Grant: Operating Grant

In bones and teeth, small calcium- and phosphate-containing crystals (and calcium- and carbonate-containing crystals in inner ear otoconia) are deposited within a scaffolding of proteins called the extracellular matrix. Exciting new evidence describes the importance of protein-crystal interactions, which in bones and teeth, define properties of the mineral making the tissues strong, and which in the inner ear, provide for small mineralized structures which help maintain balance. Our work is particularly relevant to understanding the defective/decreased mineralization occurring in osteomalacias - diseases where bone is incompletely calcified, soft and prone to fracture. It is also relevant to pathologic calcification diseases of "soft" tissues. Compelling evidence indicates that a bone and tooth protein - osteopontin (OPN) - controls mineralization. Equally important is that processing of OPN by enzymes leads to mineralization-inhibiting protein fragments (peptides) with different potencies. Processing of OPN protein and its peptides might define a control mechanism affecting biomineralization in different tissues. Here we propose to investigate this possible regulation, guided by the general hypothesis that OPN in bones, teeth and other tissues, and peptides derived from enzymatic processing of OPN, control mineralization by modulating (pyro)phosphate-regulating genes, and by binding to crystal surfaces in a very specific way to control their growth. We will examine these mechanisms in cell-free systems, cell culture models, and mouse models using biochemical measurements, high-resolution imaging approaches, biophysical approaches to characterize mineral, and computational modeling to simulate atomic-scale binding. Such work should provide insights into keeping bones and teeth strong and healthy, and maintaining balance, and may suggest ways to treat patients where these tissues are defective.