UCSF

The extracellular matrix (ECM) is an essential player in functions including cell survival, migration and differentiation. It is a dynamic reflection of the state of a tissue, both responding to and directing the behavior of local cells. The remodeling of this matrix is a common method of regulating local cell behaviors and as such, molecules involved in this remodeling process are integral to proper development as well as the prevention of disease states. The matrix metalloproteinases (MMPs) are a family of zinc-dependent cysteine proteinases collectively able to cleave all known ECM proteins. Many members of this family act in concert to provide the degradative activity required during a variety of physiological processes.

Skeletal development occurs by two distinct mechanisms: intramembranous and endochondral ossification. Intramembranous ossification results from direct differentiation of mesenchymal precursors into osteoblasts, and is restricted to the clavicle and the bones of the skull. The skeletal elements of the rib cage, spinal column and limbs are formed by endochondral ossification, wherein cartilaginous templates are remodeled into mature, mineralized skeletal elements. The process of fetal skeletal development is largely recapitulated during skeletal repair: many cell types, molecules and mechanisms are held in common by these processes.

MMPs are critical in promoting proper skeletal development and repair in a variety of settings. The studies described in this dissertation have contributed to our understanding of the roles of several MMPs during the processes of skeletal development and repair. In particular, this work demonstrates the importance of MMP13 (collagenase-3) for chondrocyte resorption and bone remodeling during endochondral bone development as well as repair by both endochondral and intramembranous ossification.