Transforming growth factor‐β regulates growth as well as collagen and fibronectin synthesis of human marrow fibroblasts

Abstract

Three growth factors present in platelets, namely platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF), have been implicated in the pathogenesis of bone marrow fibrosis frequently associated with myeloproliferative disorders. In this study, regulation of the proliferation, as well as collagen and fibronectin synthesis from marrow fibroblasts by TGF-beta was investigated. TGF-beta alone at high plating density stimulated the proliferation of cells at low concentrations, but rather showed inhibition at high concentrations in both MPD patients and control subjects. In the presence of PDGF, which has been confirmed to be a main growth factor for marrow fibroblasts, low concentration of TGF-beta inhibited the proliferation at low cell density, but there was no inhibition at high cell density. The synthesis of both type I and type III procollagen was enhanced by high concentrations of TGF-beta in both MPD patients and control subjects, while PDGF or EGF showed no effect. The fibronectin synthesis was also enhanced by TGF-beta, but not by PDGF or EGF. These results suggest that growth and stromal protein synthesis of fibroblasts causing marrow fibrosis are regulated by TGF-beta as well as PDGF and EGF, when these factors are released or leaked from platelets or megakaryocytes into marrow environment in MPD patients.

Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes

“…In other hematologic neoplasms, overproduction of fibers results from an overproduction of cytokines produced by neoplastic or inflammatory cells, such as PDGF-a or -b, TGF-b1 or bFGF. [2][3][4] However, these cytokines do not sufficiently explain the increased risk of marrow failure observed in MDS patients with MF, and in long-term bone marrow cultures, proliferation and differentiation of normal hematopoietic precursors are sufficiently supported by bone marrow mesenchymal cells from MDS patients. 36 Therefore, other reasons should be taken into consideration.…”

“…[1][2][3][4] MF appears to provide independent prognostic information during the course of chronic myeloproliferative disorders. [5][6][7] The World Health Organization (WHO) classification of myelodysplastic syndromes (MDS), 8 which has been discussed controversially, 9,10 considers numerous morphologic, cytogenetic and clinical features known to provide prognostic information not mentioned in the French-American-British classification 11 including histopathologic features, such as an atypical localization of immature precursors (ALIP).…”

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

“…As shown previously, TGF␤-1 is potent in inducing collagen genes and synthesis. 33 Therefore, we also analyzed the induction of PLOD2 and COL1 expression by TGF␤-1 that was not demonstrable in bFGF-treated cultures. Interestingly, BMP7 was no longer detectable on the RT-PCR level under both TGF␤-1 and bFGF culture conditions.…”

The role of transforming growth factor‐β in PEG‐rHuMGDF‐induced reversible myelofibrosis in rats

“…TGF-b is a pleiotropic multifunctional cytokine (the most abundant isoform of TGF-b is TGF-b1), and strongly stimulates the biosynthesis of type I and type III collagen, fibronectin and proteoglycans from fibroblasts (Kimura et al, 1989;Roberts et al, 1986). PDGF is a major mitogen for mesenchymal cells such as fibroblasts and smooth muscle cells (Heldin, 1992;Ross et al, 1986).…”