title: Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity.
abstract: The neighbor of Brca1 gene (Nbr1) functions as an autophagy receptor involved in targeting ubiquitinated proteins for degradation. It also has a dual role as a scaffold protein to regulate growth-factor receptor and downstream signaling pathways. We show that genetic truncation of murine Nbr1 leads to an age-dependent increase in bone mass and bone mineral density through increased osteoblast differentiation and activity. At 6 mo of age, despite normal body size, homozygous mutant animals (Nbr1(tr/tr)) have approximately 50% more bone than littermate controls. Truncated Nbr1 (trNbr1) co-localizes with p62, a structurally similar interacting scaffold protein, and the autophagosome marker LC3 in osteoblasts, but unlike the full-length protein, trNbr1 fails to complex with activated p38 MAPK. Nbr1(tr/tr) osteoblasts and osteoclasts show increased activation of p38 MAPK, and significantly, pharmacological inhibition of the p38 MAPK pathway in vitro abrogates the increased osteoblast differentiation of Nbr1(tr/tr) cells. Nbr1 truncation also leads to increased p62 protein expression. We show a role for Nbr1 in bone remodeling, where loss of function leads to perturbation of p62 levels and hyperactivation of p38 MAPK that favors osteoblastogenesis.
authors.affiliation: King's College London, Department of Medical and Molecular Genetics, London SE1 9RT, United Kindom. caroline.whitehouse@kcl.ac.uk
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Whitehouse
authors.forename: Sarah
authors.initials: S
authors.lastname: Waters
authors.forename: Katie
authors.initials: K
authors.lastname: Marchbank
authors.forename: Alan
authors.initials: A
authors.lastname: Horner
authors.forename: Neil W A
authors.initials: NW
authors.lastname: McGowan
authors.forename: Jelena V
authors.initials: JV
authors.lastname: Jovanovic
authors.forename: Guilherme M
authors.initials: GM
authors.lastname: Xavier
authors.forename: Takeshi G
authors.initials: TG
authors.lastname: Kashima
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Cobourne
authors.forename: Gareth O
authors.initials: GO
authors.lastname: Richards
authors.forename: Paul T
authors.initials: PT
authors.lastname: Sharpe
authors.forename: Tim M
authors.initials: TM
authors.lastname: Skerry
authors.forename: Agamemnon E
authors.initials: AE
authors.lastname: Grigoriadis
authors.forename: Ellen
authors.initials: E
authors.lastname: Solomon
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density; D019556:COS Cells; D002454:Cell Differentiation; D002522:Chlorocebus aethiops; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009929:Organ Size; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology*; D010012:Osteogenesis; D055550:Protein Stability; D021381:Protein Transport; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C490981:Gtf2h1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D050505:Mutant Proteins; C486326:Nbr1 protein, mouse; D011506:Proteins; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D048051:p38 Mitogen-Activated Protein Kinases