SYSTEMIC TRANSFORMING-GROWTH-FACTOR-BETA IN PATIENTS WITH BONE-MARROWFIBROSIS - PATHOPHYSIOLOGICAL IMPLICATIONS

Idiopathic myelofibrosis (IMF) and secondary myelofibrosis (MF) are ch aracterized by bone marrow (BM) fibrosis, neoangiogenesis, and increas ed extracellular matrix (ECM) proteins. These characteristics may be p artially attributed to transforming growth factor beta (TGF-beta), a c ytokine produced by monocytes, In myelofibrosis, monocytes are increas ed and activated with concomitant up-regulation of intracytoplasmic TG F-beta. We have therefore determined systemic TGF-beta in patients wit h either BM fibrosis: IMF, n = 18; MF, n = 16; or without BM fibrosis: hematologic disorders with normal platelets (n = 31); high platelets (n = 9); or normal controls (n = 27), Compared with nonfibrosis sera, there was significant TGF-beta elevation in BM fibrosis sera (P < 0.00 01), Most (>80%) of the TGF-beta is active and belongs to the -beta 1 isoform, In situ hybridization and immunohistochemical analyses in BM biopsy sections showed a marked increase in TGF-beta 1 only in patient s with fibrosis, Moreover, TGF-beta protein was detected mainly in mye lomonocytic-like predominant areas. To determine if another functional ly similar cytokine, basic fibroblast growth factor (bFGF), may be imp ortant to BM fibrosis, we quantitated sera levels and found elevation in 57% compared with 100% elevation for TGF-beta, The data indicate th at irrespective of etiology, systemic TGF-beta is elevated in patients with BM fibrosis, TGF-beta likely plays an important role in the deve lopment of BM fibrosis, The study also provides a significant paramete r for early therapeutic intervention in BM fibrosis, Am, J. Hematol, 5 9:133-142, 1998, (C) 1998 Wiley-Liss, Inc.