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

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. KeywordsBone resorption; osteoclasts; RANKL; RANK; OPG Normal bone modelingWith 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 the periphery of the centers of these moulds are invaded by blood vessels and undergo apoptosis. Some of this hypertrophic cartilage survives as thin islands of cartilage in the centers of ossification in growing bones. Osteoblasts, which differentiate from progenitors in a collar of connective tissue around the middle of the bones where vascular invasion takes place, follow the endothelial cells and lay down bone matrix on the surfaces of these islands of cartilage to form bone struts or trabeculae (1). Osteoclast precursors (OCPs), derived from progenitors in the spleen and liver are attracted from blood in the invading blood vessels close to newly formed bone trabeculae. These osteoclast precursors fuse with one

Runx2 deletion in smooth muscle cells inhibits vascular osteochondrogenesis and calcification but not atherosclerotic lesion formation

“…21,41 Importantly, this truncated protein contained an intact Runt DNA binding domain and domains interacting with Runx2 partner proteins, such as CBF and Smad3/4. 21,42 Using SM22aCre to remove Runx2 in vascular SMCs of ApoE À/À mice with this model, the authors found significantly reduced SMC elaboration of RANKL, a tumour necrosis factor family member important for monocyte infiltration and differentiation of mineral-resorbing osteoclasts, 43,44 along with a near complete blockage of monocyte/macrophage recruitment and atherosclerosis. 21 AIC was also completely blocked likely due to the inhibition of oxidative stress-dependent osteogenic differentiation and osteoblast-osteoclast crosstalk.…”

The Role of RANK/RANKL/OPG Signalling Pathways in Osteoclastogenesis in Odontogenic Keratocysts, Radicular Cysts, and Ameloblastomas

“…Therefore, the balance between OPG and RANKL regulates bone resorption and formation [5][6][7]. Imbalance of the RANKL/OPG system have been implicated in the pathogenesis of various primary and secondary bone malignancies [8].…”

hRpn13, a newly identified component of the 19S particle, regulates proliferation, differentiation, and function in the human osteoblast-like cell line MG63

“…RANKL, produced by osteoblasts, stimulates osteoclast differentiation through its cognate receptor RANK on the surface of osteoblasts. Therefore the RANKL-RANK system promotes the maturation of osteoclasts [4,5]. Osteoblasts also regulate the growth of osteoclasts by secreting OPG, a decoy receptor for RANKL and therefore a competitor of RANK, to restrain the activity of the RANKL-RANK system [4].…”

“…Therefore the RANKL-RANK system promotes the maturation of osteoclasts [4,5]. Osteoblasts also regulate the growth of osteoclasts by secreting OPG, a decoy receptor for RANKL and therefore a competitor of RANK, to restrain the activity of the RANKL-RANK system [4]. Thus, the ratio of RANKL to OPG dictate the activity of osteoclasts, the resorption of bone [1,24].…”