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High Levels of Matrix Metalloproteinases Regulate Proliferation and Hormone Secretion in Pituitary Cells¹

Department of Endocrinology, Max Planck Institute of Psychiatry (M.P.P., U.R., G.K.S.), 80804 Munich, Germany; Fundacion Campomar, CONICET, FCEN, Universidad de Buenos Aires (M.F.L., O.P.), Patricias Argentinas 435, 1405 Buenos Aires, Argentina; Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Buenos Aires (V.G.), 1427 Buenos Aires, Argentina; Hospital Santa Lucía (A.C., G.C.), 1232 Buenos Aires, Argentina; Hospital Ramos Mejía (H.M.), 1221 Buenos Aires, Argentina; the Department of Neurosurgery, University of Munich (A.M.), 81377 Munich, Germany; and Laboratory Fisiología y Biología Molecular, Universidad de Buenos Aires. Ciudad Universitaria (E.A.), 1428 Buenos Aires, Argentina

Address all correspondence and requests for reprints to: Prof. Dr. G. K. Stalla, Department of Endocrinology, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany. E-mail: stalla{at}mpipsykl.mpg.de or Prof. Dr. E. Arzt, Department de

Beside the digestion of the extracellular matrix during tumor invasion and metastasis, more recently, new functions for matrix metalloproteinases (MMPs) have been proposed. We studied the expression and function of these enzymes in pituitary cells. We observed the activities of MMP-2 and MMP-9 together with expression of membrane-type MMP and tissue inhibitor of metalloproteinase-1 in all types of human pituitary adenomas. We found surprisingly high levels of MMP activity and low levels of tissue inhibitor of metalloproteinases, indicating a high level of extracellular matrix-degrading activity in pituitary adenomas. To examine the function of metalloproteinase activity in pituitary cells we used the synthetic MMP inhibitor batimastat. These studies demonstrate that MMPs secreted by pituitary cells can release growth factors anchored to the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. These results define a new additional mechanism for the control of pituitary hormone secretion and indicate new potential therapeutic targets for pituitary adenomas.

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