Role of proprotein convertases in the regulation of osteoblast functions

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Most vertebrates possess a mineralized internal skeleton, a unique organ that allowed the evolution of articulated limbs and the conquest of continents by tetrapodes more then 300 millions years ago. Bones are formed and maintained through the process of ossification, which implicates the action of a highly specialized cell type: the osteoblast. This cell, which exists only in bony vertebrates, possesses the exclusive capacity to synthesize and secrete the proteins composing the bone extracellular matrix and to induce the mineralization of this matrix. The genetic program directing the formation and the activity of osteoblasts has been extensively studied over the past 20 years. However, the biochemical and enzymatic processes implicated in the capacity of osteoblasts to secrete extracellular matrix proteins remain poorly understood. Hence, we are proposing in our research program to study in the osteoblast the functions of proprotein convertases, a family of enzymes, which cut hundreds of other secreted proteins, either activating or inactivating them. This process is also called protein maturation. Like other secretory cells, osteoblasts function most likely depends on the maturation of several secreted proteins, yet the role of proprotein convertases in osteoblasts has only been superficially studied so far. To understand the role played by proprotein convertases in ossification, our laboratory takes advantage of the most widely used vertebrate model organism, the mouse. Using genetic tools developed in this organism, we will engineer modified mice lacking specific proprotein convertases only in osteoblasts. We will then characterize the bones of these animals to unravel the role of these enzymes in bone matrix formation and mineralization. Our laboratory also masters techniques to study osteoblast function outside of the organism in cell culture. These approaches will allow us to better appreciate the cellular and biochemical role played by proprotein convertases in osteoblast function. This research program is important to understand how protein maturation by proprotein convertases in osteoblasts controls ossification. It will also generate novel knowledge on this aspect of osteoblast biology and therefore make important contributions to this field.**