HES1 (Hairy and Enhancer of Split 1) Is a Determinant of Bone Mass

Zanotti, Stefano; Smerdel-Ramoya, Anna; Canalis, Ernesto

doi:10.1074/jbc.m110.183038

Cited by 49 publications

(53 citation statements)

References 62 publications

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“…Confirming previous work, the induction of Hes1 in osteoclasts was dependent not only on Notch2 activation but also on the degree of osteoclast maturation (20). Moreover, the phenotype observed in Notch2 Q2319X male mice is in accordance with the known effects of Hes1 on osteoclastogenesis and bone resorption (74). This may suggest that Hes1 is responsible for selected actions of Notch2 or of the Notch2 Q2319X mutants in the skeleton.…”

Section: Discussionsupporting

confidence: 75%

Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption

Canalis¹,

Schilling²,

Yee

et al. 2016

Journal of Biological Chemistry

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106

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Notch receptors are determinants of cell fate and function and play a central role in skeletal development and bone remodeling. Hajdu Cheney syndrome, a disease characterized by osteoporosis and fractures, is associated with NOTCH2 mutations resulting in a truncated stable protein and gain-of-function. We created a mouse model reproducing the Hajdu Cheney syndrome by introducing a 6955C3 T mutation in the Notch2 locus leading to a Q2319X change at the amino acid level. Notch2Q2319X heterozygous mutants were smaller and had shorter femurs than controls; and at 1 month of age they exhibited cancellous and cortical bone osteopenia. As the mice matured, cancellous bone volume was restored partially in male but not female mice, whereas cortical osteopenia persisted in both sexes. Cancellous bone histomorphometry revealed an increased number of osteoclasts and bone resorption, without a decrease in osteoblast number or bone formation. Osteoblast differentiation and function were not affected in Notch2 Q2319X cells. The pre-osteoclast cell pool, osteoclast differentiation, and bone resorption in response to receptor activator of nuclear factor B ligand in vitro were increased in Notch2 Q2319X mutants. These effects were suppressed by the ␥-secretase inhibitor LY450139. In conclusion, Notch2 Q2319X mice exhibit cancellous and cortical bone osteopenia, enhanced osteoclastogenesis, and increased bone resorption.Notch proteins are four single-pass transmembrane receptors that play a critical role in cell fate decisions ( Fig. 1) (1-4). Notch regulates cell renewal and plays a role in skeletal development and homeostasis and in osteoblast and osteoclast differentiation (4 -8). Jagged1 and -2 and DeltaLike1, -3, and -4 are the five classic Notch ligands (4). Notch-ligand interactions result in the proteolytic cleavage and release of the Notch intracellular domain (NICD), 2 which translocates to the nucleus to form a complex with recombination signal-binding protein for immunoglobulin J region (Rbpj) and Mastermind-like to regulate transcription (9 -12). This canonical signaling pathway leads to the transcription of Hairy Enhancer of Split (Hes)1, -5, and -7 and Hes related with YRPW motif (Hey)1, -2, and -L. Skeletal cells express Notch1, Notch2, and low levels of Notch3 transcripts (13-15). Activation of Notch in undifferentiated and differentiated osteoblasts inhibits cell differentiation and function and causes osteopenia (16,17). In contrast, activation of Notch1 in osteocytes causes a pronounced increase in bone mass due to a suppression of bone resorption (18). Results from the conditional inactivation of Notch1 and Notch2 in the developing skeleton confirmed the inhibitory role of Notch in osteoblastogenesis (6,19). Whereas substantial work has characterized the consequences of Notch1 gain-of-function in the skeleton, there is limited knowledge on the function of Notch2 in the postnatal skeleton. This knowledge is particularly important because Notch1 and Notch2 do not have redundant functions, and Notch1 inhibits, wh...

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Section: Discussionsupporting

confidence: 75%

Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption

Canalis¹,

Schilling²,

Yee

et al. 2016

Journal of Biological Chemistry

Self Cite

106

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“…Alternatively, Col2Cre;Hes1 f/f ;Hes5 −/− mutant mice might not have developed defects such as those observed in our study at E10.5-15.5 because the Col2Cre transgene targets a more committed osteo-chondro progenitor population. Prx1Cre;Hes1 f/f ; Hes3 −/− ;Hes5 −/− mutant mice have also previously been generated and shown to have increased postnatal bone mass that is consistent with other Notch LOF mutant mice Tu et al, 2012), although only limited late-stage embryonic skeletal analyses were performed that showed no obvious phenotype (Zanotti et al, 2011). Similarly, Hey1 +/− ; HeyL −/− mutant mice have been shown to have increased bone mass as compared to controls at late postnatal and adult time points (Tu et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

HES factors regulate specific aspects of chondrogenesis and chondrocyte hypertrophy during cartilage development

Rutkowski

Kohn

Sharma

et al. 2016

Journal of Cell Science

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RBPjκ-dependent Notch signaling regulates multiple processes during cartilage development, including chondrogenesis, chondrocyte hypertrophy and cartilage matrix catabolism. Select members of the HES-and HEY-families of transcription factors are recognized Notch signaling targets that mediate specific aspects of Notch function during development. However, whether particular HES and HEY factors play any role(s) in the processes during cartilage development is unknown. Here, for the first time, we have developed unique in vivo genetic models and in vitro approaches demonstrating that the RBPjκ-dependent Notch targets HES1 and HES5 suppress chondrogenesis and promote the onset of chondrocyte hypertrophy. HES1 and HES5 might have some overlapping function in these processes, although only HES5 directly regulates Sox9 transcription to coordinate cartilage development. HEY1 and HEYL play no discernable role in regulating chondrogenesis or chondrocyte hypertrophy, whereas none of the HES or HEY factors appear to mediate Notch regulation of cartilage matrix catabolism. This work identifies important candidates that might function as downstream mediators of Notch signaling both during normal skeletal development and in Notch-related skeletal disorders.

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“…6B; see also Table S1 in the supplemental material). Of note, transgenic overexpression of Hes1 results in osteopenia due to decreased OBL activity (70), while inhibition of canonical Notch signaling increased osteoblast numbers and BMD (71). The differential expression of several of these osteoblastogenesis signature markers was further validated by RT-qPCR (Fig.…”

Section: Runx3mentioning

confidence: 99%

Loss of Osteoblast Runx3 Produces Severe Congenital Osteopenia

Bauer

Sharir

Kimura

et al. 2015

Molecular and Cellular Biology

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bCongenital osteopenia is a bone demineralization condition that is associated with elevated fracture risk in human infants. Here we show that Runx3, like Runx2, is expressed in precommitted embryonic osteoblasts and that Runx3-deficient mice develop severe congenital osteopenia. Runx3-deficient osteoblast-specific (Runx3 fl/fl /Col1␣1-cre), but not chondrocyte-specific (Runx3 fl/fl /Col1␣2-cre), mice are osteopenic. This demonstrates that an osteoblastic cell-autonomous function of Runx3 is required for proper osteogenesis. Bone histomorphometry revealed that decreased osteoblast numbers and reduced mineral deposition capacity in Runx3-deficient mice cause this bone formation deficiency. Neonatal bone and cultured primary osteoblast analyses revealed a Runx3-deficiency-associated decrease in the number of active osteoblasts resulting from diminished proliferation and not from enhanced osteoblast apoptosis. These findings are supported by Runx3-null culture transcriptome analyses showing significant decreases in the levels of osteoblastic markers and increases in the levels of Notch signaling components. Thus, while Runx2 is mandatory for the osteoblastic lineage commitment, Runx3 is nonredundantly required for the proliferation of these precommitted cells, to generate adequate numbers of active osteoblasts. Human RUNX3 resides on chromosome 1p36, a region that is associated with osteoporosis. Therefore, RUNX3 might also be involved in human bone mineralization.

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HES1 (Hairy and Enhancer of Split 1) Is a Determinant of Bone Mass

Cited by 49 publications

References 62 publications

Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption

Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption

HES factors regulate specific aspects of chondrogenesis and chondrocyte hypertrophy during cartilage development

Loss of Osteoblast Runx3 Produces Severe Congenital Osteopenia

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