EVIDENCE FOR INTEGRIN RECEPTOR INVOLVEMENT IN MEGAKARYOCYTE-FIBROBLAST INTERACTION - A POSSIBLE PATHOMECHANISM FOR THE EVOLUTION OF MYELOFIBROSIS

Megakaryocytes are assumed to be functionally linked with the evolutio n of myelofibrosis, complicating chronic myeloproliferative disorders. It has already been shown that megakaryocytes will promote fibroblast growth in vitro when in spatial proximity. Here, we demonstrate that the integrin receptors alpha 3 beta 1 and alpha 5 beta 1 are involved in this megakaryocyte-fibroblast interaction. Upon addition of anti-al pha 3 and -alpha 5 antibodies to megakaryocyte-fibroblast cocultures, fibroblast growth was significantly impaired, and megakaryocyte attach ment to the fibroblast feederlayer was significantly reduced. Unilater al blocking of megakaryocytes with anti-alpha 3 or -alpha 5 antibodies resulted in a suppression of adhesion, probably reflecting the promin ent function of fibronectin receptors on the megakaryocyte surface. Mo reover, the oligopeptide RGDS (Asp-Gly-Asp-Ser) caused a significant r eduction of fibroblast growth as well as megakaryocyte adhesion. This feature reinforces that fibronectin receptors are involved. In additio n, fibroblast proliferation was impaired by the application of fibrone ctin antibodies recognizing the cell-binding domain. However, no effec t was observable with respect to megakaryocyte adhesion. In conclusion , our in vitro studies demonstrate the involvement of beta 1-integrins , in particular the fibronectin receptor in the megakaryocyte-dependen t fibroblast proliferation and therefore suggest a pivotal role of meg akaryocytes in the complex pathomechanism causing myelofibrosis. J. Ce ll. Physiol. 176:445-455, 1998. (C) 1998 Wiley-Liss, Inc.