title: STING Contributes to Abnormal Bone Formation Induced by Deficiency of DNase II in Mice.
abstract: OBJECTIVE
  Cytosolic DNA sensors detect microbial DNA and promote type I interferon (IFN) and proinflammatory cytokine production through the adaptor stimulator of IFN genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. This study sought to identify the role of STING in regulating bone formation and to define the bone phenotype and its pathophysiologic mechanisms in arthritic mice double deficient in DNase II and IFN-α/β/ω receptor (IFNAR) (DNase II-/-/IFNAR-/-double-knockout [DKO] mice) compared with controls.
  
  
  METHODS
  Bone parameters were evaluated by micro-computed tomography and histomorphometry in DKO mice in comparison with mice triple deficient in STING, DNase II, and IFNAR and control mice. Cell culture techniques were employed to determine the parameters of osteoclast and osteoblast differentiation and function. NanoString and Affymetrix array analyses were performed to identify factors promoting ectopic bone formation.
  
  
  RESULTS
  Despite the expression of proinflammatory cytokines that would be expected to induce bone loss in the skeleton of DKO mice, the results, paradoxically, demonstrated an accumulation of bone in the long bones and spleens, sites of erythropoiesis and robust DNA accrual. In addition, factors promoting osteoblast recruitment and function were induced. Deficiency of STING significantly inhibited bone accrual.
  
  
  CONCLUSIONS
  These data reveal a novel role for cytosolic DNA sensor pathways in bone in the setting of autoimmune disease. The results demonstrate the requirement of an intact STING pathway for bone formation in this model, a finding that may have relevance to autoimmune diseases in which DNA plays a pathogenic role. Identification of pathways linking innate immunity and bone could reveal novel targets for the treatment of bone abnormalities in human autoimmune diseases.
authors.affiliation: University of Massachusetts Medical School, Worcester.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Baum
authors.affiliation: University of Massachusetts Medical School, Worcester.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Indiana University School of Medicine, Indianapolis.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Organ
authors.affiliation: University Hospital Bonn, Bonn, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Jakobs
authors.affiliation: University Hospital Bonn, Bonn, Germany, and Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Indiana University School of Medicine, Indianapolis.
authors.forename: David B
authors.initials: DB
authors.lastname: Burr
authors.affiliation: University of Massachusetts Medical School, Worcester.
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.affiliation: University of Massachusetts Medical School, Worcester.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: University of Massachusetts Medical School, Worcester.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Gravallese
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities* / Q000201:enzymology*; D004706:Endodeoxyribonucleases / Q000172:deficiency*; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000099197:STING Protein
chemical_list: D004706:Endodeoxyribonucleases; D008565:Membrane Proteins; C530855:Sting1 protein, mouse; D000099197:STING Protein; C019329:deoxyribonuclease II