Abstract
The discovery of the receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) system and its role in the regulation of bone resorption exemplifies how both serendipity and a logic-based approach can identify factors that regulate cell function. Before this discovery in the mid to late 1990s, it had long been recognized that osteoclast formation was regulated by factors expressed by osteoblast/stromal cells, but it had not been anticipated that members of the tumor necrosis factor superfamily of ligands and receptors would be involved or that the factors involved would have extensive functions beyond bone remodeling. RANKL/RANK signaling regulates the formation of multinucleated osteoclasts from their precursors as well as their activation and survival in normal bone remodeling and in a variety of pathologic conditions. OPG protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from binding to its receptor, RANK. Thus, RANKL/OPG ratio is an important determinant of bone mass and skeletal integrity. Genetic studies in mice indicate that RANKL/RANK signaling is also required for lymph node formation and mammary gland lactational hyperplasia, and that OPG also protects arteries from medial calcification. Thus, these tumor necrosis factor superfamily members have important functions outside bone. Although our understanding of the mechanisms whereby they regulate osteoclast formation has advanced rapidly during the past 10 years, many questions remain about their roles in health and disease. Here we review our current understanding of the role of the RANKL/RANK/OPG system in bone and other tissues.
Highlights
Bone serves multiple functions in vertebrates, including support for muscles, protection of vital organs and hematopoietic marrow, and storage and release of vital ions, such as calcium
It has been recognized since the early 1980s, when Rodan and Martin [1] postulated that osteoblasts regulate osteoclast formation, that factors expressed by osteoblasts within bone are produced in response to known stimulators of bone resorption, such as parathyroid hormone (PTH)
Since 1981, when Rodan and Martin [1] proposed the novel hypothesis that osteoblast/stromal cells play a central role in the regulation of osteoclast formation and bone resorption, many investigators had attempted to identify the osteoclast-activating factor that completed the differentiation of precursors that had been exposed to macrophage colony-stimulating factor (M-CSF)
Summary
Bone serves multiple functions in vertebrates, including support for muscles, protection of vital organs and hematopoietic marrow, and storage and release of vital ions, such as calcium. Identification in the mid to late 1990s of the receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) signaling system provided a major breakthrough that clarified the role played by osteoblasts in these processes.
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