Rameshwar P, Chang V T, Thacker U F, Gascón P
Department of Medicine-Hematology, UMDNJ-New Jersey Medical School, Newark 07103, USA.
Am J Hematol. 1998 Oct;59(2):133-42. doi: 10.1002/(sici)1096-8652(199810)59:2<133::aid-ajh6>3.0.co;2-z.
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.
特发性骨髓纤维化（IMF）和继发性骨髓纤维化（MF）的特征是骨髓（BM）纤维化、新生血管形成以及细胞外基质（ECM）蛋白增加。这些特征可能部分归因于转化生长因子β（TGF-β），一种由单核细胞产生的细胞因子。在骨髓纤维化中，单核细胞增多并被激活，同时细胞质内TGF-β上调。因此，我们测定了以下患者的全身TGF-β水平：患有BM纤维化的患者，其中IMF患者18例、MF患者16例；或无BM纤维化的患者，包括血小板正常的血液系统疾病患者（31例）、血小板增多患者（9例）或正常对照者（27例）。与无纤维化血清相比，BM纤维化血清中的TGF-β显著升高（P < 0.0001）。大多数（>80%）的TGF-β具有活性，且属于β1亚型。BM活检切片的原位杂交和免疫组化分析显示，仅在纤维化患者中TGF-β1显著增加。此外，TGF-β蛋白主要在骨髓单核细胞样为主的区域检测到。为了确定另一种功能相似的细胞因子碱性成纤维细胞生长因子（bFGF）对BM纤维化是否重要，我们对血清水平进行了定量，发现与TGF-β 100%升高相比，bFGF升高的比例为57%。数据表明，无论病因如何，BM纤维化患者的全身TGF-β均升高。TGF-β可能在BM纤维化的发展中起重要作用。该研究还为BM纤维化的早期治疗干预提供了一个重要参数。
