Abstract
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-κB (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-κB, 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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Acknowledgements
We thank L. Barra, N. Joza and E. Wagner for discussion and reagents; K. Paiha and P. Steinlein for assistance in microscopic analysis; A. Bichl and K. Flahndorfer for maintenance of mice; J. Wada and Y. Nakashima for genotype determinations; S. Hirota and T. Hirota for technical assistance; and Y. Kobayashi, N. Udagma, N. Takahashi, H. Yasuda and H. Takayanagi for technical suggestions. T.W. is supported by the H15th fellowship of the Japan Society for the Promotion of Science. This work was supported by the Institute for Molecular Biotechnology of the Austrian Academy of Sciences and the Jubilaeumsfonds of the Austrian National Bank.
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Supplementary information
Supplementary Fig. 1
Gene targeting of mouse Gab2. (PDF 1707 kb)
Supplementary Fig. 2
Normal osteoblast function. (PDF 6118 kb)
Supplementary Fig. 3
Impaired osteoclastogenesis but normal RANK expression. (PDF 7299 kb)
Supplementary Fig. 4
RANKL/RANK-mediated signaling in preosteoclasts. (PDF 2800 kb)
Supplementary Table 1
Micro-CT analysis in Gab2-deficient mouse femurs (PDF 613 kb)
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Wada, T., Nakashima, T., Oliveira-dos-Santos, A. et al. The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nat Med 11, 394–399 (2005). https://doi.org/10.1038/nm1203
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DOI: https://doi.org/10.1038/nm1203
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