Modulation of osteoclast differentiation and bone resorption by Rho GTPases

Abstract

Bone is a dynamic tissue constantly renewed through a regulated balance between bone formation and resorption. Excessive bone degradation by osteoclasts leads to pathological decreased bone density characteristic of osteolytic diseases such as post-menopausal osteoporosis or bone metastasis. Osteoclasts are multinucleated cells derived from hematopoietic stem cells via a complex differentiation process. Their unique ability to resorb bone is dependent on the formation of the actin-rich sealing zone. Within this adhesion structure, the plasma membrane differentiates into the ruffled border where protons and proteases are secreted to demineralize and degrade bone, respectively. On the bone surface, mature osteoclasts alternate between stationary resorptive and migratory phases. These are associated with profound actin cytoskeleton reorganization, until osteoclasts die of apoptosis. In this review, we highlight the role of Rho GTPases in all the steps of osteoclasts differentiation, function, and death and conclude on their interest as targets for treatment of osteolytic pathologies.

Keywords: :

• osteoclast
• bone and bones
• podosome
• Rho GTPase
• Rac
• Cdc42
• RhoU
• actin
• RANK ligand
• guanine nucleotide exchange factor

10.4161/sgtp.28119

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was supported by research grants from the Institut National du Cancer (grant # INCa-4361 to A.B.) and the Agence Nationale de la Recherche (ANR grant # ANR-2011-BLAN-006 to A.B.).