Regulation of bone mass and osteoclast function depend on the F-actin modulator SWAP-70

Bone remodeling involves tightly regulated bone‐resorbing osteoclasts and bone‐forming osteoblasts. Determining osteoclast function is central to understanding bone diseases such as osteoporosis and osteopetrosis. Here, we report a novel function of the F‐actin binding and regulatory protein SWAP‐70...

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Bibliographic Details
Published in:Journal of bone and mineral research 2012-10, Vol.27 (10), p.2085-2096
Main Authors: Garbe, Annette I, Roscher, Anne, Schüler, Christiane, Lutter, Anne-Helen, Glösmann, Martin, Bernhardt, Ricardo, Chopin, Michael, Hempel, Ute, Hofbauer, Lorenz C, Rammelt, Stefan, Egerbacher, Monika, Erben, Reinhold G, Jessberger, Rolf
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Biological and medical sciences
BONE
Bone and Bones - pathology
Bone Resorption - complications
Bone Resorption - pathology
Cell Line
Cell Movement
DNA-Binding Proteins - deficiency
DNA-Binding Proteins - metabolism
F-ACTIN
Fundamental and applied biological sciences. Psychology
Guanine Nucleotide Exchange Factors - deficiency
Guanine Nucleotide Exchange Factors - metabolism
Humans
Indexing in process
Mice
Minor Histocompatibility Antigens
Nuclear Proteins - deficiency
Nuclear Proteins - metabolism
Organ Size
Osteoblasts - pathology
OSTEOCLASTS
Osteoclasts - metabolism
Osteoclasts - pathology
Osteopetrosis - complications
Osteopetrosis - pathology
RESORPTION
Skeleton and joints
SWAP-70
Vertebrates: osteoarticular system, musculoskeletal system
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Summary:Bone remodeling involves tightly regulated bone‐resorbing osteoclasts and bone‐forming osteoblasts. Determining osteoclast function is central to understanding bone diseases such as osteoporosis and osteopetrosis. Here, we report a novel function of the F‐actin binding and regulatory protein SWAP‐70 in osteoclast biology. F‐actin ring formation, cell morphology, and bone resorption are impaired in Swap‐70−/− osteoclasts, whereas the expression of osteoclast differentiation markers induced in vitro by macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL) remains unaffected. Swap‐70−/− mice develop osteopetrosis with increased bone mass, abnormally dense bone, and impaired osteoclast function. Ectopic expression of SWAP‐70 in Swap‐70−/− osteoclasts in vitro rescues their deficiencies in bone resorption and F‐actin ring formation. Rescue requires a functional pleckstrin homology (PH) domain, known to support membrane localization of SWAP‐70, and the F‐actin binding domain. Transplantation of SWAP‐70–proficient bone marrow into Swap‐70−/− mice restores osteoclast resorption capacity in vivo. The identification of the role of SWAP‐70 in promoting osteoclast function through modulating membrane‐proximal F‐actin rearrangements reveals a new pathway to control osteoclasts and bone homeostasis. © 2012 American Society for Bone and Mineral Research.
ISSN:0884-0431
1523-4681
DOI:10.1002/jbmr.1670