Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity.
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.
Whitehouse
Caroline A
CA
King's College London, Department of Medical and Molecular Genetics, London SE1 9RT, United Kindom. caroline.whitehouse@kcl.ac.uk
Waters
Sarah
S
Marchbank
Katie
K
Horner
Alan
A
McGowan
Neil W A
NW
Jovanovic
Jelena V
JV
Xavier
Guilherme M
GM
Kashima
Takeshi G
TG
Cobourne
Martyn T
MT
Richards
Gareth O
GO
Sharpe
Paul T
PT
Skerry
Tim M
TM
Grigoriadis
Agamemnon E
AE
Solomon
Ellen
E
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*
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