Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

ORTHOPAEDICBIOLOGY ANDBIOENGINEERINGThe Department of Biomedical EngineeringExtracellular Matrix and Its Remodelingby MetalloproteasesTHE APTELABORATORYFELLOWSJ. Michael Engle, Ph.D.Robert Somerville, Ph.D.SENIOR TECHNOLOGISTWeiping (Lauren) Wang, M.S.RESEARCH TECHNICIANSKatherine Jungers, B.S.Samantha Oblander, B.S.Extracellular proteases are essential fordevelopment and play a major role in thepathogenesis of diseases such as cancerand arthritis. Remodeling alters tissue architecture,and at the cellular level, proteolysis affectscell behavior and cell fate through processing ofgrowth factors, receptors, cytokines, andadhesion molecules.The laboratory works on two families ofmolecules—the matrix metalloproteases (MMPs)and a novel family of ADAMTSenzymes. Specific ongoing studies are asfollows:1. We are determining thebiological role of novel ADAMTSproteases previously discovered by usthrough the generation of knockoutmice and analysis of human diseases.Two specific functions being addressedare the processing of the aminopropeptideof fibrillar collagens andproteolysis of large aggregatingproteoglycans such as aggrecan andversican. These projects have relevancefor the Ehlers-Danlos syndrome,arthritis and cancer.2. We are investigating thestructural biochemistry of specificdomains within the ADAMTS enzymesas well as in a novel family ofnonproteolytic ADAMTS-like moleculesthat we have recently discovered. This is beingdone by expression and characterization ofrecombinant enzymes.3. We previously generated a line oftransgenic mice with targeted deletion of theMMP-14 gene. These mice have a number ofanomalies, which are presently being characterizedby various morphological and biochemicalapproaches. In particular, we are determining themechanisms of abnormal skeletogenesis andangiogenesis in these mice.Hurskainen, T.L., Hirohata, S., Seldin M.F., and S.S.Apte (1999) ADAM-TS5,ADAM-TS6 and ADAM-TS7, novel members of a new family of zinc metalloproteases(ADAM-TS, A Disintegrin And Metalloprotease domain with ThromboSpondin typeI motifs). General features and genomic distribution of the ADAM-TS family. J.Biol. Chem. 274:25555-25563.Zhou, Z., Apte, S.S., Wang, J., Rauser, R., Baaklini, G., Soininen, R., and K.Tryggvason (2000) Defective skeletal growth, angiogenesis and premature death inMMP-14 deficient mice. Proc. Natl. Acad. Sci. USA 97:4052-4057.Fernandes, R.J., Hirohata H., Engle, J.M., Colige, A., Cohn, D.H., Eyre D.R., andS.S. Apte (2001) Procollagen II amino propeptide processing by ADAMTS-3: insightson dermatosparaxis. J. Biol. Chem. 276:31502-31509.Hirohata, S., Wang, L.W., Miyagi, M., Yan, L., Seldin, M.F., Keene, D.R., Crabb,J.W., and S.S. Apte (2002) Punctin, a novel ADAMTS-like molecule (ADAMTSL-1),in extracellular matrix. J. Biol. Chem. 277:12182-12189.34