title: Elevated plasma levels of TIMP-1 correlate with plasma suPAR/uPA in patients with chronic myeloproliferative disorders.
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 microg/L vs. 80.8 microg/L), free- (P < 0.0001) (median: 126.4 microg/L vs. 65.8 microg/L) and complexed TIMP-1 (P = 0.0009) (median: 17.7 microg/L vs. 10.7 microg/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.
authors.affiliation: Department of Haematology L, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark. mkj@dadlnet.dk
authors.forename: Morten Krogh
authors.initials: MK
authors.lastname: Jensen
authors.forename: Mads Nikolai
authors.initials: MN
authors.lastname: Holten-Andersen
authors.forename: Rikke
authors.initials: R
authors.lastname: Riisbro
authors.forename: Peter
authors.initials: P
authors.lastname: de Nully Brown
authors.forename: Maj Britt
authors.initials: MB
authors.lastname: Larsen
authors.forename: Lars
authors.initials: L
authors.lastname: Kjeldsen
authors.forename: Lene
authors.initials: L
authors.lastname: Heickendorff
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Hans Carl
authors.initials: HC
authors.lastname: Hasselbalch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000097:blood*; D011956:Receptors, Cell Surface / Q000097:blood; D055293:Receptors, Urokinase Plasminogen Activator; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood*
chemical_list: D015415:Biomarkers; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9