Review
Functions of RANKL/RANK/OPG in bone modeling and remodeling

https://doi.org/10.1016/j.abb.2008.03.018Get rights and content

Abstract

The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-κB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.

Section snippets

Normal bone modeling

With the exception of the bones of the calvaria, all bones in the mammalian skeleton are preformed in cartilage moulds from mesenchymal progenitors, which under appropriate stimuli also have the potential to differentiate into a variety of tissue types, including fibrous tissue, fat and muscle. Chondrocytes proliferate near the ends of the cartilage moulds to drive their longitudinal growth, while others in the centers of undergo hypertrophic differentiation. The hypertrophic chondrocytes at

Bone remodeling

Bone has multiple functions in vertebrates, including protection of vital organs and hematopoietic marrow, structural support for muscles, and storage and release of vital ions, such as calcium, and of growth factors stored in the matrix. Bone in the adult skeleton is renewed continuously in response to a variety of stimuli by the process of bone remodeling. This involves removal of trenches or tunnels of bone from the surfaces of trabecular and cortical bone, respectively, by osteoclasts [19].

Regulation of osteoclast formation and activation by OPG, RANKL and RANK

Osteoclasts are derived from mononuclear precursors in the myeloid lineage of hematopoietic cells that also give rise to macrophages. Understanding of the molecular mechanisms that regulate osteoclast formation and activation has advanced rapidly in the last 12 years since the discovery of the RANKL/RANK signaling system. M-CSF expression by osteoblastic stromal cells is required for progenitor cells to differentiate into osteoclasts, but M-CSF on its own is unable to complete this process.

RANKL

RANKL exists as a homotrimeric protein and is typically membrane-bound on osteoblastic and activated T cells or is secreted by some cells, such as activated T cells [43], [44], [45]. The secreted protein is derived from the membrane form as a result of either proteolytic cleavage or alternative splicing [46]. The proteolytic cleavage of RANKL is carried out by matrix metalloproteases (MMP3 or 7) [47] or ADAM (a disintegrin and metalloprotease domain) [48]. Most of the factors known to stimulate

RANK

RANK is a homotrimeric transmembrane protein member of the TNF receptor superfamily. It appears to be expressed in fewer tissues than RANKL at the protein level, but in addition to OCPs, mature osteoclasts and dendritic cells, it is expressed in mammary glands [50] and some cancer cells, including breast and prostate cancers [51], [62], two tumors with high bone metastatic potential. No humans with osteopetrosis have been identified to date with mutations in rank. However, a deletion mutation

OPG

OPG is secreted by many cell types in addition to osteoblasts, including those in the heart, kidney, liver, and spleen. A recent study reports that B cells may be responsible for 64% of total bone marrow OPG production and B cell-deficient mice are consistently osteoporotic, consistent with B cells being a major source of OPG in the bone marrow of normal mice [65]. Most of the factors that induce RANKL expression by osteoblasts also regulate OPG expression [66]. Although there some are

Transcription factor activation by RANKL/RANK in osteoclasts and OCPs

A key preliminary step in downstream signaling after RANKL ligation to RANK is the binding of TNF receptor-associated factors (TRAFs) to specific sites in the cytoplasmic domain of RANK [32], [81]. RANK is a transmembrane protein, which like other TNF family receptors has no intrinsic protein kinase activating activity to mediate signaling. TRAFs 2, 5 and 6 all bind to RANK [81], but only TRAF6 appears to have essential functions in OCPs and osteoclasts, since deletion of only TRAF6 and no

Immunoreceptors, osteoimmunology and RANKL

Activation of calcium signaling during osteoclast formation appears to involve the Fc receptor common γ subunit (FcRγ) immunoreceptor expressed by osteoclasts and the adapter protein, DNAX-activating protein 12 (DAP12), which associates with an immunoreceptor tyrosine-based activation motif (ITAM) [95]. DAP12/FcRγ double knockout mice are severely osteopetrotic due to impaired RANKL-induced NFATc1 activation and they do not form osteoclasts, while mice deficient in either gene have only mildly

Pharmacologic inhibition of RANKL/RANK signaling

Numerous preclinical in vivo studies using inhibitors of RANKL/RANK signaling have confirmed the important roles of this system in rodents and non-human primates. For example, OPG and RANK:Fc inhibited bone loss in models of sex-steroid deficiency and glucocorticoid-induced osteoporosis, rheumatoid arthritis, multiple myeloma, and metastatic bone disease [102], [103], [104], [105]. These studies were followed by phase 1 clinical trials of two forms of OPG: Fc-OPG and OPG-Fc, Single injections

Summary

Discovery of the RANKL/RANK/OPG system has been one of the most important advances in bone biology in the last decade. This signaling system is essential for skeletal homeostasis, and disruption of it leads to inhibition of bone resorption in vitro and in animal models of most bone diseases characterized by increased resorption. RANKL/RANK signaling plays important roles in tissues other than bone. Elucidation of the specific roles of RANKL/RANK in these various types of cells will likely link

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