Deciphering the function and therapeutic potential of bone-specific alkaline phosphatase in tissue mineralization imbalances

Pathological vascular calcification is an independent risk factor for mortality and the most common cause of death among patients with chronic kidney disease. It has much in common with skeletal mineralization, an organized process mediated by bone-forming osteoblasts.

Mineralization and vascular calcification are likely regulated by similar mechanisms, since many bone-associated proteins are also found at sites of vascular calcification; however, the details are elusive.

Bone alkaline phosphatase (ALP) is one such protein.In this project, we will investigate the role of ALP in mineralization and soft tissue calcification, and the possibility of its therapeutic targeting for the latter.

We will: i) decipher the structural and functional properties of bone ALP isoforms in relation to promotors and inhibitors of mineralization; ii) do functional studies using powerful animal models (brown bears, knockout, and knockin mice); iii) do clinical studies of bone disorders and vascular calcification; and iv) evaluate bone ALP isoforms as targets for novel compounds inhibiting vascular calcification.We anticipate that this project will provide groundbreaking insights into mechanisms of skeletal mineralization and soft tissue calcification abnormalities; inform improved diagnostics and validated biomarkers of skeletal mineralization and vascular calcification; and inspire potential therapeutic approaches to prevent or ameliorate vascular calcification.