title: Bone morphogenetic proteins are overexpressed in the bone marrow of primary myelofibrosis and are apparently induced by fibrogenic cytokines.
abstract: Primary myelofibrosis (PMF) is a myeloproliferative neoplasia characterized by progressive deposition of extracellular matrix components in the bone marrow. The involvement of members of the bone morphogenetic protein (BMP) family in aberrant bone marrow matrix homeostasis in PMF has not yet been investigated. Therefore, we analyzed expression of BMP1, an activator of latent transforming growth factor beta-1 (TGFbeta-1) and processor of collagen precursors, and other BMPs in bone marrow from PMF patients and controls (n = 95). Expression of BMP1, BMP6, BMP7, and BMP-receptor 2 was significantly increased in advanced stages of myelofibrosis compared with controls (P < or = 0.01), and enhanced levels of BMP6 expression were already evident in prefibrotic stages of PMF. Immunohistochemistry showed that bone marrow stromal cells and megakaryocytes were the major cellular sources of BMP1 protein. Because TGFbeta-1 and basic fibroblast growth factor have been shown to be important in the development of myelofibrosis, we studied the induction of BMPs by these cytokines in cultured fibroblasts. Fibroblasts treated with TGFbeta-1 showed a pronounced up-regulation of BMP6, suggesting that stromal cells may be susceptible to BMP activation by cytokines with a proven role in the pathogenesis of PMF. We conclude that BMP family members may play an important role in the pathogenesis of myelofibrosis in PMF and are apparently induced by cytokines such as TGFbeta-1.
authors: Assistant Professor, Institute of Pathology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, Germany. Bock.Oliver@MH-Hannover.de
authors: Oliver
authors: O
authors: Bock
authors: Julia
authors: J
authors: Höftmann
authors: Katharina
authors: K
authors: Theophile
authors: Kais
authors: K
authors: Hussein
authors: Birgitt
authors: B
authors: Wiese
authors: Jerome
authors: J
authors: Schlué
authors: Hans
authors: H
authors: Kreipe
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D050505:Mutant Proteins / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000378:metabolism* / Q000473:pathology*; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D050505:Mutant Proteins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; C479138:PLOD2 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D052006:Bone Morphogenetic Protein Receptors, Type II