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

Caroline A. Whitehouse; Sarah Waters; Katie Marchbank; Alan Horner; Neil W. A. McGowan; Jelena V. Jovanovic; Guilherme Machado Xavier; Takeshi G. Kashima; Martyn T. Cobourne; Gareth O. Richards; Paul T. Sharpe; Tim M. Skerry; Agamemnon E. Grigoriadis; Ellen Solomon

doi:10.1073/pnas.0913058107

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

Caroline A. Whitehouse, Sarah Waters, Katie Marchbank, Alan Horner, Neil W. A. McGowan, Jelena V. Jovanovic, Guilherme Machado Xavier, Takeshi G. Kashima, Martyn T. Cobourne, Gareth O. Richards, Paul T. Sharpe, Tim M. Skerry, Agamemnon E. Grigoriadis, Ellen Solomon

Research output: Contribution to journal › Article › peer-review

79 Citations (Scopus)

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 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.

Original language	English
Pages (from-to)	12913 - 12918
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	107
Issue number	29
DOIs	https://doi.org/10.1073/pnas.0913058107
Publication status	Published - 20 Jul 2010

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Whitehouse, C. A., Waters, S., Marchbank, K., Horner, A., McGowan, N. W. A., Jovanovic, J. V., Machado Xavier, G., Kashima, T. G., Cobourne, M. T., Richards, G. O., Sharpe, P. T., Skerry, T. M., Grigoriadis, A. E., & Solomon, E. (2010). Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity. Proceedings of the National Academy of Sciences of the United States of America, 107(29), 12913 - 12918. https://doi.org/10.1073/pnas.0913058107

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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 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.",

author = "Whitehouse, {Caroline A.} and Sarah Waters and Katie Marchbank and Alan Horner and McGowan, {Neil W. A.} and Jovanovic, {Jelena V.} and {Machado Xavier}, Guilherme and Kashima, {Takeshi G.} and Cobourne, {Martyn T.} and Richards, {Gareth O.} and Sharpe, {Paul T.} and Skerry, {Tim M.} and Grigoriadis, {Agamemnon E.} and Ellen Solomon",

year = "2010",

month = jul,

day = "20",

doi = "10.1073/pnas.0913058107",

language = "English",

volume = "107",

pages = "12913 -- 12918",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Whitehouse, CA, Waters, S, Marchbank, K, Horner, A, McGowan, NWA , Jovanovic, JV , Machado Xavier, G, Kashima, TG, Cobourne, MT, Richards, GO, Sharpe, PT, Skerry, TM, Grigoriadis, AE & Solomon, E 2010, 'Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 29, pp. 12913 - 12918. https://doi.org/10.1073/pnas.0913058107

Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity. / Whitehouse, Caroline A.; Waters, Sarah; Marchbank, Katie et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 29, 20.07.2010, p. 12913 - 12918.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity

AU - Whitehouse, Caroline A.

AU - Waters, Sarah

AU - Marchbank, Katie

AU - Horner, Alan

AU - McGowan, Neil W. A.

AU - Jovanovic, Jelena V.

AU - Machado Xavier, Guilherme

AU - Kashima, Takeshi G.

AU - Cobourne, Martyn T.

AU - Richards, Gareth O.

AU - Sharpe, Paul T.

AU - Skerry, Tim M.

AU - Grigoriadis, Agamemnon E.

AU - Solomon, Ellen

PY - 2010/7/20

Y1 - 2010/7/20

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.0913058107

DO - 10.1073/pnas.0913058107

M3 - Article

C2 - 20616007

SN - 1091-6490

VL - 107

SP - 12913

EP - 12918

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 29

ER -

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

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