Osteoclasts are multinucleated cells of monocyte/ macrophage origin that resorb bone. Regulation of  their differentiation and function is crucial to our understanding of the pathogenesis and treatment of bone diseases such as osteoporosis, Paget’s disease, autoimmune arthritis, and osteolytic metastatic cancer. It has been known for many years that osteoclast differentiation and function are regulated by multiple hormones and cytokines interacting with cells of the osteoblast lineage.

The consecutive discovery of new members of the tumour necrosis factor (TNF) receptor-ligand family has elucidated the molecular mechanism by which osteoblasts regulate osteoclast differentiation, function and survival. Receptor activator of NF-kB ligand, (RANKL), is a member of the TNF ligand family that is  produced by osteoblast lineage cells and exerts its biological effects by binding to its cognate receptor, RANK, on osteoclast lineage cells. The RANKL/RANK interaction was shown to be required for osteoclast formation, survival and the activation of mature osteoclasts.

Osteoprotegerin (OPG) which is also a member of the TNF receptor family is produced by osteoblasts  and acts as a soluble, decoy receptor for RANKL, thereby counterbalancing the RANKL/RANK signalling system. The central role of these factors in regulating bone turnover was demonstrated by the extremes of skeletal phenotype (osteoporosis vs. osteopetrosis) in mice by targeted ablation of OPG and RANKL respectively.  RANKL/RANK and OPG are three key molecules that regulate osteoclast recruitment and function. This review will focus on the cellular and molecular mechanisms of  RANKL/RANK and OPG in the skeleton that result in increased bone resorption. Further understanding of this axis will provide the opportunity to design novel therapies to treat osteoporosis, inflammatory arthritis and other diseases of bone loss.