The osteoclast is generated by differentiation and fusion ofprecursors of the monocyte/macrophage lineage, giving rise toa polykaryon with unique cellular and molecular properties.Two cytokines mediate basal osteoclastogenesis, RANKL (58) andM-CSF, also called CSF-1 (59). Both proteins, produced by marrowstromal cells and their derivative osteoblasts, are membranebound, and thus differentiation of osteoclasts requires directinteraction of these nonhematopoietic, bone-residing cells withosteoclast precursors (60). The discovery of RANKL was precededby identification of its physiological inhibitor OPG, to whichit binds with high affinity (61). M-CSF regulates many aspectsof myeloid precursors and mature osteoclasts, including proliferationand/or survival, differentiation, and the cytoskeletal rearrangementsrequired for efficient bone resorption (59).
A combination of biochemistry and genetics helps to explainhow osteoclasts resorb bone (58, 62). The capacity of osteoclaststo isolate the enclosed area between themselves and the underlyingbone is at the heart of their function. The acidic pH (4.5)decalcifies the tissue, exposing the organic matrix to degradationby lysosomal-derived proteases, particularly cathepsin K (Figure3). The fact that dysfunction of the proton pump, Cl–channel, or cathepsin K results in human diseases of excessbone mass, namely osteopetrosis or pyknodysostosis (58, 62),attests to their critical role in osteoclast function.
This model of bone degradation requires close apposition betweenthe osteoclast and bone, a role provided by integrins in theform of αß heterodimers (63). Consistent with the factthat αvß3 is the principal integrin in osteoclasts,ß3–/– mice are hypocalcemic and generatefewer and shallower resorptive lacunae on dentin slices thando their wild-type counterparts (62). Based on these and manyin vitro observations, small-molecule inhibitors of osteoclastfunction that target αvß3 are in development (64).
Integrin activation mediates both cellular adhesion and transmembranesignaling (65). Important downstream transducers include theproto-oncogene c-src, important for membrane ruffling and osteoclastmigration (66), and Rac and Rho, members of a small subfamilyof the small GTPase superfamily that are central to remodelingof the actin cytoskeleton in many cell types (67) and play asimilar role in osteoclastic bone resorption (68). It is nowclear that bisphosphonates block bone resorption by inhibitingmembrane targeting of a number of small GTPases (69).