Molecular mechanisms implicated in bone resorption

Abstract

Bone remodeling is a physiological process by which old bone is replaced by new bone. Osteoclasts are multinucleated giant cells of the monocytic lineage. Their function is bone resorption, the first step of bone remodeling. The work of this thesis is in continuity with a theme long developed in our laboratory, that of the actin cytoskeleton organization in boneresorbing osteoclasts. Our first study investigated the role of the podosome organization in osteoclast spreading, adhesion and migration. Our results showed that podosome patterning into rings exerted outward tension upon the substrate and thereby triggered cell migration. Through cycles of assembly, growth and alternating disassembly, rings promote a saltatory mode of migration universal to all osteoclasts. The main objective of this thesis, however, was dedicated to finding new genes that govern podosome patterning in resorption-related processes such as osteoclast migration and sealing zone formation. To find such new genes, we employed a differential transcriptomic analysis of osteoclasts and osteoclast-like cells that exhibit podosomes but are unable to resorb bone. Among a list of six genes highly and exclusively expressed in osteoclasts, we chose to investigate RhoE, a constitutively active GTP-binding protein known for its regulation of actin structures. We provided evidence, using primary RhoE-deficient osteoclasts, that RhoE activity is essential to bone resorption. We unveiled a new role for RhoE in the control of actin turnover in podosomes through a Rock-antagonistic function. Finally, we demonstrated that the role of RhoE in osteoclasts is essential to their migration and sealing zone formation.