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 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.
Institute of Physiological Chemistry, Dresden University of Technology, Dresden, Germany. annette.garbe@tu-dresden.de
Annette I
AI
Garbe
Anne
A
Roscher
Christiane
C
Schüler
Anne-Helen
AH
Lutter
Martin
M
Glösmann
Ricardo
R
Bernhardt
Michael
M
Chopin
Ute
U
Hempel
Lorenz C
LC
Hofbauer
Stefan
S
Rammelt
Monika
M
Egerbacher
Reinhold G
RG
Erben
Rolf
R
Jessberger
D000199:Actins / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000150:complications / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology*; D002460:Cell Line; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D009929:Organ Size; D010006:Osteoblasts / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology*; D010022:Osteopetrosis / Q000150:complications / Q000473:pathology
D000199:Actins; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; C113365:Swap70 protein, mouse