Osteoblast Menin Regulates Bone Mass in Vivo

Kanazawa, Ippei; Canaff, Lucie; Abi‐Rafeh, Jad; Angrula, Aarti; Li, Jingjing; Riddle, Ryan C.; Boraschi-Diaz, Iris; Komarova, Svetlana V.; Clemens, Thomas L.; Murshed, Monzur; Hendy, Geoffrey N.

doi:10.1074/jbc.m114.629899

Cited by 31 publications

(46 citation statements)

References 38 publications

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“…Also, knockout of Men1 in the liver (using albumin promoter/ALB-Cre), a tissue not targeted in MEN1, does not lead to tumors in the liver despite the complete loss of Men1 (Scacheri, et al 2004). Other mouse models with knockout of Men1 in pancreatic endocrine cell lineages, bone cells, and intestinal cells have also helped to gain insight into the physiological actions of menin (Bonnavion, et al 2015; Kanazawa, et al 2015; Liu, et al 2017; Sundaresan, et al 2016; Veniaminova, et al 2012). These elegant studies in genetically engineered mouse models show that menin may function as a cell-type-specific tumor suppressor, and that its action is only required in MEN1-associated target tissues to prevent tumorigenesis.…”

Section: Genetically Engineered Mouse Modelsmentioning

confidence: 99%

The future: genetics advances in MEN1 therapeutic approaches and management strategies

Agarwal¹

2017

Endocrine-Related Cancer

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The identification of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997 has shown that germline heterozygous mutations in the MEN1 gene located on chromosome 11q13, predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of the MEN1 gene in MEN1-target tissues. Therefore, MEN1 is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by the MEN1 gene, menin, holds true in mouse models with germline heterozygous Men1 loss wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of the Men1 gene. The availability of genetic testing for mutations in the MEN1 gene has become an essential part of the diagnosis and management of MEN1. Genetic testing is also helping to exclude mutation negative cases in MEN1 families from the burden of lifelong clinical screening. In the past 20 years, efforts of various groups world-wide have been directed at mutation analysis, molecular genetic studies, mouse models, gene expression studies, epigenetic regulation analysis, biochemical studies, and anti-tumor effects of candidate therapies in mouse models. This review will focus on the findings and advances from these studies to identify MEN1 germline and somatic mutations, the genetics of MEN1-related states, several protein partners of menin, the three-dimensional structure of menin, and menin-dependent target genes. The ongoing impact of all these studies on disease prediction, management and outcomes will continue in the years to come.

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Section: Genetically Engineered Mouse Modelsmentioning

confidence: 99%

The future: genetics advances in MEN1 therapeutic approaches and management strategies

Agarwal¹

2017

Endocrine-Related Cancer

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“…7 In vitro studies in cell lines and primary osteoblasts derived from 6-month-old mice showed that menin promotes early osteoblast differentiation in committed cells. Knockdown of Men1 with antisense oligonucleotides lead to enhanced BMP2 signaling 8, 9, 10 and to facilitated inhibition of the late stage of osteoblast differentiation by potentiating TGF β -dependent Smad3 signaling.…”

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confidence: 99%

“…11, 12 Accordingly, reduced bone mass and reduced bone formation due to decreased osteoblast proliferation and differentiation and enhanced apoptosis have been reported using aged osteocalcin-cre mice crossed to Men1 floxed mice that leads to a conditional deletion of menin in the late stage of differentiated osteoblasts. 7 On the other hand, aged osteoblast-specific menin transgenic mice were found to display increased bone mass. 7 However, whether Men1 plays a role in bone cells to control bone integrity in young or middle-aged mice is completely unknown.…”

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Loss of menin in osteoblast lineage affects osteocyte–osteoclast crosstalk causing osteoporosis

et al. 2017

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During osteoporosis bone formation by osteoblasts is reduced and/or bone resorption by osteoclasts is enhanced. Currently, only a few factors have been identified in the regulation of bone integrity by osteoblast-derived osteocytes. In this study, we show that specific disruption of menin, encoded by multiple endocrine neoplasia type 1 (Men1), in osteoblasts and osteocytes caused osteoporosis despite the preservation of osteoblast differentiation and the bone formation rate. Instead, an increase in osteoclast numbers and bone resorption was detected that persisted even when the deletion of Men1 was restricted to osteocytes. We demonstrate that isolated Men1-deficient osteocytes expressed numerous soluble mediators, such as C-X-C motif chemokine 10 (CXCL10), and that CXCL10-mediated osteoclastogenesis was reduced by CXCL10-neutralizing antibodies. Collectively, our data reveal a novel role for Men1 in osteocyte-osteoclast crosstalk by controlling osteoclastogenesis through the action of soluble factors. A role for Men1 in maintaining bone integrity and thereby preventing osteoporosis is proposed. Cell Death and Differentiation (2017) 24, 672-682; doi:10.1038/cdd.2016.165; published online 20 January 2017The maintenance of bone mass is severely affected in osteoporotic patients and other bone disorders and can have multiple etiologies. The complex communication of boneforming osteoblasts, bone-residing osteocytes, and boneresorbing osteoclasts is still not fully understood. Two hallmark studies 1,2 have demonstrated that osteocytes are the major source of the osteoclastogenesis-stimulating factor RANKL and thus key components in the control of bone mass. This property goes beyond their previously suggested function of sensing the mechanical loading of bone. 3 PTH 4 and sclerostin 5 have been reported to stimulate osteocytes to support osteoclastogenesis via a RANKL-dependent pathway. High-mobility group box 1 (HMGB1), which is chemotactic to osteoclasts, is enhanced in apoptotic MLO-Y4 cells; 6 however, there is little information on other factors controlling osteoclast activity by osteoblast-derived osteocytes.The nuclear protein menin encoded by the gene Men1 (multiple endocrine neoplasia type 1) has recently been suggested to control bone mass at higher age through its influence on the differentiation and function of osteoblasts. 7 In vitro studies in cell lines and primary osteoblasts derived from 6-month-old mice showed that menin promotes early osteoblast differentiation in committed cells. Knockdown of Men1 with antisense oligonucleotides lead to enhanced BMP2 signaling [8][9][10] and to facilitated inhibition of the late stage of osteoblast differentiation by potentiating TGFβ-dependent Smad3 signaling. 11,12 Accordingly, reduced bone mass and reduced bone formation due to decreased osteoblast proliferation and differentiation and enhanced apoptosis have been reported using aged osteocalcin-cre mice crossed to Men1 floxed mice that leads to a conditional deletion of menin in the late stage of differentiate...

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“…Patients with MEN1 commonly develop bone disease with osteoporosis thought secondary to the hyperparathyroidism (56) (57). However, recent studies show that menin has important effects in bone particularly in regulating osteoblast activity which plays a key role in bone deveopment, remodeling and maintenance (58). Some MEN1 patients require multiple re-operations to control the recurrent or persistent hyperparathyroidism and reoperation can be difficult and associated with increased morbidity.…”

Section: Multiple Endocrine Neoplasia Type 1 (Men-1)mentioning

confidence: 99%

Multiple Endocrine Neoplasia

Norton¹,

Krampitz²,

Jensen³

2015

Surgical Oncology Clinics of North America

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Osteoblast Menin Regulates Bone Mass in Vivo

Abstract: Background: Constitutive homozygous Men1Ϫ/Ϫ mice at mid-gestation are small with craniofacial defects.

Cited by 31 publications

References 38 publications

The future: genetics advances in MEN1 therapeutic approaches and management strategies

The future: genetics advances in MEN1 therapeutic approaches and management strategies

Loss of menin in osteoblast lineage affects osteocyte–osteoclast crosstalk causing osteoporosis

Multiple Endocrine Neoplasia

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