Chapter 9 - Integrin and Calcitonin Receptor Signaling in the Regulation of the Cytoskeleton and Function of Osteoclasts

Abstract

Osteoclast function starts with adhesion to the bone matrix, leading to cytoskeletal reorganization that is important for the migration of these cells to and between the resorption sites and their polarization during the resorption process. This chapter focuses on the signaling pathways that mediate cytoskeletal organization during osteoclast migration and polarization. Integrins, a superfamily of heterodimeric transmembrane receptors, mediate cell–matrix and cell–cell interactions. Upon ligand binding, integrins usually undergo receptor clustering, leading to the formation of focal adhesion contacts, where these receptors are linked to intracellular cytoskeletal complexes and bundles of actin filaments. Integrin-mediated signaling has been shown to change phosphoinositide metabolism, raise intracellular calcium, and induce tyrosine or serine phosphorylation of signaling molecules. Adhesion of osteoclasts to the bone surface involves the interaction of integrins with extracellular matrix proteins within the bone matrix. In bones, the tyrosine kinase c-Src is essential for osteoclast-resorbing activity and/or motility. Targeted disruption of c-Src in mice induces osteopetrosis due to a loss of osteoclast function, without a reduction in osteoclast number. c-Src is associated with the plasma membrane and multiple intracellular organelles and it is concentrated in the actin ring and the cell periphery, regions that are involved in osteoclast attachment and migration. This suggests that the absence of Src might compromise these aspects of osteoclast function. Pyk2 has been identified as a major adhesion-dependent tyrosine kinase in osteoclasts, both in vivo and in vitro. These cells do not resorb bone accompanied with defects in cell adhesion, spreading, and sealing zone organization, thus suggesting that Pyk2 is also important for cytoskeletal organization in osteoclasts.