title: Sharpin is a key regulator of skeletal homeostasis in a TNF-dependent manner.
abstract: OBJECTIVE
  SHARPIN is a subunit of LUBAC and regulates activation of NF-κB, a pivotal transcription factor in skeletal homeostasis. Mutated SHARPIN gene (cpdm) mice develop chronic proliferative dermatitis and systemic inflammation. Cpdm mice have an osteopaenic phenotype characterised by decreased cortical and trabecular bone volume, but whether this is a consequence of the hyper-inflammatory phenotype is unknown. The inflammatory phenotype of cpdm mice is prevented by Tnf deficiency so we examined cpdm.Tnf (-/-) mice to examine the role of SHARPIN in skeletal development.
  
  
  METHODS
  This research determined the extent to which SHARPIN and TNF interact within the skeleton through analyses of gene expression, μCT and biomechanical properties of bones of control (CTRL), cpdm, Tnf (-/-) (TNF KO) and cpdm.Tnf (-/-) (cpdm/TNF KO) mice.
  
  
  RESULTS
  Gene expression of IL-1β, TNF and caspase-3 increased in cpdm mice but was comparable to control values in cpdm/TNF KO mice. Decreased cortical and trabecular bone in cpdm mice translated to a loss in bone strength (ultimate stress and peak force). Cpdm/TNF KO mice developed bones similar to, or stronger than, control bones.
  
  
  CONCLUSIONS
  Our results suggest that SHARPIN plays a significant role in skeletal homeostasis and that this role is strongly regulated through TNF pathways.
authors.affiliation: La Trobe University, Department of Human Biosciences, La Trobe University, Bundoora, Australia.
authors.forename: H W
authors.initials: HW
authors.lastname: McGowan
authors.forename: J A
authors.initials: JA
authors.lastname: Schuijers
authors.forename: B L
authors.initials: BL
authors.lastname: Grills
authors.forename: S J
authors.initials: SJ
authors.lastname: McDonald
authors.forename: J A
authors.initials: JA
authors.lastname: Rickard
authors.forename: J
authors.initials: J
authors.lastname: Silke
authors.forename: A C
authors.initials: AC
authors.lastname: McDonald
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013718:Tensile Strength; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C554944:Sipl1 protein, mouse; D014409:Tumor Necrosis Factor-alpha