Grant: Project Grant

The skeleton in humans and other vertebrate organisms is essential for survival and function. Our groups have previously identified that mutations in a protein localized outside cells, called fibronectin, cause a severe form of skeletal disease termed "spondylometaphyseal dysplasia corner fracture type" (SMDCF). Affected patients suffer from many skeletal defects, including short stature/dwarfism, abnormal curvature of the spine (scoliosis), mobility defects, and several other pathological issues. Many of these patients need corrective surgery; no known treatment is available. We obtained skin cells from two SMDCF patients and generated a stem cell model system to mimic this pathology in cell culture. We also developed mouse models to delete the two major types of fibronectin, the so-called cellular fibronectin in the cartilage and the plasma fibronectin in the liver and blood. We analyzed skeletal development in the mice from birth until adulthood and found that complete deletion of FN reduced bone formation and skeletal growth. We discovered that fibronectin mutations impaired the ability of the stem cells to differentiate into cartilage-forming cells. We identified novel cell and matrix-associated mechanisms that can potentially be modified for therapeutic approaches to treat SMDCF. Hence, in the proposed study, we will use mutant mouse and cell culture models for the following goals: 1) To identify strategies to improve the skeletal defects caused by fibronectin mutations. 2) To discover the molecules on the surface of cells and the signaling pathways that will facilitate the interaction of fibronectin with early mesenchymal cells and their differentiation into cartilage-forming cells. 3) To understand how fibronectin induces the maturation of bone and cartilage cells, including the potential transition of cartilage cells to bone-forming cells. These findings will provide critical insights into how fibronectin regulates the formation of a functional skeleton.