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

• 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
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.1670

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.