Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 29, Pages 12913-12918Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0913058107
Keywords
bone remodeling; osteoblasts; p62; autophagy; light chain 3
Categories
Funding
- Arthritis Research United Kingdom Fellowship
- British Heart Foundation
- Guy's & St Thomas' Charity
- Leukaemia and Lymphoma Research of Great Britain
- Biotechnology and Biological Sciences Research Council (BBSRC)
- MRC [G9800001] Funding Source: UKRI
- Medical Research Council [G9800001] Funding Source: researchfish
- Versus Arthritis [17655] Funding Source: researchfish
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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 similar to 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.
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