Pathophysiological mechanisms operating in the development of myelofibrosis: role of megakaryocytes.

In this article current concepts on the regulation of bone marrow collagen are reviewed and a hypothesis regarding the mechanisms leading to marrow fibrosis associated with Primary Myelofibrosis (PMF) is presented. Type I and type III collagen, products of marrow fibroblasts, are the main constituents of myelofibrotic tissue and megakaryocytes are the predominant cells proliferating in PMF. There is evidence for the clonal nature of the hematopoietic cell proliferation and the secondary origin of myelofibrosis. Also, evidence exists indicating that defective megakaryocyte maturation, i.e. ineffective megakaryocytopoiesis occurs in patients with PMF. It is postulated that ineffective megakaryocytopoiesis leads to an excessive concentration of megakaryocyte components in the marrow intercellular space and that the development of marrow fibrosis involves mainly 2 megakaryocytic products: growth factor and factor 4. The growth factor stimulates fibroblast proliferation and collagen secretion. Factor 4 inhibits the activity of the enzyme collagenase. Thus, the imbalance between increased collagen production and decreased collagen degradation leads to an excessive deposition of collagens in bone marrow matrix.