osteoprotegerin and Polycythemia-Vera

Patients with polycythemia vera (PV) have an increased risk for the development of thrombohemorrhagic complications. The pathogenesis of these complications is still unclear. An important role in vascular disease has recently been attributed to osteoprotegerin (OPG). It has been shown that various tissues of the cardiovascular system produce OPG, and there is growing evidence of an association between elevated serum OPG levels and cardiovascular morbidity. We evaluated if OPG was associated with an increased risk of venous thrombosis or bleeding complications in a cohort of 114 PV patients. The analysis consisted of a retrospective and a prospective part. In the retrospective univariate analysis, a one unit change in OPG caused the odds of venous thrombosis to increase by 40% (p=0.005) and the odds of bleeding to increase by 52% (p=0.001). Multivariate analysis only slightly attenuated the association to 33% (p=0.03) and 37% (p=0.013) for venous thrombosis and bleeding, respectively. OPG was also related to the development of the combined outcome of venous thrombosis and bleeding in the prospective analysis (log-rank-test: p=0.017). This is the first report that links the occurrence of venous thrombosis or bleeding to elevated OPG levels.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Female; Glycoproteins; Hemorrhage; Humans; Male; Middle Aged; Osteoprotegerin; Polycythemia Vera; Prospective Studies; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Retrospective Studies; Risk Factors; Venous Thrombosis

Transforming growth factor beta-1 (TGF beta-1) is a potent inducer of fibrosis and has been shown to be essential for the development of bone marrow fibrosis in an animal model of idiopathic myelofibrosis (IMF). IMF belongs to the Philadelphia chromosome negative chronic myeloproliferative disorders (Ph(-) CMPD). Megakaryocytes and platelets have been suggested as the major cellular source of TGF beta-1 in IMF. The osteoclastogenesis inhibitory factor osteoprotegerin (OPG) seems to be regulated by TGF beta-1 and substantial involvement of OPG expression in the process of osteosclerosis in IMF has recently been suggested. In order to determine TGF beta-1 expression in IMF and other Ph(-) CMPD, total bone marrow cells as well as laser-microdissected megakaryocytes were quantitatively analysed by real-time RT-PCR. OPG mRNA expression in fibrotic IMF was correlated with TGF beta-1 mRNA expression in a case-specific manner. Both OPG and TGF beta-1 were detected immunohistochemically in order to delineate cellular origin. When total bone marrow cells were investigated, TGF beta-1 mRNA expression was increased in some but not all cases of IMF (n = 21), with highest values in fibrotic cases. Unexpectedly, increased values were also observed in essential thrombocythaemia (ET, n = 11) when compared to non-neoplastic haematopoiesis (n = 38). Megakaryocytes isolated by laser microdissection displayed elevated TGF beta-1 mRNA levels in most of the CMPD samples with no significant differences discernible between fibrotic IMF, polycythaemia vera (PV) and ET. TGF beta-1 protein was predominantly expressed by the myeloid lineage in Ph(-) CMPD and non-neoplastic haematopoiesis, which, however, displayed lower expression. IMF cases with advanced fibrosis concomitantly overexpressed TGF beta-1 and OPG. Immunohistochemically, OPG expression was found in different stromal cells and a subfraction of megakaryocytes. In conclusion, enhanced TGF beta-1 expression occurs in megakaryocytes as well as myeloid cells in Ph(-) CMPD. TGF beta-1 may be necessary, but is not sufficient, to induce bone marrow fibrosis in IMF because non-fibrotic Ph(-) CMPD entities share this feature with IMF and cannot be discriminated from each other on the basis of TGF beta-1 expression.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Bone Marrow Cells; Chronic Disease; Diagnosis, Differential; Female; Gene Expression; Glycoproteins; Hematopoiesis; Humans; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Male; Megakaryocytes; Microdissection; Middle Aged; Myeloproliferative Disorders; Osteoprotegerin; Polycythemia Vera; Primary Myelofibrosis; Protein Array Analysis; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thrombocythemia, Essential; Transforming Growth Factor beta; Transforming Growth Factor beta1