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Contempo Updates | Clinician's Corner

Clinical Implications of the Osteoprotegerin/RANKL/RANK System for Bone and Vascular Diseases

Lorenz C. Hofbauer, MD; Michael Schoppet, MD
JAMA. 2004;292(4):490-495. doi:10.1001/jama.292.4.490.
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Bone resorption by osteoclasts is coupled with bone formation by osteoblasts, and this balanced process continuously remodels and adapts the skeleton. The receptor activator of nuclear factor κB ligand (RANKL) has been identified as an essential cytokine for the formation and activation of osteoclasts. The effects of RANKL are physiologically counterbalanced by the decoy receptor osteoprotegerin (OPG). Estrogen deficiency, glucocorticoid exposure, T-cell activation (eg, rheumatoid arthritis), and skeletal malignancies (eg, myeloma, metastases) enhance the ratio of RANKL to OPG and, thus, promote osteoclastogenesis, accelerate bone resorption, and induce bone loss. Moreover, alterations of the OPG/RANKL/RANK system have been implicated in vascular diseases. RANKL blockade (using OPG or RANK fusion proteins or RANKL antibodies) has prevented bone loss caused by osteoporosis, chronic inflammatory disorders, and malignant tumors in animal models and may emerge as a therapy in humans based on studies in postmenopausal osteoporosis, myeloma bone disease, and osteolytic metastases. This review summarizes the clinical implications of the OPG/RANKL/RANK system for bone and vascular diseases.

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Figure. Role of the OPG/RANKL/RANK System on Bone Metabolism, the Immune System, and Vascular Biology
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In the OPG/RANKL/RANK system, RANKL expression and OPG production are modulated by various cytokines, hormones, drugs, and mechanical strains (insets).1 A, In bone, osteoblasts and their precursor cells (stromal cells) express receptor activator of nuclear factor κB ligand (RANKL) in a cellular form and a truncated form generated by the protease tumor necrosis factor α (TNF-α)–converting enzyme (TACE). RANKL stimulates the receptor RANK on osteoclast precursors and mature osteoclasts and activates intracellular pathways to promote osteoclast differentiation and activation (NF-κB and c-Jun N-terminal kinase pathways), and cytoskeletal reorganization and survival (PKB/Akt pathway) that increase bone resorption and bone loss. Stromal cells and osteoblasts secrete osteoprotegerin (OPG), which acts as a decoy receptor and blocks RANKL. B, In the immune system, RANKL is expressed and secreted by activated T cells. T-cell–derived RANKL can activate RANK on osteoclasts (to promote bone loss in inflammatory bone diseases), T cells, and antigen-presenting dendritic cells (to enhance activity and survival of both immune cells). Dendritic cells may modulate these processes by secreting OPG. C, In the vascular system, RANKL is expressed by endothelial cells that also express the specific receptor RANK. RANKL/RANK interactions regulate endothelial survival. RANKL may be blocked by OPG, which is secreted by endothelial and smooth muscle cells. The physiological role of the OPG/RANKL/RANK system in the vascular wall and interactions with other ligands are currently under investigation. IL indicates interleukin; TGF-β, transforming growth factor β; BMP-2, bone morphogenic protein 2; PTH, parathyroid hormone; PDGF-BB, platelet-derived growth factor BB.

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