title: Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells.
abstract: The cytosolic protein Sharpin is a component of the linear ubiquitin chain assembly complex, which regulates NF-κB signaling in response to specific ligands, such as TNF-α. Its inactivating mutation in chronic proliferative dermatitis mutation (Cpdm) mice causes multiorgan inflammation, yet this phenotype is not transferable into wild-type mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, and that this osteopenia is corrected by Tnf deletion. Because the cellular mechanism underlying this pathology, however, was still undefined, we performed a thorough skeletal phenotyping of Cpdm mice on the basis of nondecalcified histology and cellular and dynamic histomorphometry. We show that the trabecular and cortical osteopenia in Cpdm mice is solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. Consistently, Cpdm primary calvarial cells display reduced osteogenic capacity ex vivo, and the same was observed with CD11b(-) bone marrow cells. Unexpectedly, short-term treatment of these cultures with TNF-α did not reveal an impaired molecular response in the absence of Sharpin. Instead, genome-wide and gene-specific expression analyses revealed that Cpdm mesenchymal cells display increased responsiveness toward TNF-α-induced expression of specific cytokines, such as CXCL5, IL-1β, and IL-6. Therefore, our data not only demonstrate that the skeletal defects of Cpdm mice are specifically caused by impaired differentiation of osteoprogenitor cells, they also suggest that increased cytokine expression in mesenchymal bone marrow cells contributes to the inflammatory phenotype of Cpdm mice.
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Anke
authors.initials: A
authors.lastname: Jeschke
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Philip
authors.initials: P
authors.lastname: Catala-Lehnen
authors.affiliation: Department of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sieber
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Bickert
authors.affiliation: Center of Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Till
authors.initials: T
authors.lastname: Koehne
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Kristofer
authors.initials: K
authors.lastname: Wintges
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Robert P
authors.initials: RP
authors.lastname: Marshall
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Mautner
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Lara
authors.initials: L
authors.lastname: Duchstein
authors.affiliation: Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany; and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Otto
authors.affiliation: Institute of Experimental Immunology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Horst
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.affiliation: Department of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany; kreienkamp@uke.de schinke@uke.de.
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Kreienkamp
authors.affiliation: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany; kreienkamp@uke.de schinke@uke.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003872:Dermatitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D010012:Osteogenesis / Q000235:genetics / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C554944:Sipl1 protein, mouse