardiomyopathyJournal of Cellular Biochemistry 1996;63(2):185–198. [pmid: 8913870]
17. Dziankowska-Bartkowiak B,Waszczykowska E,Zalewska A,Sysa-Jędrzejowska A. Correlation of endostatin and tissue inhibitor of metalloproteinases 2 (TIMP2) serum levels with cardiovascular involvement in systemic sclerosis patientsMediators of Inflammation 2005;2005(3):144–149. [pmid: 16106100]
18. Masi AT,Rodnan GP,Medsger TA. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria CommitteeArthritis and Rheumatism 1980;23(5):581–590. [pmid: 7378088]
19. LeRoy CE,Black C,Fleischmajer R,et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesisJournal of Rheumatology 1988;15(2):202–205. [pmid: 3361530]
20. Clements P,Lachenbruch P,Siebold J,et al. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosisJournal of Rheumatology 1995;22(7):1281–1285. [pmid: 7562759]
21. Morelli S,Barbieri C,Sgreccia A,et al. Relationship between cutaneous and pulmonary involvement in systemic sclerosisJournal of Rheumatology 1997;24(1):81–85. [pmid: 9002015]
22. Takeda K,Hatamochi A,Ueki H,Nakata M,Oishi Y. Decreased collagenase expression in cultured systemic sclerosis fibroblastsJournal of Investigative Dermatology 1994;103(3):359–363. [pmid: 8077701]
23. Yazawa N,Kikuchi K,Ihn H,et al. Serum levels of tissue inhibitor of metalloproteinases 2 in patients with systemic sclerosisJournal of the American Academy of Dermatology 2000;42(1 pt 1):70–75. [pmid: 10607322]
24. Mattila L,Airola K,Ahonen M,et al. Activation of tissue inhibitor of metalloproteinases-3 (TIMP-3) mRNA expression in scleroderma skin fibroblastsJournal of Investigative Dermatology 1998;110(4):416–421. [pmid: 9540985]
25. Kikuchi K,Kadono T,Furue M,Tamaki K. Tissue inhibitor of metalloproteinase 1 (TIMP-1) may be an autocrine growth factor in scleroderma fibroblastsJournal of Investigative Dermatology 1997;108(3):281–284. [pmid: 9036925]
26. Raza SL,Cornelius LA. Matrix metalloproteinases: pro- and anti-angiogenic activitiesJournal of Investigative Dermatology Symposium Proceedings 2000;5(1):47–54.
27. Kähäri V-M,Saarialho-Kere U. Matrix metalloproteinases in skinExperimental Dermatology 1997;6(5):199–213. [pmid: 9450622]
28. Greene J,Wang M,Liu YE,Raymond LA,Rosen C,Shi YE. Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4Journal of Biological Chemistry 1996;271(48):30375–30380. [pmid: 8939999]
29. Toubi E,Kessel A,Grushko G,Sabo E,Rozenbaum M,Rosner I. The association of serum matrix metalloproteinases and their tissue inhibitor levels with scleroderma disease severityClinical and Experimental Rheumatology 2002;20(2):221–224. [pmid: 12051403]
30. Zurita-Salinas CS,Krötzsch E,Díaz De León L,Alcocer-Varela J. Collagen turnover is diminished by different clones of skin fibroblasts from early- but not late-stage systemic sclerosisRheumatology International 2004;24(5):283–290. [pmid: 14600784]
31. Brauer PR,Cai DH. Expression of tissue inhibitor of metalloproteinases (TIMPs) during early cardiac developmentMechanisms of Development 2002;113(2):175–179. [pmid: 11960708]
32. Siwik DA,Colucci WS. Regulation of matrix metalloproteinases by cytokines and reactive oxygen/nitrogen species in the myocardiumHeart Failure Reviews 2004;9(1):43–51. [pmid: 14739767]
33. González AA,Segura AM,Horiba K,et al. Matrix metalloproteinases and their tissue inhibitors in the lesions of cardiac and pulmonary sarcoidosis: an immunohistochemical studyHuman Pathology 2002;33(12):1158–1164. [pmid: 12514782]
34. Fujimoto S,Kagoshima T,Nakajima T,Dohi K. Doppler echocardiographic assessment of left ventricular diastolic function in patients with progressive systemic sclerosisCardiology 1993;83(4):217–227. [pmid: 8281537]
35. Bogdanov AP,Malov AG,Moiseev SV,Guseva NG. The assessment of left ventricular diastolic function in patients with systemic scleroderma by radionuclide ventriculographyTerapevticheskii Arkhiv 1995;67(4):30–32. [pmid: 7784969]
36. Valentini G,Vitale DF,Giunta A,et al. Diastolic abnormalities in systemic sclerosis: evidence for associated defective cardiac functional reserveAnnals of the Rheumatic Diseases 1996;55(7):455–460. [pmid: 8774164]
37. Valentini G,Maione S. Cardiopathy in systemic sclerosisRecenti Progressi in Medicina 1996;87(11):557–63. [pmid: 9122540]
38. D'Angelo WA,Fries JF,Masi AT,Shulman LE. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controlsAmerican Journal of Medicine 1969;46(3):428–440. [pmid: 5780367]
39. Kostis JB,Seibold JR,Turkevich D,et al. Prognostic importance of cardiac arrhythmias in systemic sclerosisAmerican Journal of Medicine 1988;84(6):1007–1015. [pmid: 3376974]
40. Follansbee WP. The cardiovascular manifestations of systemic sclerosis (scleroderma)Current Problems in Cardiology 1986;11(5):241–298. [pmid: 3487417]

Figures

[Figure ID: F1]
Figure 1 

Linear regression line fit plot showing the significant relation between TIMP-2 levels and CT score in DSSc patients.



[Figure ID: F2]
Figure 2 

Linear regression line fit plot showing the nonsignificant relation between TIMP-2 levels and CT score in lSSc patients.



Tables
[TableWrap ID: T1] Table 1 

Clinical and laboratory data of dSSc patients, dSSc patients with elevated levels of TIMP-2 (Group 1), and dSSc patients with normal levels (Group 2).


Parameter dSSc patients (n = 22) Group 1 (n = 9) Group 2 (n = 13) P

Age (years)a 39.9 ± 11.7 39.9 ± 6.1 39 ± 16.2 NS
Duration (years)a 6.4 ± 4.6 5.3 ± 2.7 7.2 ± 5.8 NS
ESRa 44.4 ± 23.9 54.3 ± 30.2 33.3 ± 9.9 NS
TIMP-2 (ng/ml)a 94.6 ± 79.8 168.1 ± 79.1 43.7 ± 10.6 P = .05
Rodnan skin scorea 19 ± 9.1 22 ± 11 17 ± 7.3 NS
Raynaud's phenomenonb 18 (81.8) 7 (77.8) 11 (84.6) NS
Esophageal dysmotilityb 16 (72.7) 7 (77.8) 9 (69.2) NS
Telangectasiab 4 (18.2) 1 (11.1) 3 (23.1) NS
Hypertensionb 9 (40.9) 2 (22.2) 7 (53.9) NS
HRCT scorea 4.9 ± 4.9 6.1 ± 5.7 2.8 ± 2.9 P = .05
Cardiac lesionb 7 (31.8) 4 (44.4) 3 (23.1) NS
Valvular lesionb 4 (18.2) 2 (22.2) 2 (15.4) NS
Diastolic dysfunctionb 1 (4.5) 1 (11.1) 0 NS
Conduction defect 2 (9.1) 1 (11.1) 1 (7.7) NS
Cardiomegally 2 (9.1) 1 (11.1) 1 (7.7) NS
Anti-Scl-70 18 (81.8) 8 (88.9) 10 (76.9) NS
A.centro.b 0 0 0

TF1aMean ± SD.

TF2bNumber (%).

dSSc: diffuse systemic sclerosis.

ESR: erythrocyte sedimentation rate.

A.centro.: anticentromere antibodies.

Mann-Whitney test, chi-square with Fisher's exact test, and Student t test were used.


[TableWrap ID: T2] Table 2 

Clinical and laboratory data of lSSc patients, lSSc patients with elevated levels of TIMP-2 (Group 3), and lSSc patients with normal levels (Group 4).


Parameter lSSc patients (n = 20) Group 3 (n = 5) Group 4 (n = 15) P

Age (years)a 44.7 ± 9.9 49.2 ± 10.6 43.1 ± 9.7 NS
Duration (years)a 6.6 ± 5.8 12.4 ± 7.5 4.6 ± 3.7 P=.014
ESRa 50.3 ± 25.8 52 ± 40.9 49.7 ± 20.7 NS
TIMP-2 (ng/ml)a 61.3 ± 58.5 145.4 ± 65.6 33.2 ± 6.6 P = .05
Rodnan skin scorea 13.8 ± 8.9 10.6 ± 2.1 11.3 ± 4.2 NS
Raynaud's phenomenonb 19 (95) 5 (100) 14 (93.3) NS
Esophageal dysmotilityb 15 (75) 4(80) 11 (73.3) NS
Telangectasiab 6 (30) 1 (20) 5 (33.3) NS
Hypertensionb 1 (5) 0 1 (6.7) NS
HRCT scorea 3.9 ± 3.3 5.4 ± 3.3 3.3 ± 3.3 NS
Cardiac lesionb 8 (40) 4 (80) 4 (26.7) NS
Valvular lesionb 5 (25) 1 (20) 4 (26.7) NS
Diastolic dysfunctionb 6 (30) 4 (80) 2 (13.3) P = .014
A.centro.b 16 (80) 4 (80) 12 (80) NS

TF3aMean ± SD (range).

TF4bNumber (%).

lSSc: limited systemic sclerosis.

ESR: erythrocyte sedimentation rate.

A.centro.: anticentromere antibodies.

Mann-Whitney test, chi-square with Fisher's exact test, and Student t test were used.



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