GPCR kinase 2 interacting protein 1 (GIT1) regulates osteoclast function and bone mass
| Autor: | Elaine M. Smolock, Prashanthi Menon, Bradford C. Berk, Chen Yan, Guoyong Yin, Michael J. Zuscik |
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| Rok vydání: | 2010 |
| Předmět: |
Bone density
Podosome Physiology Clinical Biochemistry Osteoclasts Cell Cycle Proteins Biology Article Bone resorption Bone remodeling Mice Calcification Physiologic Bone Density Osteoclast medicine Animals Femur Bone Resorption Phosphorylation Cells Cultured Mice Knockout Osteoblasts Receptor Activator of Nuclear Factor-kappa B Phospholipase C gamma GTPase-Activating Proteins Cell Differentiation Osteoblast X-Ray Microtomography Cell Biology Alkaline Phosphatase Cell biology Mice Inbred C57BL Phenotype src-Family Kinases medicine.anatomical_structure Microscopy Fluorescence Biochemistry Tyrosine Bone Remodeling Cell Surface Extensions Bone marrow Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Journal of Cellular Physiology. 225:777-785 |
| ISSN: | 0021-9541 |
| DOI: | 10.1002/jcp.22282 |
| Popis: | G-protein-coupled receptor (GPCR) kinase 2 interacting protein-1 (GIT1) is a scaffold protein expressed in various cell types including neurons, endothelial, and vascular smooth muscle cells. The GIT1 knockout (KO) mouse has a pulmonary phenotype due to impaired endothelial function. Because GIT1 is tyrosine phosphorylated by Src kinase, we anticipated that GIT1 KO should have a bone phenotype similar to Src KO. Microcomputed tomography of the long bones revealed that GIT1 KO mice have a 2.3-fold increase in bone mass compared to wild-type controls. Histomorphometry showed increased trabecular number and connectivity suggesting impaired bone remodeling. Immunoblot analysis of GIT1 expression showed that it was expressed in both osteoclasts and osteoblasts. Osteoblast activity and function assayed by alkaline phosphatase, mineral nodule formation, and in vivo calcein labeling were normal in GIT1 KO mice suggesting that the observed increase in bone mass was due to an osteoclast defect. GIT1 KO bone marrow cells differentiated into multinucleated osteoclasts, but had defective bone resorbing function on dentin slices. This defect was likely caused by loss of podosome belt based on immunofluorescence analysis and previous studies showing that GIT1 is required for podosome formation. Furthermore, we found that GIT1 was a regulator of receptor activator of NFκB (RANK) signaling since it was tyrosine phosphorylated in a Src-dependent manner and was required for phospholipase C-γ2 phosphorylation. These data show that GIT1 is a key regulator of bone mass in vivo by regulating osteoclast function and suggest GIT1 as a potential target for osteoporosis therapy. J. Cell. Physiol. 225: 777–785, 2010. © 2010 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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