title: Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis.
abstract: OBJECTIVE
  To test whether the tyrosine kinase Tyro3 affects arthritis. Tyro3, the ligand of growth arrest-specific protein 6 (GAS6) is a receptor tyrosine kinase involved in cell survival. Tyro3 and GAS6 are expressed in the arthritic synovium, and in vitro studies have shown their role in osteoclast differentiation.
  
  
  METHODS
  Bone was assessed by micro CT and histomorphometry in Tyro3-deficient (Tyro3(-/-)) and wild-type mice. Arthritis was induced in both genotypes, and Gas6 level was measured by ELISA. Synovitis, synovial hyperplasia, bone erosion, osteoclast activation and osteoclast gene expression were assessed by histomorphometry and reverse transcriptase-PCR, respectively. In vitro osteoclast differentiation assays were performed in Tyro3(-/-) and wild-type mice. Furthermore, effects of Tyro3 and GAS6 on human synovial fibroblast proliferation and osteoclastogenesis were assessed in human cells.
  
  
  RESULTS
  Tyro3(-/-) mice had significantly higher bone mass than wild-type littermates. Induction of arthritis increased GAS6 serum levels. Arthritic Tyro3(-/-) mice showed less synovial hyperplasia, osteoclast numbers and bone damage compared with controls. In vivo expression of osteoclast-associated receptor and receptor activator of nuclear factor-κB and in vitro osteoclastogenesis were impaired in Tyro3(-/-) mice. GAS6 also induced synovial fibroblast proliferation and osteoclast differentiation in human cells in Tyro3-dependent manner.
  
  
  CONCLUSIONS
  These findings indicate that Tyro3 is a critical signal for synovial hyperplasia, osteoclast differentiation and bone erosion during arthritis. GAS6 and Tyro3 therefore constitute therapeutic targets to inhibit synovial hyperplasia and associated bone erosion.
authors: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, , Erlangen, Germany.
authors: Gisela
authors: G
authors: Ruiz-Heiland
authors: Yi
authors: Y
authors: Zhao
authors: Anja
authors: A
authors: Derer
authors: Tobias
authors: T
authors: Braun
authors: Klaus
authors: K
authors: Engelke
authors: Elena
authors: E
authors: Neumann
authors: Ulf
authors: U
authors: Mueller-Ladner
authors: Yi
authors: Y
authors: Liu
authors: Jochen
authors: J
authors: Zwerina
authors: Georg
authors: G
authors: Schett
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications* / Q000201:enzymology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000201:enzymology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D055786:Gene Knockout Techniques; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000517:prevention & control; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010024:Osteoporosis / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000099255:Growth Arrest-Specific Protein 6; C513478:Tyro3 protein, mouse
keywords: Arthritis; Rheumatoid Arthritis; Synovitis