[New paradigms in the regulation of bone metabolism].
Although multiple hormones and cytokines regulate various aspects of osteoclast formation, the two final effectors, osteoprotegerin (OPG) and its ligand (OPGL/RANKL) have been recently identified. Since then, there have been important advances in the understanding of the molecular mechanisms that regulate the crosstalk between osteoblasts/stromal and hematopoietic osteoclast precursor cells. In this article, we describe the new concepts from the identification of OPG, a protein with potent osteoclastogenesis inhibitory activity, to the isolation of RANKL, a transmembrane ligand expressed on osteoblasts/stromal cells that bind to RANK, a transmembrane receptor on osteoclast cells and its precursors. The interaction between RANK and RANKL triggers a series of mechanisms that result in differentiation, maturation and activation of osteoclasts. OPG inhibits osteoclastogenesis binding to RANKL and blocks its interaction with RANK. Many hormones and cytokines, like PTH and IL-11, act inhibiting production of OPG and stimulating production of RANKL. Contrary to this, estrogens inhibit production of RANKL and RANKL-stimulated osteoclastogenesis. The knowledge of the RANK/RANKL/OPG system and the understanding of osteoclast differentiation and activation has had a great impact on the field of bone metabolism, with new possible treatment strategies for diseases characterized by excessive bone resorption.
Rosa-Rañal
M
M
Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México D. F.
de la Cruz
D A
DA
Lorena-Rubio
Y
Y
Larrea
F
F
D000818:Animals; D030801:Animals, Genetically Modified; D016723:Bone Remodeling / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D053244:Osteoprotegerin; D053245:RANK Ligand; D051381:Rats; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*
D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C506032:Tnfrsf11b protein, rat