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

Annette I. Garbe, Anne Roscher, Christiane Schüler, Anne Helen Lutter, Martin Glösmann, Ricardo Bernhardt, Michael Chopin, Ute Hempel, Lorenz C. Hofbauer, Stefan Rammelt, Monika Egerbacher, Reinhold G. Erben, Rolf Jessberger

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

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-ÎB 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.

Original languageEnglish
Pages (from-to)2085-2096
Number of pages12
JournalJournal of Bone and Mineral Research
Volume27
Issue number10
DOIs
StatePublished - Oct 2012
Externally publishedYes

Keywords

  • BONE
  • F-ACTIN
  • OSTEOCLASTS
  • RESORPTION
  • SWAP-70

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