Activation Of Nfatc2 in osteoblasts causes osteopenia

Zanotti, Stefano; Canalis, Ernesto

doi:10.1002/jcp.24928

Cited by 15 publications

(13 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This potential discrepancy may be due to variability in the cellular composition of entheses (49), resulting in site-specific roles for NFATc2. In addition, recent studies also showed NFATc2 can directly inhibit osteoblast function and osteogenesis (50, 51), consistent with our finding.…”

Section: Discussionsupporting

confidence: 93%

NFAT restricts osteochondroma formation from entheseal progenitors

Ge¹,

Tsang²,

He³

et al. 2016

JCI Insight

View full text Add to dashboard Cite

Osteochondromas are common benign osteocartilaginous tumors in children and adolescents characterized by cartilage-capped bony projections on the surface of bones. These tumors often cause pain, deformity, fracture, and musculoskeletal dysfunction, and they occasionally undergo malignant transformation. The pathogenesis of osteochondromas remains poorly understood. Here, we demonstrate that nuclear factor of activated T cells c1 and c2 (NFATc1 and NFATc2) suppress osteochondromagenesis through individual and combinatorial mechanisms. In mice, conditional deletion of NFATc1 in mesenchymal limb progenitors, Scleraxis-expressing (Scx-expressing) tendoligamentous cells, or postnatally in Aggrecan-expressing cells resulted in osteochondroma formation at entheses, the insertion sites of ligaments and tendons onto bone. Combinatorial deletion of NFATc1 and NFATc2 gave rise to larger and more numerous osteochondromas in inverse proportion to gene dosage. A population of entheseal NFATc1- and Aggrecan-expressing cells was identified as the osteochondroma precursor, previously believed to be growth plate derived or perichondrium derived. Mechanistically, we show that NFATc1 restricts the proliferation and chondrogenesis of osteochondroma precursors. In contrast, NFATc2 preferentially inhibits chondrocyte hypertrophy and osteogenesis. Together, our findings identify and characterize a mechanism of osteochondroma formation and suggest that regulating NFAT activity is a new therapeutic approach for skeletal diseases characterized by defective or exaggerated osteochondral growth.

show abstract

Section: Discussionsupporting

confidence: 93%

NFAT restricts osteochondroma formation from entheseal progenitors

Ge¹,

Tsang²,

He³

et al. 2016

JCI Insight

View full text Add to dashboard Cite

show abstract

“…Importantly, the phenotype of 1-month-old mice revealed a lack of a bone-forming response to enhanced bone resorption, possibly invoking a direct or indirect inhibition of this process under conditions of Notch2 activation. In this context, we have found that Notch2 induces Nfatc2 in skeletal cells, and Nfatc2 suppresses osteoblast differentiation and function and may contribute to the uncoupling of a bone-forming response to the increase in bone resorption (70,71). 3 Histomorphometric analysis of cortical bone confirmed an increase in osteoclast number and bone resorption in the endocortical surface of 1-month-old Notch2 Q2319X mutants.…”

Section: Discussionmentioning

confidence: 81%

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

Canalis¹,

Schilling²,

Yee

et al. 2016

Journal of Biological Chemistry

Self Cite

106

View full text Add to dashboard Cite

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...

show abstract

“…129 Moreover, thapsigargin stimu-lation of LS8 cells resulted in activation of NFAT (R.L., unpublished data), a family of transcription factors regulated by Ca 2+ signals. 130 As NFAT plays an emerging role in bone formation and bone remodeling, 131,132 SOCE-mediated NFAT activity in enamel cells may become an important are of study.…”

Section: Soce In Ameloblast Signaling and Developmentmentioning

confidence: 99%

Diseases caused by mutations in ORAI1 and STIM1

Lacruz

Feske

2015

Annals of the New York Academy of Sciences

402

406

View full text Add to dashboard Cite

Ca2+ release-activated Ca2+ (CRAC) channels mediate a specific form of Ca2+ influx called store-operated Ca2+ entry (SOCE) that contributes to the function of many cell types. CRAC channels are formed by ORAI1 proteins located in the plasma membrane, which form its ion-conducting pore. ORAI1 channels are activated by stromal interaction molecule (STIM) 1 and STIM2 located in the endoplasmic reticulum. Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes. CRAC channelopathy is caused by loss-of-function mutations in ORAI1 and STIM1 that abolish CRAC channel function and SOCE; it is characterized by severe combined immunodeficiency (SCID)-like disease, autoimmunity, muscular hypotonia, and ectodermal dysplasia, with defects in dental enamel. The latter defect emphasizes an important role of CRAC channels in tooth development. By contrast, autosomal dominant gain-of-function mutations in these genes result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca2+ levels that are associated with an overlapping spectrum of diseases, including non-syndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes, two syndromes defined, besides myopathy, by thrombocytopenia, thrombopathy, and bleeding diathesis. The fact that myopathy results from loss- and gain-of-function mutations in ORAI1 and STIM1 highlights the importance of CRAC channels for Ca2+ homeostasis in skeletal muscle function. The cellular dysfunction and clinical disease spectrum observed in mutant patients provide important information about the molecular regulation of ORAI1 and STIM1 proteins and the role of CRAC channels in human physiology.

show abstract

Activation Of Nfatc2 in osteoblasts causes osteopenia

Cited by 15 publications

References 39 publications

NFAT restricts osteochondroma formation from entheseal progenitors

NFAT restricts osteochondroma formation from entheseal progenitors

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

Diseases caused by mutations in ORAI1 and STIM1

Contact Info

Product

Resources

About