Matrix Metalloproteinases in the Hematopoietic Microenvironment

Matrix metalloproteinases (MMPs) are structurally and functionally related zinc-dependent endopeptidases capable of degrading the components of extracellular matrix (ECM) and basement membranes. MMPs participate in many physiological processes and have also been implicated in various pathological conditions including tumor invasion and metastasis. The functions of MMPs are known to be controlled by mechanisms leading to activation of their latent forms and through inhibition of both active and latent forms by natural tissue inhibitors of metalloproteinases (TIMPs). The complex relationships between MMPs and TIMPs within the bone marrow microenvironment during normal hematopoiesis as well as during leukemic growth and dissemination have not been extensively investigated. We reported that primary acute myelogenous leukemia (AML) blasts and leukemic KG-1 cells penetrate reconstituted basement membrane (Matrigel) in an in vitro invasion assay, secrete the gelatinases (MMP-2 and MMP-9) and express active MMP-2 on the cell surface. We also analyzed MMP/TIMP expression in normal bone marrow cells of the myeloid and stromal lineages and showed that MMP-2, MMP-9, TIMP-1 and TIMP-2 are produced in the bone marrow microenvironment. Furthermore, we examined the role of gelatinases in the transmigration of stem/progenitor cells from the bone marrow into peripheral blood. We found that steady-state bone marrow CD34(+) cells, unlike circulating peripheral blood CD34(+) cells, did not express MMP-2 and MMP-9 mRNA transcripts and proteins, and that various cytokines were able to upregulate expression of these MMPs in bone marrow CD34(+) cells and trans-Matrigel migration of these cells. Thus, we now have evidence that MMPs and TIMPs are constituents of the hematopoietic microenvironment although their roles in hematopoiesis have yet to be determined.