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Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease

Ann E. Kearns, Sundeep Khosla, and Paul J. Kostenuik

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor κB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.

BONE REMODELING IS the lifelong process by which old bone is replaced by new bone. Bone remodeling also helps to maintain mineral homeostasis via the liberation of calcium and phosphorus into the circulation. The remodeling process occurs at discrete sites on cortical and cancellous bone surfaces and involves the integrated and sequential actions of osteoclasts and osteoblasts. The basic multicellular unit is the term given to this localized collaborative cellular team. The remodeling cycle leads to the formation of a new “osteon” via four steps: activation, resorption, reversal, and formation. A previously quiescent bone surface is “activated” by unknown signals that attract osteoclast precursors from the circulation to the skeleton where they fuse and form multinucleated cells. These multinucleated preosteoclasts attach to the bone surface, differentiate, and begin resorbing bone matrix (resorption phase). The completion of resorption is associated with apoptosis of osteoclasts, followed by a reversal phase during which additional cells including preosteoblasts move to the bone surface. Osteoblasts orchestrate the formation of new bone matrix and regulate its mineralization. The return of the bone surface to its quiescent state involves the apoptosis of osteoblasts, their incorporation into the bone as osteocytes, or their transformation into bone surface-lining cells.

In many pathological states, and perhaps in healthy adults, each bone remodeling cycle leads to a net loss of bone due to a modest deficiency in the amount of new bone formed relative to old bone removed. This relative deficit in bone formation could be related at least in part to trabecular perforations that occur during the resorptive phase, leading to the loss of bone surface on which osteoblasts could deposit new bone. Acceleration of the bone remodeling rate, which is common in many metabolic bone diseases including postmenopausal osteoporosis, thereby leads to a greater rate of bone loss. Inhibition of bone remodeling has therefore become a major therapeutic strategy for preventing bone loss. This review will focus on the recent discovery of the OPG/RANKL/RANK signaling pathway, its critical involvement in the cellular regulation of bone remodeling, and the effects of bone remodeling suppression via RANKL inhibition.

The first component identified for a novel pathway regulating bone resorption and remodeling was osteoprotegerin (OPG), which was discovered in mice via a genomics-based approach. Expressed sequence tags were generated by sequencing randomly selected clones from a fetal rat intestine cDNA library. The relevant expressed sequence tag for OPG encoded an open reading frame with significant homology to TNF receptor 2. Subsequent cloning of the full-length gene revealed that it encoded a novel member of the TNF receptor family. The full-length rat OPG gene was overexpressed in its native soluble form in transgenic mice, under the control of a human apolipoprotein E promoter. These OPG transgenic mice were born with high bone mass, and this phenotype progressed as animals aged with no evidence of resolution. High bone mass in these animals was associated with marked reductions in osteoclast numbers and activity. The protein was therefore named “osteoprotegerin” based on its ability to protect bone. Independent of this effort, scientists in Japan isolated a protein secreted by cultured human fibroblasts that proved to be identical to OPG. This molecule was referred to as osteoclastogenesis inhibitory factor (OCIF) based on its ability to suppress osteoclastogenesis in vitro. OPG/OCIF was shown soon thereafter to also suppress osteoclast activity, survival, and adhesion to bone surfaces. The name OPG was officially adopted by the nomenclature committee of the American Society of Bone and Mineral Research (ASBMR).