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Elevated plasma levels of TIMP-1 correlate with plasma suPAR/uPA in patients with chronic myeloproliferative disorders

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Jensen MK, Holten-Andersen MN, Riisbro R, de Nully Brown P, Larsen MB, Kjeldsen L, Heickendorff L, Brünner N, Hasselbalch HC. Elevated plasma levels of TIMP-1 correlate with plasma suPAR/uPA in patients with chronic myeloproliferative disorders.

Eur J Haematol 2003: 71: 377–384. © Blackwell Munksgaard 2003. Abstract:

Chronic myeloproliferative disorders (MPD) are characterized by progressive remodelling of bone marrow stroma as evidenced by increased deposition of extracellular matrix proteins, neoangiogenesis and displacement of normal haematopoietic cells by fibrotic tissue. The family of metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) serve to facilitate and inhibit matrix degradation processes, respectively. In an attempt to investigate potential markers for bone marrow remodelling processes, we investigated plasma levels of total-, free- and complexed TIMP-1, TIMP-2, MMP-2 and MMP-9 in a patient cohort comprising 17 with myelofibrosis (MF), 17 with polycythaemia vera (PV), 15 with essential thrombocythaemia (ET), 1 with a transitional MPD and 30 controls. Compared with controls, total- (P < 0.0001) (median: 132.6 g/L vs. 80.8 g/L), free- (P < 0.0001) (median: 126.4 g/L vs. 65.8 g/L) and complexed TIMP-1 (P = 0.0009) (median: 17.7 g/L vs. 10.7 g/L) concentration was significantly higher in the patients. TIMP-1 was significantly correlated with plasma soluble urokinase plasminogen activator receptor (P = 0.003) and urokinase plasminogen activator (P < 0.0001), respectively, suggesting a common cellular origin. No statistical significant difference between TIMP-2 and MMP-2 levels was observed between patients and controls. Furthermore, a significant correlation between free TIMP-1 and TIMP-2 levels was detected (r = 0.56; P < 0.0001). Median MMP-9 concentration was significantly higher among PV patients compared with controls (P = 0.0015), and 41% of patients with PV (7/17) had MMP-9 values that were above the mean + 2SD of plasma MMP-9 levels found in controls. The ratio of total TIMP-1/MMP-9 was significantly higher in patients with MF compared with controls (P = 0.0004). These findings suggest that a disturbed TIMP-1/MMP ratio may reflect an imbalance of the extracellular homeostasis towards an increased matrix deposition promoting fibrosis.
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Keywords: bone marrow remodelling; fibrosis; metalloproteinase; myeloproliferative disorders; tissue inhibitor of metalloproteinase

Document Type: Research Article

Affiliations: 1: Department of Haematology L 2: Finsen Laboratory, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark 3: Department of Clinical Biochemistry, Aarhus Amtssygehus, University Hospital of Aarhus, Denmark

Publication date: November 1, 2003

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