THE ROLE OF TRANSFORMING-GROWTH-FACTOR-BETA IN PEG-RHUMGDF-INDUCED REVERSIBLE MYELOFIBROSIS IN RATS

Pegylated recombinant human megakaryocyte growth and development facto r (PEG-rHuMGDF) injected at a suprapharmacologic dose (100 mu g/kg) da ily for 5d in normal rats caused marked increases in marrow megakaryoc ytes and platelet counts at 6-8d followed by gradual decreases to cont rol levels at 10-20d. Interestingly, in addition to the expected throm bopoiesis, PEG-rHuMGDF was associated with myelofibrosis with a predom inance of reticulin fibres at day 10 followed by complete normalizatio n by day 20, At 6-8d, the levels of transforming growth factor-beta (T GF-beta 1) in the extracellular fluid of the marrow the platelet poor plasma, and the platelet extract were increased 23-, 7- and 2-fold, re spectively. The elevated levels of TGF-beta 1 were gradually reduced t o baseline levels at 13-20d in accordance with the normalization of my elofibrosis and thrombopoiesis. An ultrastructural analysis showed tha t large fragments of megakaryocytes were deposited in the marrow paren chyma of PEG-rHuMGDF-treated rats at day 6. PEG-rHuMGDF administration at pharmacologic doses (1 and 10 mu g/kg) did not induce the depositi on of reticulin fibres in the marrow. These findings suggest that TGF- beta 1 leaked from megakaryocytes is involved in the development of th e PEG-rHuMGDF-induced myelofibrosis and that this is a reversible proc ess related to the regulation of the excess production of platelets.