title: Ablation of p38α MAPK Signaling in Osteoblast Lineage Cells Protects Mice From Bone Loss Induced by Estrogen Deficiency.
abstract: Estrogen deficiency causes bone loss by increasing the number of bone-resorbing osteoclasts. Selective p38α MAPK inhibitors prevent bone-wasting effects of estrogen withdrawal but implicated mechanisms remain to be identified. Here, we show that inactivation of the p38α-encoding gene in osteoblast lineage cells with the use of an osteocalcin-cre transgene protects mice from ovariectomy-induced bone loss (a murine model of postmenopausal osteoporosis). Ovariectomy fails to induce bone loss, increase bone resorption, and stimulate receptor activator of nuclear factor κB ligand and IL-6 expression in mice lacking p38α in osteoblasts and osteocytes. Finally, TNFα or IL-1, which are osteoclastogenic cytokines overproduced in the bone marrow under estrogen deficiency, can activate p38α signaling in osteoblasts, but those cytokines cannot enhance Rankl and Il6 expressions or increase osteoclast formation in p38a-deficient osteoblast cultures. These findings demonstrate that p38α MAPK signaling in osteoblast lineage cells mediates ovariectomy-induced bone loss by up-regulating receptor activator of nuclear factor κB ligand and IL-6 production.
authors.affiliation: Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, 1205 Geneva, Switzerland.
authors.forename: Cyril
authors.initials: C
authors.lastname: Thouverey
authors.affiliation: Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, 1205 Geneva, Switzerland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Caverzasio
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D015153:Blotting, Western; D001862:Bone Resorption / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004967:Estrogens / Q000172:deficiency*; D055785:Gene Knockdown Techniques; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics*; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D010011:Osteocytes / Q000378:metabolism; D015663:Osteoporosis, Postmenopausal / Q000235:genetics* / Q000378:metabolism; D010052:Ovariectomy; D053245:RANK Ligand / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D055114:X-Ray Microtomography
chemical_list: D024042:Collagen Type I; D004967:Estrogens; D007375:Interleukin-1; D015850:Interleukin-6; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D048308:Mitogen-Activated Protein Kinase 14