The formation and remodeling of bone are processes that require tightly coupled activities of osteoblasts and osteoclasts. Osteoblasts form bone tissue and are derived from mesenchymal stem cells of the bone marrow stroma. Osteoclasts remodel bone tissue and originate from hematopoietic stem cells that are also progenitors of monocytes and macrophages. Osteoporosis, the most common bone disease in this country and major contributor to the hundreds of thousands of bone fractures (of hip ~300,000, spine, and wrist) that occur annually in women with postmenopausal osteoporosis, is characterized by a decrease in bone density and an increase in bone fragility.

Recent advances re-emphasize the role of excessive osteoclastic activity in the pathogenesis of postmenopausal osteoporosis and as a potential therapeutic target for this common bone disease (review by McClung, M.R., Curr Osteoporosis Rep. 4, 28-33, 2006). This understanding is based on the molecular biological characterization of three components of a signaling pathway: RANK, the receptor activator of nuclear factor NF-kappa B that commits macrophages to the osteoclast lineage ( Xu, D., et al., J Biol Chem 281, 4678-90, 2006); RANKL, the receptor activator of nuclear factor NF-kappa B ligand which is an endogenous activator of osteoclastogenesis; and osteoprotegerin (OSG), an inhibitor protein (and member of the tumor necrosis factor receptor superfamily) with antiresorptive activity that blocks RANKL or its interaction (Œcross-talk‚) with RANK.

The signaling pathways of gene regulation by nuclear transcription factor NF-kappa B, discovered more than two decades ago, are also implicated in innate immunity, inflammation, and cancer. Further, a specific monoclonal antibody (denosumab) against RANKL is under evaluation in early clinical studies of bone diseases of increased osteoclastic activity (McClung, M.R., Curr Osteoporosis Rep. 4, 28-33, 2006).

---

---