Systemic transforming growth factor-beta in patients with bone marrow fibrosis--pathophysiological implications.
Idiopathic myelofibrosis (IMF) and secondary myelofibrosis (MF) are characterized by bone marrow (BM) fibrosis, neoangiogenesis, and increased extracellular matrix (ECM) proteins. These characteristics may be partially attributed to transforming growth factor beta (TGF-beta), a cytokine produced by monocytes. In myelofibrosis, monocytes are increased and activated with concomitant up-regulation of intracytoplasmic TGF-beta. We have therefore determined systemic TGF-beta in patients with 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 < 0.0001). Most (>80%) of the TGF-beta is active and belongs to the-beta1 isoform. In situ hybridization and immunohistochemical analyses in BM biopsy sections showed a marked increase in TGF-beta1 only in patients with fibrosis. Moreover, TGF-beta protein was detected mainly in myelomonocytic-like predominant areas. To determine if another functionally similar cytokine, basic fibroblast growth factor (bFGF), may be important to BM fibrosis, we quantitated sera levels and found elevation in 57% compared with 100% elevation for TGF-beta. The data indicate that irrespective of etiology, systemic TGF-beta is elevated in patients with BM fibrosis. TGF-beta likely plays an important role in the development of BM fibrosis. The study also provides a significant parameter for early therapeutic intervention in BM fibrosis.
Department of Medicine-Hematology, UMDNJ-New Jersey Medical School, Newark 07103, USA.
P
P
Rameshwar
V T
VT
Chang
U F
UF
Thacker
P
P
Gascón
D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000502:physiology; D001854:Bone Marrow Cells / Q000378:metabolism; D001856:Bone Marrow Examination; D015550:Cell Degranulation / Q000502:physiology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000378:metabolism* / Q000503:physiopathology; D020033:Protein Isoforms / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000097:blood* / Q000235:genetics / Q000502:physiology*
D020033:Protein Isoforms; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2