Related Experiment Videos
The role of transforming growth factor-beta in PEG-rHuMGDF-induced reversible myelofibrosis in rats
1Pharmaceutical Development Laboratory, Kirin Brewery Co. Ltd, Gunma, Japan.
Abstract:
Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) injected at a suprapharmacologic dose (100 microg/kg) daily for 5 d in normal rats caused marked increases in marrow megakaryocytes and platelet counts at 6-8 d followed by gradual decreases to control levels at 10-20 d. Interestingly, in addition to the expected thrombopoiesis, PEG-rHuMGDF was associated with myelofibrosis with a predominance of reticulin fibres at day 10 followed by complete normalization by day 20. At 6-8 d, the levels of transforming growth factor-beta1 (TGF-beta1) in the extracellular fluid of the marrow, the platelet poor plasma, and the platelet extract were increased 23-, 7- and 2-fold, respectively. The elevated levels of TGF-beta1 were gradually reduced to baseline levels at 13-20 d in accordance with the normalization of myelofibrosis and thrombopoiesis. An ultrastructural analysis showed that large fragments of megakaryocytes were deposited in the marrow parenchyma of PEG-rHuMGDF-treated rats at day 6. PEG-rHuMGDF administration at pharmacologic doses (1 and 10 microg/kg) did not induce the deposition of reticulin fibres in the marrow. These findings suggest that TGF-beta1 leaked from megakaryocytes is involved in the development of the PEG-rHuMGDF-induced myelofibrosis and that this is a reversible process related to the regulation of the excess production of platelets.
Insights
Suprapharmacologic doses of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) induced thrombopoiesis and reversible myelofibrosis in rats. Transforming growth factor-beta1 (TGF-beta1) release from megakaryocytes appears to mediate this myelofibrotic response.
Area of Science:
- Hematology
- Regenerative Medicine
- Fibrosis Research
Background:
- Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a thrombopoietic agent.
- High-dose cytokine administration can have unintended side effects on hematopoietic tissues.
Purpose of the Study:
- To investigate the effects of suprapharmacologic PEG-rHuMGDF dosing on rat bone marrow.
- To explore the role of transforming growth factor-beta1 (TGF-beta1) in PEG-rHuMGDF-induced bone marrow changes.
Main Methods:
- Rats were administered suprapharmacologic doses of PEG-rHuMGDF.
- Bone marrow cellularity, platelet counts, and myelofibrosis were assessed.
- Levels of TGF-beta1 in marrow extracellular fluid, plasma, and platelet extracts were measured.
- Ultrastructural analysis was performed on bone marrow samples.
Main Results:
- Suprapharmacologic PEG-rHuMGDF induced significant thrombopoiesis and transient myelofibrosis characterized by reticulin fiber deposition.
- Elevated TGF-beta1 levels were observed in conjunction with myelofibrosis, decreasing as the condition resolved.
- Large megakaryocyte fragments were found in the bone marrow, suggesting a source for TGF-beta1 release.
- Pharmacologic doses of PEG-rHuMGDF did not induce myelofibrosis.
Conclusions:
- TGF-beta1 released from megakaryocytes likely mediates PEG-rHuMGDF-induced myelofibrosis.
- The myelofibrotic effect of PEG-rHuMGDF is reversible and linked to the regulation of platelet production.