title: SMURF2 regulates bone homeostasis by disrupting SMAD3 interaction with vitamin D receptor in osteoblasts.
abstract: Coordination between osteoblasts and osteoclasts is required for bone health and homeostasis. Here we show that mice deficient in SMURF2 have severe osteoporosis in vivo. This low bone mass phenotype is accompanied by a pronounced increase in osteoclast numbers, although Smurf2-deficient osteoclasts have no intrinsic alterations in activity. Smurf2-deficient osteoblasts display increased expression of RANKL, the central osteoclastogenic cytokine. Mechanistically, SMURF2 regulates RANKL expression by disrupting the interaction between SMAD3 and vitamin D receptor by altering SMAD3 ubiquitination. Selective deletion of Smurf2 in the osteoblast lineage recapitulates the phenotype of germline Smurf2-deficient mice, indicating that SMURF2 regulates osteoblast-dependent osteoclast activity rather than directly affecting the osteoclast. Our results reveal SMURF2 as an important regulator of the critical communication between osteoblasts and osteoclasts. Furthermore, the bone mass phenotype in Smurf2- and Smurf1-deficient mice is opposite, indicating that SMURF2 has a non-overlapping and, in some respects, opposite function to SMURF1.
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Pathology, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Greenblatt
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA.
authors.forename: Sutada
authors.initials: S
authors.lastname: Lotinun
authors.affiliation: Department of Lab Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Nicholas
authors.identifier: 0000-0002-2928-0232
authors.initials: N
authors.lastname: Brady
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.affiliation: State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zou
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D053245:RANK Ligand; D018167:Receptors, Calcitriol; D051900:Smad3 Protein; C533325:Smurf2 protein, mouse; D044767:Ubiquitin-Protein Ligases