MATRIX METALLOPROTEINASES REGULATE MORPHOGENESIS, MIGRATION AND REMODELING OF EPITHELIUM, TONGUE SKELETAL-MUSCLE AND CARTILAGE IN THE MANDIBULAR ARCH

We have investigated the role of proteinases in the developmental prog ram of bone, cartilage, tongue muscle and epithelial differentiation a nd remodeling in the mandibular arch during murine embryogenesis. Expr ession of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) was tissue-specific with little or no expression in the epith elium of tooth buds, tongue or oral cavity. Gelatinase A mRNA transcri pts were strongly expressed in the perichondrium of Meckel's cartilage and mesenchymal areas of embryonic day 13-15 mandibles, whereas gelat inase B, collagenase-3, TIMP-1 and TIMP-2 mRNA were found primarily in the ossifying areas of the mandibles. The skeletal muscle of the tong ue expressed stromelysin-3, TIMP-2 and TIMP-3 mRNA while stromelysin-3 , TIMP-2 and gelatinase A were seen in the overlying connective tissue layer. Gelatinase A, gelatinase B, stromelysin-1, urokinase, TIMP-1 a nd TIMP-2 mRNA and protein activities were also detected in cultured m andibular explants. Culture of day 10 mandibular explants with a hydro xamic acid metalloproteinase inhibitor, but not with inhibitors of met alloendopeptidases (thiorphan and phosphoramidon), serine proteinases (aprotinin), cysteine proteinases (leupeptin) and urokinase (amiloride ), altered mandibular morphogenesis dramatically. Development of the t ongue (glossogenesis) and cartilage, but not bone or teeth was affecte d. Formation of the oral sulcus and fusion of the two epithelia of the medial sulcus were inhibited, and number and migration of myoblasts d ecreased. The resulting 'tongue-tied phenotype' indicates that MMPs ar e involved in epithelial morphogenesis and the migration of myoblasts to the region of the tongue. Development of the anterior segment of Me ckel's cartilage was also inhibited and proteoglycan content of the ca rtilage was reduced by inhibiting MMPs. Our data suggest that matrix m etalloproteinases play a pivotal role in the morphogenesis of structur es derived from epithelium (oral sulcus), cranial paraxial mesoderm (t ongue) and cranial neural crest (Meckel's cartilage).