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Genetic influences on the circulating cytokines involved in osteoclastogenesis
  1. G Livshits1,
  2. I Pantsulaia1,2,
  3. S Trofimov1,
  4. E Kobyliansky1
  1. 1Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Israel
  2. 2Department of Biomedicine, Institute of Medical Biotechnology, Georgian Academy of Sciences, Georgia
  1. Correspondence to:
 Prof. G Livshits
 Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Tel Aviv, Israel;

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The tumour necrosis factor family molecule RANKL (receptor activator of nuclear factor-kB ligand), its cellular receptor RANK, and the decoy receptor, osteoprotegerin (OPG) represent a novel cytokine triad with pleiotropic effects on bone metabolism, the immune system, and endocrine functions.1 As illustrated in figure 1, RANKL is expressed on the osteoblast/stromal cell surface, binds to its receptor-RANK on the surface of haematopoietic precursor cells and, in the presence of macrophage colony stimulating factor (M-CSF), stimulates differentiation, fusion, activation, and survival of osteoclasts.2,3 These four molecules, acting in accord, are the major regulators of osteoclast formation and function. It has been claimed that binding M-CSF and RANKL to their respective receptors is the necessary and sufficient condition to initiate osteoclastogenesis.4 On the other hand, RANKL is abundantly produced by activated T lymphocytes, and it prevents apoptosis and prolongs survival of dendritic cells, which also express large amounts of the receptor for RANKL (fig 1). This dual function of the RANKL/RANK/OPG system explains why autoimmune diseases, cancers, leukemias, asthma, chronic viral infections, and periodontal disease result in systemic and local bone loss.

Figure 1

Schematic representation of the cellular interactions linking the immune system with bone homeostasis. RANK, receptor activator of nuclear factor kB; RANKL, RANK ligand; OPG, osteoprotegerin; M-CSF, macrophage colony stimulating factor; CFU-M, colony forming unit macrophage; PTH, parathyroid hormone. RANKL, expressed by activated T cells as well as osteoblasts under the influence of many proresorptive stimuli, binds to its specific membrane bound receptor RANK, thereby promoting osteoclast or dendritic cell differentiation, activation, and survival. OPG downregulates osteoclastic resorption by acting as a soluble sink for RANKL.

Numerous reports now implicate the altered RANKL/RANK/OPG system physiology as a factor in the development and severity of many diseases. Three such maladies for which a growing volume of literature exists …

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