title: Death Receptor 3 (TNFRSF25) Increases Mineral Apposition by Osteoblasts and Region Specific New Bone Formation in the Axial Skeleton of Male DBA/1 Mice.
abstract: Objectives. Genome wide association studies identified TNFSF member TNF-like protein 1A (TL1A, TNFSF15) as a potential modulator of ankylosing spondylitis (AS). TL1A is the only confirmed TNFSF ligand of death receptor 3 (DR3, TNFRSF25); however, its role in disease pathology is not characterised. We evaluated DR3's role in controlling osteoblast- (OB-) dependent bone formation in vitro and in vivo. Methods. Osteoprogenitor cells and OB were cultured from male DR3-deficient (DR3(ko)) and wild-type (DR3(wt)) DBA/1 mice. DR3 and RANKL expression were tested by flow cytometry. Alkaline phosphatase and mineralization were quantified. Osteopontin, osteoprotegerin, and pro MMP-9 were measured by ELISA. A fluorescent probe (BoneTag) was used to measure in vivo mineralization in 10-month-old mice. Results. DR3 was expressed on osteoprogenitors and OB from DR3(wt) mice. Alkaline phosphatase, osteopontin, and mineral apposition were significantly elevated in DR3(wt) cultures. Levels of RANKL were comparable whilst osteoprotegerin was significantly increased in DR3(wt) cultures. In vivo incorporation of BoneTag was significantly lower in the thoracic vertebrae of 10-month-old DR3(ko) mice. Conclusions. These data identify new roles for DR3 in regulating OB-dependent bone mineral apposition. They potentially begin to explain the atypical pattern of new bone formation observed in the axial skeleton of grouped, aging DBA/1 mice.
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Fraser L
authors.initials: FL
authors.lastname: Collins
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Jessica O
authors.initials: JO
authors.lastname: Williams
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Anja C
authors.initials: AC
authors.lastname: Bloom
authors.affiliation: University Hospital Llandough, Cardiff & Vale University Health Board, Cardiff CF64 2XX, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Stone
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Ernest
authors.initials: E
authors.lastname: Choy
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Eddie C Y
authors.initials: EC
authors.lastname: Wang
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D053244:Osteoprotegerin; D053219:Receptors, Tumor Necrosis Factor, Member 25; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; C506031:Tnfrsf11b protein, mouse; D014157:Transcription Factors; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D020780:Matrix Metalloproteinase 9