Bone marrow-derived matrix metalloproteinase-14 - A novel target for plaque stability

Our understanding of the role of bone marrow (BM) derived cells in the pathogenesis of vascular disease has been evolving rapidly. It is generally accepted that circulating monocytes, the precursors of macrophages, migrate to the vascular wall and differentiate into lipid-laden macrophages in the process of atherogenesis.(1) BM-derived cells with smooth muscle cell (SMC)-like phenotype also participate in the pathogenesis of vascular disease.(2,3) Circulating endothelial progenitor cells migrate to the site of vascular injury and participate in arterial repair and angiogenesis.(4) A recent study revealed an important role of T cells in hypertension and vascular dysfunction.(5) The vasculature possesses several agonist/receptor systems that affect recruitment and differentiation of BM-derived cells, including granulocyte-macrophage colony stimulating factor,(6) stromal cell-derived factor1,(7) and erythropoietin.(8,9) These accumulating findings have established the role of BM-derived cells (eg, macrophages, lymphocytes, and vascular progenitors) in the pathogenesis of cardiovascular disease. Activated SMCs, macrophages, and immune cells are abundant in vulnerable atheroma that is often covered with a thin and collagen-poor fibrous cap and/or aggregating platelets (the Figure). Activated SMCs and macrophages are major cell components that produce matrix metalloproteinases (MMPs) in the atherosclerosis plaque. MMPs degrade extracellular matrix and play crucial roles in the pathogenesis of plaque disruption and subsequent thrombosis.(10) Among these MMPs, MMP-14 is a membrane-bound MMP that activates pro-MMP-2 and is closely associated with migration of monocyte-derived cells.(11) However, the role of MMP-14 in atherosclerosis in vivo remains poorly defined.