Bone Morphogenetic Proteins Are Overexpressed in the Bone Marrow of Primary Myelofibrosis and Are Apparently Induced by Fibrogenic Cytokines

Oliver Bock^*, Julia Höftmann^*, Katharina Theophile^*, Kais Hussein^*, Birgitt Wiese, Jerome Schlué^* and Hans Kreipe^*

From the Institute of Pathology,^* and the Institute of Biometrics, Hannover Medical School, Hannover, Germany

Primary myelofibrosis (PMF) is a myeloproliferative neoplasiacharacterized by progressive deposition of extracellular matrixcomponents in the bone marrow. The involvement of members ofthe bone morphogenetic protein (BMP) family in aberrant bonemarrow matrix homeostasis in PMF has not yet been investigated.Therefore, we analyzed expression of BMP1, an activator of latenttransforming growth factor β-1 (TGFβ-1) and processorof collagen precursors, and other BMPs in bone marrow from PMFpatients and controls (n = 95). Expression of BMP1, BMP6, BMP7,and BMP-receptor 2 was significantly increased in advanced stagesof myelofibrosis compared with controls (P $≤$ 0.01), and enhancedlevels of BMP6 expression were already evident in prefibroticstages of PMF. Immunohistochemistry showed that bone marrowstromal cells and megakaryocytes were the major cellular sourcesof BMP1 protein. Because TGFβ-1 and basic fibroblast growthfactor have been shown to be important in the development ofmyelofibrosis, we studied the induction of BMPs by these cytokinesin cultured fibroblasts. Fibroblasts treated with TGFβ-1showed a pronounced up-regulation of BMP6, suggesting that stromalcells may be susceptible to BMP activation by cytokines witha proven role in the pathogenesis of PMF. We conclude that BMPfamily members may play an important role in the pathogenesisof myelofibrosis in PMF and are apparently induced by cytokinessuch as TGFβ-1.