Systemic transforming growth factor-beta in patients with bone marrow fibrosis—pathophysiological implications

Abstract

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-), a cytokine produced by monocytes. In myelofibrosis, monocytes are increased and activated with concomitant up-regulation of intracytoplasmic TGF-. We have therefore determined systemic TGF-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-elevation in BM fibrosis sera (P < 0.0001). Most (>80%) of the TGF-is active and belongs to the −1 isoform. In situ hybridization and immunohistochemical analyses in BM biopsy sections showed a marked increase in TGF-1 only in patients with fibrosis. Moreover, TGF-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-. The data indicate that irrespective of etiology, systemic TGF-is elevated in patients with BM fibrosis. TGF-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. Am.

The effects of a single high-dose injection of vitamin-D on healing of condylar fractures in osteoporotic rats

“…16,19,21 TGFβ1 regulates osteoblast differentiation and plays a key role in tissue repair. 17,18 We found that TGFβ1 expression was significantly higher in the group D than the control group, consistent with earlier results. Van Leeuwen et al showed that production of osteocalcin and osteopontin by osteoblasts was stimulated by vitamin D. 19 We found that osteopontin expression was significantly higher in the group D than control group, again consistent with earlier results.…”

“…13,14,43 Positive effect of vitamin D on bone; It increases TGF synthesis and release, regulates osteoblast differentiation, stimulates tissue repair and osteocalcin and osteopontin production. [16][17][18][19][20][21] The use of vitamin D to accelerate fracture healing will allow an early return to daily activity by, and reduce the morbidity of, patients with condylar fractures associated with osteoporosis. We explored the effects of a single high-dose systemic injection of vitamin D on condylar fracture healing in osteoporotic rats.…”

“…[12][13][14][15] Positive effect of vitamin D on bone; it increases TGF synthesis and release, regulates osteoblast differentiation, stimulates tissue repair and osteocalcin and osteopontin production. [16][17][18][19][20][21] Although many recent studies have evaluated the effects of vitamin D on fracture healing in general, the effects of vitamin D injection on condylar fracture healing, particularly in osteoporotic patients, have been but rarely investigated. We aimed to evaluate the positive effect of vitamins on the condyle fractures treated with closed reduction of the patients with high risk of poor recovery such as advanced age, metabolic or primary bone diseases or malnoutrevulation.…”

Aberrant expression of transforming growth factor β‐1 (TGFβ‐1) per se does not discriminate fibrotic from non‐fibrotic chronic myeloproliferative disorders

“…Previous studies have demonstrated elevated intracellular levels of TGFβ‐1 in platelets, megakaryocytes, and peripheral blood mononuclear cells as well as higher plasma concentrations in patients with IMF 23–26 and provide clinical evidence for a potential pivotal role of TGFβ‐1 in bone marrow fibrosis. However, there is a lack of data regarding TGFβ‐1 gene expression level in haematopoiesis, megakaryocytes, as well as total bone marrow cells, in different CMPD subtypes.…”

Comparing transforming growth factor‐β2, talc and bleomycin as pleurodesing agents in sheep

“…Transforming growth factor‐β is a potent profibrotic cytokine and extensive evidence has shown that its overexpression plays a crucial role in mediating the fibrotic process, 12,20 including pulmonary fibrosis, 21 pneumoconiosis, 22 radiation fibrosis, 23 myelofibrosis, 24 peritoneal adhesions 25 and hypertrophic scarrings 26 . Conversely, strategies targeted at neutralizing TGF‐β activity can reduce fibrotic damage in the lung, 27–29 liver 30,31 and skin 32 .…”