ABOUT
Research in our laboratory is focused on understanding cellular and molecular mechanisms that regulate physiological and pathological bone metabolism, skeletal and craniofacial bone development and diseases. In particular, we are interested in the following lines of research:
THE ROLES OF AUTOPHAGY IN SKELETAL AND CRANIOFACIAL BONE METABOLISM
Autophagy is a conserved lysosomal degradation process that has important roles in both normal human physiology and disease. However, the function of autophagy in skeletal and craniofacial bone homeostasis is not well understood. We found that autophagy is activated during osteoblast differentiation. Ablation of FIP200 (focal adhesion kinase family interacting protein of 200 kD), an essential component of mammalian autophagy, leads to multiple autophagic defects in osteoblasts. Osteoblast-specific deletion of FIP200 leads to osteopenia in mice. Our current effort is to determine the molecular mechanisms and signaling pathways by which autophagy regulates mesenchymal stem cell, craniofacial osteogenic stem cell and osteoblast function using a combination of molecular, cell biological and mouse genetic approaches.
THE REGULATION OF SKELETAL AND CRANIOFACIAL BONE DEVELOPMENT BY mTOR SIGNALING
Tuberous sclerosis (TS) is a genetic disorder characterized by the presence of benign congenital tumors in multiple organs and is caused by mutations in one of two genes, called TSC1 and TSC2. Tuberous sclerosing bone dysplasia is characterized by osteosclerotic changes in skeletal and craniofacial bones. In this disease, hyperactivity of mTOR (mammalian target of rapamycin) signaling is implicated. Despite the high frequency of osseous manifestation (>66%) in TSC patients, it is unknown to what extent and how mTOR signaling regulates bone metabolism in vivo. We established the first craniofacial sclerotic bone lesion mouse model of Tuberous sclerosis and found that enhanced mTOR signaling in neural crest-derived cells can increase bone mass through enlargement of the osteoprogenitor pool, which likely explains the sclerotic bone lesion observed in Tuberous sclerosis patients. We are currently using various genetic mouse models to elucidate the mechanisms by which mTOR signaling regulates skeletal and craniofacial bone development.
The regulation of bone development and health by FAK signaling
FAK (Focal adhesion kinase) is a major mediator of signal transduction by integrins. We recently demonstrated that FAK deletion in osteoblast progenitor cells leads to an osteopenia phenotype associated with increased bone marrow adiposity. The decreased bone mass in FAK-deficient mice is accounted for by decreased proliferation, compromised osteogenic differentiation, and increased adipogenic differentiation of bone marrow mesenchymal stromal/stem cells. Mechanistically, FAK deficiency leads to decreased Wnt/β-catenin signaling evidenced by lowered β-catenin protein levels and decreased mRNA expression of Wnt ligands and target genes. Our findings demonstrated that FAK plays an important role in bone mass acquisition and also identified a novel mechanism accountable for the negative correlation between bone mass and bone marrow adiposity. We are currently determining the function of FAK in mesenchymal stem cells and the impact of FAK inhibition on bone health.
