The production of tissue inhibitors of metalloproteinases (TIMPs) in megakaryopoiesis: possible role of platelet- and megakaryocyte-derived TIMPs in bone marrow fibrosis.
We quantified tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in serum and plasma in normal control subjects and patients with a low or high platelet count, using one-step sandwich enzyme immunoassays. The serum levels of TIMP-1 and TIMP-2 were 101.1 +/- 13.3 ng/ml, and 82.7 +/- 26.3 ng/ml, respectively, in normal subjects. In patients with an elevated platelet count, such as in essential thrombocytosis, polycythaemia vera, and myelofibrosis, serum levels of TIMP-1 and TIMP-2 were 351.6 +/- 200.9 ng/ml and 148.9 +/- 84.0 ng/ml, respectively. Serum levels of TIMP-1 and TIMP-2 in patients with a low platelet count, such as in aplastic anaemia and idiopathic thrombocytopenic purpura, were 57.2 +/- 25.8 ng/ml and 19.7 +/- 7.68 ng/ml, respectively. The serum level of TIMP-1 was significantly correlated with the platelet count in all subjects. The correlation between the serum level of TIMP-2 and the platelet count was not as strong. The level of TIMP-1 in platelet-depleted plasma was not correlated with the platelet count. Immunohistochemical staining using monoclonal antibodies against TIMP-1 and TIMP-2 showed that megakaryocytes and platelets were positive for both TIMP-1 and TIMP-2, confirming that they are rich sources of TIMPs. TIMP-1 and TIMP-2 stimulated the proliferation of bone marrow fibroblasts, although their effect was less potent than that of TGF-beta and PDGF. Erythroleukaemia and megakaryoblastic cell lines showed the highest secretion of TIMP-1 among the leukaemia cell lines examined. There was no lineage specificity for TIMP-2 secretion. These results suggest that TIMPs released from megakaryocytes or from local platelet coagulation may be important in the development of bone marrow fibrosis.
Murate
T
T
First Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Yamashita
K
K
Isogai
C
C
Suzuki
H
H
Ichihara
M
M
Hatano
S
S
Nakahara
Y
Y
Kinoshita
T
T
Nagasaka
T
T
Yoshida
S
S
Komatsu
N
N
Miura
Y
Y
Hotta
T
T
Fujimoto
N
N
Saito
H
H
Hayakawa
T
T
D001791:Blood Platelet Disorders / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism*; D015152:Blotting, Northern; D002455:Cell Division; D006801:Humans; D007150:Immunohistochemistry; D007945:Leukemia, Lymphoid / Q000378:metabolism / Q000473:pathology; D008533:Megakaryocytes / Q000378:metabolism*; D010976:Platelet Count; D055728:Primary Myelofibrosis / Q000378:metabolism / Q000473:pathology*; D013921:Thrombocytopenia / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2