Multiple functions of tissue inhibitors of metalloproteinases (TIMPs): new aspects in hematopoiesis.

The extracellular matrix (ECM), the product of stromal cells, is now thought to make a dynamic network in tissues. Stromal cells can support other cells not only by direct contact but also via this ECM network. The regulated turnover and remodeling of ECM needs both ECM degrading enzymes named matrix metalloproteinases (MMPs) and their inhibitors called tissue inhibitors of metalloproteinases (TIMPs). Through an understanding of their molecular structure, the nature of the enzymic activity of MMPs and the inhibitory action of TIMPs against MMPs have been well elucidated. Considering their potent inhibitory action against MMPs, TIMPs are thought to play an important role in maintaining ECM. However, other unique functions of TIMPs have been reported, such as erythroid potentiating activity, cell growth-promoting activity, embryogenesis-stimulating activity, steroidogenesis-stimulating activity and so on. This review covers this new field, and discusses what role TIMPs can play in controlling life. In the second part, we briefly introduce our recent date on TIMPs and hematopoiesis. Because TIMPs have a dual function, i.e. a potent inhibitory action against MMPs and cell growth promoting action, TIMPs are good candidates for tissue fibrosis. Our recent measurements of TIMP-1 and TIMP-2 levels using serum and plasma from patients with platelet number disorders and cultured medium from various leukemia cell lines, shows that platelets are a rich source of TIMPs and that TIMP-1 is secreted in large amounts by megakaryoblastic- and erythro-leukemia cell lines. Proliferation of bone marrow fibroblasts can be stimulated by TIMP-1 and TIMP-2. Taken together, TIMPs might be one of the important factors for the process of myelofibrosis in some pathological conditions.