The Role of Receptor Activator of Nuclear Factor-κB Ligand and Osteoprotegerin in the Pathogenesis and Treatment of Metabolic Bone Diseases¹

Abstract

BONE IS permanently turned over by the balanced and coordinated action of bone-resorbing osteoclasts and bone-forming osteoblasts, resulting in continuous renewal, functional response to external and internal stimuli, and structural integrity (1-3). Inappropriate bone resorption caused by enhanced osteoclast formation and activity has been previously implicated in the pathogenesis of many metabolic bone diseases. Strategies to inhibit bone resorption have emerged as potent and promising tools for the prevention and treatment of bone and mineral disorders (1-3). The recent discovery and characterization of a novel cytokine system, the tumor necrosis factor (TNF) ligand family member, receptor activator of nuclear factor-B ligand (RANKL/ OPGL/ODF/TRANCE) (4 -7); 1 its receptor, receptor activator of nuclear factor B (RANK/ODAR) (7); and its soluble (decoy) receptor, osteoprotegerin (OPG/OCIF/TR1) (8 -11), has established a novel paradigm of osteoclast biology: RANKL, RANK, and OPG constitute the three essential regulatory components of osteoclast formation, fusion, survival, activation, and apoptosis (12)(13)(14). This article 2 reviews the molecular aspects of this novel cytokine system and its regulation and modulation by various osteotropic agents. Moreover, we summarize the implications of this cytokine system on the pathogenesis of various bone diseases and discuss the therapeutic potential of OPG in the clinical setting. RANKL/OPGL/ODF/TRANCE: the ligandThe TNF ligand family member, osteoprotegerin ligand (OPGL)/osteoclast differentiation factor (ODF) was discovered in 1998 by two groups (4, 5) as the cognate ligand for OPG/ osteoclastogenesis inhibitory factor (OCIF) (8, 9). This factor had been identified by the same two groups the year before and was shown to be identical to TNF-related activation-induced cytokine (TRANCE) (6) and receptor activator of nuclear factor-B ligand (RANKL) (7). RANKL will be the preferred term according to a consensus nomenclature (12). RANKL is a cellbound polypeptide of 317 amino acids (4, 5) that is cleaved by a protease, TNF␣-converting enzyme-like protease (TACE) (15), at position 140 or 145, respectively, to give rise to a shorter soluble ectodomain variant of similar activity (4, 15).The major sources of RANKL production in the bone/bone marrow microenvironment are bone marrow stromal cells, osteoblasts, chondrocytes, mesenchymal cells of the periosteum, osteoclasts, endothelial cells, and T cells (4 -7, 16). Detailed analyses of its extraskeletal tissue distribution revealed RANKL messenger ribonucleic acid (mRNA) and protein production in brain, heart, kidney, skeletal muscle, and skin (16). Of note, RANKL production is highest in undifferentiated stromal cells and is greatly reduced once these multipotential mesenchymal cells become terminally committed to the osteoblastic phenotype (17-19). Interestingly, the RANKL gene promoter structure contains both vitamin D and glucocorticoid response elements as well as a binding site for the essential osteoblastic transcriptio...

Vascular calcification and osteolysis in diabetic neuropathy?is RANK-L the missing link?

“…RANK-L is expressed in a number of cell types, including monocytes/tissue macrophages, osteoblasts and activated T cells. Increased RANK-L expression has been defined in a wide variety of conditions characterised by osteolysis: osteoporosis (age-related and steroid-induced), malignant bone disease (especially myeloma), Paget's disease (juvenile and later onset), and rheumatoid arthritis [18,19,20,21].…”

“…Expression of OPG and RANK-L is modulated, directly or indirectly, by a large number of factors, including TNF-α, IL-1 and IL-17, other interleukins, sex steroids, growth hormone and IGF-1, macrophage colony stimulating factor (M-CSF, CSF-1), nitric oxide, leptin, fetuin-matrix Gla protein (MGP) complex, thyroid and parathyroid hormones, 1,25 dihydoxy vitamin D and lipoproteins [18,19,20,21]. Most significantly, the signalling pathway is also affected by calcitonin and related hormones, calcitonin gene-related peptide (CGRP) and islet amyloid polypeptide (IAPP) [22,23,24].…”

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“…How they interplay is also not completely understood. For PTHrP as well as the cytokines the RANKL-RANK pathway represents a final common pathway to osteoclastogenesis and stimulation of bone resorption [107]. Bone remodelling is a continous process achieved by osteoblasts and osteoclasts.…”

Effects of vitamin D3 and methylenebisphosphonate on immune system of rats at disuse osteoporosis

“…Більшість регуляторних взаємодій спрямовані на контролювання процесу резорбції, що здійснюється остеокластами. Ключовим ме-ханізмом контролю диференціації й активації остеокластів є сигнальний каскад, що включає рецептор активатора фактора транскрипції κВ (RANK -receptoracti va torofthenuclearfactorkappaB), його ліганд (RANKL) та остеопротегерин (OPG -osteoprotegerin) [14]. RANKL, зв'язуючись із RANK на поверхні преостеокластів, акти-вує їхню диференціацію в остеокласти, що посилює резорбцію кістки.…”