Embryonic bone formation occurs through either intramembranous or endochondral ossification. Intramembranous ossification is involved in forming the flat bones of the skeleton and is accomplished through the direct differentiation of osteoblasts, or bone cells, from mesenchymal condensations. During endochondral ossification, a hyaline cartilage model is first formed, creating a matrix to which osteoblasts then infiltrate. It is through this process that the long bones are formed. In both events, mature osteoblasts lay down an extracellular matrix of proteins and hydroxyapatite crystals forming mineralized bone tissue. The mouse provides an excellent model system for the study of skeletal development, as the processes involved are very similar to those of human skeletal development. Additionally, the mouse genome can be manipulated to allow deletion, mis-expression, or mutation of genes of interest. In our laboratory, we are interested in what roles the Wnt/β-catenin and Bmp/Tak1 signaling pathways play during skeletal development as well as postnatal skeletal homeostasis. Using the mouse Cre-loxP system, we are able to specifically delete members of these pathways in certain cell types of mesenchymal origin to determine their contribution to the developmental process. For example, we have shown that chondrocyte-specific expression of a constitutively active form of β-catenin results in early chondrocyte maturation and ossification of the limbs, whereas, chondrocyte-specific deletion of β-catenin results in delayed chondrocyte maturation and ossification. Currently, we are actively investigating the molecular mechanisms responsible for these phenotypes including the identification of those genes directly downstream of β-catenin that promote chondrocyte maturation.
In addition to the Wnt/β-catenin studies, we are interested in the role of non-canonical BMP signaling during skeletal development. Tak1, a member of the MAP3K family, was initially identified as a mediator of TGF-β and BMP signal transduction through the p38 MAPK pathway. We have shown that Tak1 signaling is required by chondrocytes for normal endochondral bone formation as deletion of Tak1 specifically in chondro-osteo progenitor cells leads to severe chondrodysplasia with defects in both chondrocyte proliferation and maturation. We are currently investigating the role of Tak1 in osteoblasts and limb mesenchymal stem cells during development and postnatal bone homeostasis.