9 Cytokine and Growth Factor Regulation of Osteoclastogenesis

Abstract

Osteoclast differentiation is an important biological process that determines the level of bone resorption in vivo. Numerous cytokines and growth factors are involved in the regulation of this process by directly acting on osteoclast precursor cells or through their effect on osteoclastogenesis-supporting mesenchymal cells, such as osteoblasts. Receptor activator of NF-κB ligand (RANKL) is an essential cytokine that promotes osteoclastogenesis and, in most cases, the effects of other factors can be explained in the context of cross talk with RANKL signaling. This chapter describes recent advances in the understanding of the intracellular signaling mechanism of RANKL and its interaction with other signaling events during osteoclastogenesis, which may provide a molecular basis for therapeutic intervention in pathological bone resorption.

THE ESSENTIAL ROLE OF THE RANKL-RANK SYSTEM IN OSTEOCLASTOGENESIS
Osteoclast differentiation is a tightly regulated process because the balance between osteoclasts and osteoblasts is critical for bone homeostasis. Osteoclasts differentiate from hematopoietic cells of monocyte/macrophage lineage, but osteoclastogenesis-supporting cells of mesenchymal origin are required for the differentiation commitment. Thus, osteoclasts have traditionally been formed in a coculture of hematopoietic cells derived from bone marrow and calvarial osteoblasts, which were thought to express an unknown osteoclast differentiation factor. Before this factor was identified, information about the molecules involved in osteoclast differentiation had been obtained from the analysis of osteopetrotic mice (Fig. 1) (Asagiri and Takayanagi 2006).

RANKL, a type II membrane protein of the TNF superfamily, was identified as the long sought-after osteoclast differentiation factor expressed by osteoblasts, but interestingly, the same molecule...