title: The cytoskeletal regulatory scaffold protein GIT2 modulates mesenchymal stem cell differentiation and osteoblastogenesis.
abstract: G protein-coupled receptor kinase interacting protein 2 (GIT2) is a signaling scaffold protein involved in the regulation of cytoskeletal structure, membrane trafficking, and G protein-coupled receptor internalization. Since dynamic cytoskeletal reorganization plays key roles both in osteoblast differentiation and in the maintenance of osteoclast polarity during bone resorption, we hypothesized that skeletal physiology would be altered in GIT2(-/-) mice. We found that adult GIT2(-/-) mice have decreased bone mineral density and bone volume in both the trabecular and cortical compartments. This osteopenia was associated with decreased numbers of mature osteoblasts, diminished osteoblastic activity, and increased marrow adiposity, suggesting a defect in osteoblast maturation. In vitro, mesenchymal stem cells derived from GIT2(-/-) mice exhibited impaired differentiation into osteoblasts and increased adipocyte differentiation, consistent with a role for GIT2 in mesenchymal stem cell fate determination. Despite elevated osteoclast inducing cytokines and osteoclast numbers, GIT2(-/-) mice also exhibit impaired bone resorption, consistent with a further role for GIT2 in regulating osteoclast function. Collectively, these findings underscore the importance of the cytoskeleton in both osteoblast and osteoclast function and demonstrate that GIT2 plays essential roles in skeletal metabolism, affecting both bone formation and bone resorption in vivo.
authors: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors: Xiaojuan
authors: X
authors: Wang
authors: Shaoxi
authors: S
authors: Liao
authors: Erik R
authors: ER
authors: Nelson
authors: Robert
authors: R
authors: Schmalzigaug
authors: Robert F
authors: RF
authors: Spurney
authors: Farshid
authors: F
authors: Guilak
authors: Richard T
authors: RT
authors: Premont
authors: Diane
authors: D
authors: Gesty-Palmer
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics; D001862:Bone Resorption / Q000235:genetics*; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D020690:GTPase-Activating Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; C120767:Git2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D010750:Phosphoproteins