Caroline M. Alexander

Extracellular Matrix Degradation

Many processes are included within the scope of the term matrix degradation. Specialized matrices such as bone and cartilage, which provide structural support for the animal, are dynamic structures that resorb or expand in response to hormonal stimuli. The enzymatic machinery for the degradation of large quantities of collagen and other matrix components must be under the appropriate transcriptional regulation in the controlling cell type. Similarly, if a whole organ or tissue is removed, such as during uterine and mammary involution, enzymes are required that are capable of lysing basement membranes and interstitial matrix and processing cellular debris so that all the components can be absorbed by scavenging cell types. Matrix degradation is also a part of invasive cellular migration, when cells displace gels of interstitial molecules or cross basement membranes, the natural barriers to cell migration. In contrast to the involution reaction, lysis associated with cell motility is a limited reaction that leaves the bulk of the matrix intact and is directed only at the “structural kingpins,” those molecules that constitute a barrier to cell displacement. Cell growth, division, and expansion also demand flexibility in the growth matrix, such as that associated with tissue regeneration and during development. Matrix is also a reservoir of growth factors and possible morphogens, and rather specific cleavage reactions directed against carrier molecules like vitronectin and heparan sulfate may have a role in determining the course of further cell growth and proteolysis.

Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis

During puberty, mouse mammary epithelial ducts invade the stromal mammary fat pad in a wave of branching morphogenesis to form a complex ductal tree. Using pharmacologic and genetic approaches, we find that mammary gland branching morphogenesis requires transient matrix metalloproteinase (MMP) activity for invasion and branch point selection. MMP-2, but not MMP-9, facilitates terminal end bud invasion by inhibiting epithelial cell apoptosis at the start of puberty. Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty. In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy. Nevertheless, the mammary gland is able to develop lactational competence in MMP mutant mice. Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis.