Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 29; pp. 12913 - 12918
• Main Authors: Whitehouse, Caroline A., Waters, Sarah, Marchbank, Katie, Horner, Alan, McGowan, Neil W. A., Jovanovic, Jelena V., Xavier, Guilherme M., Kashima, Takeshi G., Cobourne, Martyn T., Richards, Gareth O., Sharpe, Paul T., Skerry, Tim M., Grigoriadis, Agamemnon E., Solomon, Ellen, Olson, Eric N.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20-07-2010; National Acad Sciences
• Subjects: Animals; Animals, Newborn; Autophagy; Biological Sciences; Bone Density; Bone formation; Bones; Cell Differentiation; Cells; Chlorocebus aethiops; COS Cells; Cytoplasmic Vesicles - metabolism; Femur; Gene expression regulation; Genetic mutation; Genetics; Intracellular Signaling Peptides and Proteins; Mice; Mice, Mutant Strains; Microtubule-Associated Proteins - metabolism; Mutant Proteins - metabolism; Mutation; Organ Size; Osteoblasts; Osteoblasts - cytology; Osteoblasts - enzymology; Osteoclasts; Osteogenesis; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Stability; Protein Transport; Proteins; Proteins - genetics; Proteins - metabolism; Subcellular Fractions - metabolism; Transcription Factor TFIIH; Transcription Factors - metabolism; Truncation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0913058107

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 ∼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.