Chapter 9 - Osteoclast Generation

Abstract

Osteoclasts are multinucleated giant cells that resorb bone, and develop from hematopoietic cells of the monocytemacrophage lineage. Another essential factor for osteoclastogenesis is receptor activator of nuclear factor κB ligand (RANKL). Development of osteoclasts has opened a wide new area in bone biology focused on the investigation of the molecular mechanism of osteoclast development and function. Osteoblasts/stromal cells, through the expression of RANKL and M-CSF, are involved throughout the osteoclast lifetime of their differentiation, survival, fusion, and activation. OPG produced by osteoblasts/stromal cells is an important negative regulator of osteoclast differentiation and function. RANKL(–/–) mice and RANK(–/–) mice have shown similar features of osteopetrosis with a complete absence of osteoclasts in bone. Furthermore, gain-of-function mutations of RANK have been found in patients suffering from familial expansile osteolysis and familial Paget's disease of bone. Loss-of function mutation of OPG also results in juvenile Paget's disease in bone. In addition, loss-of-function mutations in the gene encoding RANKL have been found in patients with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These findings confirm that the RANKL–RANK interaction is indispensable for osteoclastogenesis, not only in mice, but also in humans. Finally, studies have also shown that inflammatory cytokines, TNF α and IL-1, can substitute for RANKL in inducing osteoclast differentiation and function. These results suggest that in addition to RANKL, inflammatory cytokines play important roles in osteoclastic bone resorption under pathological conditions.