Grant: Operating Grant

In bones and teeth, small calcium phosphate crystals deposit within a scaffolding of proteins called the extracellular matrix. Protein-crystal interactions in bones and teeth define properties of the mineral phase making the tissues strong and hard. Our work is relevant to understanding the decreased mineralization that occurs in osteomalacias - diseases where bone is incompletely calcified, soft and deformable and/or prone to fracture. The research is also relevant to pathologic calcification diseases of normally "soft" tissues. Compelling evidence indicates that a protein called osteopontin (OPN) controls mineralization in most tissues. Also important is that processing of OPN by enzymes leads to mineralization-inhibiting protein fragments (peptides) with different potencies. We investigate whether processing of OPN defines a control mechanism affecting biomineralization in different tissues. Here we propose to examine this possible regulation, guided by the general hypothesis that OPN in bones, teeth and other tissues, and peptides derived from enzymatic processing of OPN, controls mineralization by binding to crystal surfaces in a way that modulates crystal growth. We will investigate these mechanisms in cell-free systems in which calcium-phosphate crystals are grown in the presence of OPN/peptides (in cell culture models, and in mouse models) using biochemical measurements, microscopies, high-resolution imaging approaches, biophysical methods to characterize mineral, and computational modeling to simulate atomic-scale binding. Such work should provide insight into keeping bones and teeth strong and healthy, and may suggest ways to treat patients where these tissues are defective.