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

Whitehouse, Caroline; Waters, Sarah L.; Marchbank, Katie; Hörner, A.; McGowan, Neil; Jovanović, Jelena; Xavier, Guilherme M.; Kashima, Takeshi; Cobourne, Martyn T.; Richards, Gareth O.; Sharpe, Paul T.; Skerry, Timothy M.; Grigoriadis, Agamemnon E.; Solomon, Ellen

doi:10.1073/pnas.0913058107

Cited by 76 publications

(71 citation statements)

References 38 publications

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“…The age-dependent decrease in bone mass induced by osteoblast-specific deletion of p38a supports previous observations of Whitehouse et al [14] in their homozygous truncated Nbr1 (trNbr1) mutant mice. Genetic truncation of Nbr1, a receptor for selective autophagosomal degradation of ubiquitinated target proteins, was shown to induce an age-dependent increase in bone mass due to stimulated bone formation.…”

Section: Discussionsupporting

confidence: 90%

“…In cultures, trNbr1 osteoblasts were highly active and had elevated activation of p38 MAPK. The pharmacological inhibition of p38 MAPK could abrogate the increased trNbr1 osteoblast activity [14]. Interestingly, the bone phenotype of our Dp38a mutant mice was the opposite to that of trNbr1 mutant mice.…”

Section: Discussionmentioning

confidence: 69%

“…Another MAP3K, mixed-lineage kinase 3 (MLK3) acting downstream of faciogenital dysplasia protein 1, has also been identified as a regulator of osteoblastogenesis and bone development by modulating ERK and p38 MAPK pathways [13]. In addition, the genetic disruption of the neighbor of Brca1 gene-encoding Nbr1, a receptor for selective autophagosomal degradation of ubiquitinated target proteins, has been shown to induce an age-dependent increase in bone mass due to continuous osteoblastic p38 MAPK activation and subsequent stimulated bone formation [14].…”

Section: Introductionmentioning

confidence: 99%

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The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

Thouverey

Caverzasio

2012

Cell. Mol. Life Sci.

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Bone continuously remodels throughout life by coordinated actions of osteoclasts and osteoblasts. Abnormalities in either osteoclast or osteoblast functions lead to bone disorders. The p38 MAPK pathway has been shown to be essential in controlling osteoblast differentiation and skeletogenesis. Although p38a is the most abundant p38 member in osteoblasts, its specific individual contribution in regulating postnatal osteoblast activity and bone metabolism is unknown. To elucidate the specific role of p38a in regulating osteoblast function and bone homeostasis, we generated mice lacking p38a in differentiated osteoblasts. Osteoblast-specific p38a knockout mice were of normal weight and size. Despite non-significant bone alterations until 5 weeks of age, mutant mice demonstrated significant and progressive decrease in bone mineral density from that age. Adult mice deficient in p38a in osteoblasts displayed a striking reduction in cancellous bone volume at both axial and appendicular skeletal sites. At 6 months of age, trabecular bone volume was reduced by 62 % in those mice. Mutant mice also exhibited progressive decrease in cortical thickness of long bones. These abnormalities correlated with decreased endocortical and trabecular bone formation rate and reduced expressions of type 1 collagen, alkaline phosphatase, osteopontin and osteocalcin whereas bone resorption and osteoclasts remained unaffected. Finally, osteoblasts lacking p38a showed impaired marker gene expressions and defective mineralization in vitro. These findings indicate that p38a is an essential positive regulator of osteoblast function and postnatal bone formation in vivo.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

Thouverey

Caverzasio

2012

Cell. Mol. Life Sci.

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“…44 Indeed, global genetic truncation of Nbr1 (trNbr1) results in progressive increase in bone mass with age due to enhanced bone formation, osteoblast differentiation and p38 activity. 44 Unlike the full-length protein, trNBR1 could not bind activated p38 MAPK and target it for degradation. 44 Interestingly, NBR1 truncation leads to negligible effect on osteoclastogenesis and bone resorption, indicating a specific regulation of p38 activity in osteoblasts.…”

Section: Upstream Activators Of P38 Mapk In Osteoblastsmentioning

confidence: 99%

“…44 A neighbor of Brca1 gene protein 1 (NBR1), a receptor for selective autophagosomal degradation of ubiquitinated target proteins, has been described as a negative regulator of p38 MAPK in osteoblasts. 44 Indeed, global genetic truncation of Nbr1 (trNbr1) results in progressive increase in bone mass with age due to enhanced bone formation, osteoblast differentiation and p38 activity. 44 Unlike the full-length protein, trNBR1 could not bind activated p38 MAPK and target it for degradation.…”

Section: Upstream Activators Of P38 Mapk In Osteoblastsmentioning

confidence: 99%

Focus on the p38 MAPK signaling pathway in bone development and maintenance

2015

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The p38 mitogen-activated protein kinase (MAPK) signaling pathway can be activated in response to a wide range of extracellular signals. As a consequence, it can generate many different biological effects that depend on the stimulus and on the activated cell type. Therefore, this pathway has been found to regulate many aspects of tissue development and homeostasis. Recent work with the aid of genetically modified mice has highlighted the physiological functions of this pathway in skeletogenesis and postnatal bone maintenance. In this review, emphasis is given to the roles of the p38 MAPK pathway in chondrocyte, osteoblast and osteoclast biology. In particular, we describe the molecular mechanisms of p38 MAPK activation and downstream targets. The requirement of this pathway in physiological bone development and homeostasis is demonstrated by the ability of p38 MAPK to regulate master transcription factors controlling geneses and functions of chondrocytes, osteoblasts and osteoclasts.

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Autophagy: A new player in skeletal maintenance?

Hocking

Whitehouse

Helfrich

2012

Journal of Bone and Mineral Research

133

114

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Imbalances between bone resorption and formation lie at the root of disorders such as osteoporosis, Paget's disease of bone (PDB), and osteopetrosis. Recently, genetic and functional studies have implicated proteins involved in autophagic protein degradation as important mediators of bone cell function in normal physiology and in pathology. Autophagy is the conserved process whereby aggregated proteins, intracellular pathogens, and damaged organelles are degraded and recycled. This process is important both for normal cellular quality control and in response to environmental or internal stressors, particularly in terminally-differentiated cells. Autophagic structures can also act as hubs for the spatial organization of recycling and synthetic process in secretory cells. Alterations to autophagy (reduction, hyperactivation, or impairment) are associated with a number of disorders, including neurodegenerative diseases and cancers, and are now being implicated in maintenance of skeletal homoeostasis. Here, we introduce the topic of autophagy, describe the new findings that are starting to emerge from the bone field, and consider the therapeutic potential of modifying this pathway for the treatment of age-related bone disorders. ß

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

Cited by 76 publications

References 38 publications

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

Focus on the p38 MAPK signaling pathway in bone development and maintenance

Autophagy: A new player in skeletal maintenance?

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