Nature Medicine11, 394 - 399 (2005)
Published online: 6 March 2005; | doi:10.1038/nm1203
The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis
Teiji Wada1, Tomoki Nakashima1, Antonio J Oliveira-dos-Santos2, Juerg Gasser3, Hiromitsu Hara1, Georg Schett4
& Josef M Penninger1
1
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3-5, A-1030 Vienna, Austria.
2
University Health Network, Department of Immunology, University of Toronto, 620 University Avenue, Toronto, Ontario M5G 2C1, Canada. Present address: Amgen Cambridge Research Center, One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, USA.
3
Arthritis & Bone Metabolism Department, Novartis, CH-4002 Basel, Switzerland.
4
Department of Internal Medicine III, Division of Rheumatology, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Morphogenesis and remodeling of bone involve synthesis of bone matrix by osteoblasts and coordinate resorption of bone by osteoclasts. Defective bone remodeling caused by altered osteoclast activity underlies a multitude of osteopenic disorders. Receptor activator of NF-B (RANK) and its ligand RANKL have been identified as essential factors involved in osteoclast development and bone remodeling, but their mechanism and interacting factors have not been fully characterized. Here we report that the molecular adapter Grb-2-associated binder-2 (Gab2) associates with RANK and mediates RANK-induced activation of NF-B, Akt and Jnk. Inactivation of the gene encoding Gab2 in mice results in osteopetrosis and decreased bone resorption as a result of defective osteoclast differentiation. We also show that Gab2 has a crucial role in the differentiation of human progenitor cells into osteoclasts. We have thus identified a new, key regulatory scaffold molecule, Gab2, that controls select RANK signaling pathways and is essential for osteoclastogenesis and bone homeostasis.
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B (RANK) and its ligand RANKL have been identified as essential factors involved in osteoclast development and bone remodeling, but their mechanism and interacting factors have not been fully characterized. Here we report that the molecular adapter Grb-2-associated binder-2 (Gab2) associates with RANK and mediates RANK-induced activation of NF-
