Division of Molecular Medicine
622 West 168th Street
New York, NY 10032
The research in
our laboratory centers on several projects directed at understanding the role of
matrix metalloproteinases in tissue destruction during certain disease
processes. Our laboratory has made
use of transgenic mice in which to express these enzymes at pathophysiological
levels in specific tissues so as to recreate the natural proteolytic imbalance
that occurs during a disease process. Through
the generation of these transgenic animals we have been able to develop several
mouse models of emphysema, atherosclerosis and heart failure and also gain
insight into the role these enzymes may be playing in the pathogenesis of these
Several years ago
we have shown that transgenic mice which express human MMP-1 (matrix
metalloproteinase 1, interstitial collagenase) in the lung develop emphysema.
We have recently demonstrated that human patients with emphysema express
MMP-1 within their lung parenchyma and normal patients do not.
In this study it was shown that the type II pneumocyte of the lung of
patients with emphysema expressed MMP-1 (Imai et al, 2001).
Therefore, we are proceeding with in vitro studies to determine the
mechanism by which MMP-1 is induced in the type II pneumocyte.
In our preliminary work we have found that Il-1 and cigarette smoke
extract can induce MMP-1 expression in lung epithelial cells.
These studies will allow us to identify the molecular pathway leading to
upregulation of MMP-1 in the emphysema lung and possibly provide us with
alternative drug targets.
Changes in the
balance of matrix synthesis and degradation are also believed to be important in
the process of ventricular remodeling and in the pathophysiology of chronic
heart failure. Transgenic mice have been generated harboring a collagenase
transgene that dictates cardiac myocyte specific expression (cardiac-collagenase
transgenic mice). Histological analyses reveal that the transgenic mouse hearts
develop myofibrillar disarray and increased numbers of mitochondria consistent
with hypertrophy. In addition,
hemodynamic measurements demonstrated increased left ventricular systolic
function in the hearts of these mice at 6 months of age that significantly
deteriorates over time when compared to normal mice.
The collagenase transgenic mouse model directly demonstrates a role for
MMP-1, in the development of cardiac dysfunction and further implicate this
enzyme in the process of cardiac remodeling providing an important new model in
which to study these processes.
Dalal, S., Okada, Y., Berg, R. A., And Chada, K. (1992).
Collagenase Expression In The Lungs Of Transgenic Mice Causes Pulmonary
Emphysema. Cell, 71:955-961.
Kim, H., Dalal., S.S., Young, E., Legado,M., Weisfeldt, M.L., and D’Armiento, J. (2000) Disruption of the cardiac matrix leads to altered myocardial function in transgenic mice expressing collagenase (MMP-1) in the heart. J. Clin. Invest. 106:857-866.
K., Dalal, S., Chen, E.S.,
Lemaitre, V., O’Byrne, T.K., Borczuk, A. C., Okada, Y., Tall, A.R. and D’Armiento, J (2001) ApoE knock-out mice expressing human interstitial collagenase (MMP-1) in macrophages have less advanced atherosclerosis. J. Clin. Invest. 107:1227-1234.
B. and D’Armiento, J. (2001) The role of collagenase in emphysema.
Respiratory Review. 2:348-352..
D’Armiento, J. (2001) Matrix metalloproteinase Disruption of the Extracellular matrix and Cardiac Dysfunction Trends in Cardiovascular Medicine. In Press.
Lemaitre, V., Soloway, P.D., and D’Armiento, J. (2001) Increased Aortic Aneurysm Formation in ApoE Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1. Submitted PNAs.
Imai, K., Dalal, S.S., Hambor, J., Okada, Y., Horton, W.C., Poole, R.A., and D’Armiento, J. (2001) Bone Growth retardation in Mouse Embryos Expressing Human Collagenase 1. Submitted J. Cell Biol.
Shiomi, T., Okada, Y., Foronjy, B., Schiltz, J., Jaenish, R., and D'Armiento, J. (2001). Emphysematous changes are caused by degradation of type III collagen in transgenic mice overexpressing tissue collagenase. Submitted Exp. Lung Res.