title: Selective signaling by Akt1 controls osteoblast differentiation and osteoblast-mediated osteoclast development.
abstract: Maintaining optimal bone integrity, mass, and strength throughout adult life requires ongoing bone remodeling, which involves coordinated activity between actions of bone-resorbing osteoclasts and bone forming-osteoblasts. Osteoporosis is a disorder of remodeling in which bone resorption outstrips deposition, leading to diminished bone mass and an increased risk of fractures. Here we identify Akt1 as a unique signaling intermediate in osteoblasts that can control both osteoblast and osteoclast differentiation. Targeted knockdown of Akt1 in mouse primary bone marrow stromal cells or in a mesenchymal stem cell line or genetic knockout of Akt1 stimulated osteoblast differentiation secondary to increased expression of the osteogenic transcription factor Runx2. Despite enhanced osteoblast differentiation, coupled osteoclastogenesis in Akt1 deficiency was markedly inhibited, with reduced accumulation of specific osteoclast mRNAs and proteins and impaired fusion to form multinucleated osteoclasts, defects secondary to diminished production of receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (m-CSF), critical osteoblast-derived osteoclast differentiation factors. Delivery of recombinant lentiviruses encoding Akt1 but not Akt2 to Akt1-deficient osteoblast progenitors reversed the increased osteoblast differentiation and, by boosting accumulation of RANKL and m-CSF, restored normal osteoclastogenesis, as did the addition of recombinant RANKL to conditioned culture medium from Akt1-deficient osteoblasts. Our results support the idea that targeted inhibition of Akt1 could lead to therapeutically useful net bone acquisition, and they indicate that closely related Akt1 and Akt2 exert distinct effects on cellular differentiation pathways.
authors: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon, USA.
authors: Aditi
authors: A
authors: Mukherjee
authors: Peter
authors: P
authors: Rotwein
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt