Hajdu-Cheney syndrome: a review

Canalis, Ernesto; Zanotti, Stefano

doi:10.1186/s13023-014-0200-y

Cited by 80 publications

(74 citation statements)

References 83 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Some of the facial features of the syndrome appear in the first few months of life, but the clinical manifestations of the syndrome, including osteoporosis and acral osteolysis, are progressive and more evident during adolescence and adulthood (68,69). It is of interest that Notch2 Q2319X mutant Hajdu Cheney mice did not exhibit detectable acral osteolysis or obvious neurological manifestations reported in humans affected by the disease.…”

Section: Discussionmentioning

confidence: 99%

“…Although one needs to be cautious with the extrapolation of these results to human disease, an increase in bone resorption could explain the pronounced osteoporosis suffered by subjects with Hajdu Cheney syndrome. The osteolytic lesions observed in these patients reflect a localized resorptive event as well as an inflammatory process (68). If enhanced bone resorption is responsible for the disease, anti-resorptive therapy could prove beneficial to patients with Hajdu Cheney syndrome; however, clinical data on its effectiveness are sparse.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

show abstract

“…In clinical practice, bisphosphonate, which suppresses osteoclast formation, is commonly used for treating patients with HCS (Canalis and Zanotti, 2014; Galli-Tsinopoulou et al, 2012). Recent studies indicate that NOTCH2-dependent osteoclastic bone resorption results in HCS development (Canalis et al, 2017; Canalis et al, 2016; Isidor et al, 2011; Simpson et al, 2011; Vollersen et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis

et al. 2017

View full text Add to dashboard Cite

Summary Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acroosteolysis, severe osteoporosis, short stature, neurological symptoms, cardiovascular defects, and polycystic kidneys. Recent studies identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with the bone-related disorder pathogenesis, but the exact molecular mechanisms remain unclear. Here, we demonstrate that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C-terminus that escapes FBW7-mediated ubiquitination and degradation. Mice with osteoclast-specific Fbw7 ablation revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 signaling. Importantly, administration of Notch inhibitors in Fbw7 conditional knockout mice alleviated progressive bone resorption. These findings highlight the molecular basis of HCS pathogenesis and provide clinical insights into potential targeted therapeutic strategies for skeletal disorders associated with the aberrant FBW7/NOTCH2 pathway as observed in patients with HCS.

show abstract

“…Notch signaling is activated in SSc, playing an important role in fibrosis (40), but its contribution to AO is not known. However, in Hajdu-Cheney syndrome, a rare disease evolving with AO due to Notch2 gain-of-function mutation, osteoclast hyperactivation along with endothelial impairment are involved (41).…”

Section: Hypoxia In Systemic Sclerosis: the Hif Pathway And Its Dysrementioning

confidence: 99%

Acroosteolysis in systemic sclerosis: An insight into hypoxia-related pathogenesis

Siao-Pin

Damian

Muntean

et al. 2016

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. Acro-osteolysis, or bony resorption of the terminal digital tufts, is a well-recognized, but under-researched, feature of systemic sclerosis. The mechanisms that disturbs local homeostatic balance of bone formation and resorption in favor of osteoclast activation and pathological bone loss remain to be established. Vascular alterations and reduced capillary density impair tissue oxygenation in systemic sclerosis, and the resulting hypoxia might contribute directly to the disease progression. In this paper we summarize the current evidence for hypoxia as the common pathophysiological denominator of digital vasculopathy and enhanced osteoclastic activity in systemic sclerosis-associated acroosteolysis. The hypoxia-inducible transcription factor HIF-1α and VEGF signaling has a critical role in regulating osteoclastic bone-resorption and angiogenesis, and increased osteoclastogenesis and higher VEGF levels may contribute to acroosteolysis in systemic sclerosis. The cells of the osteoblast lineage also have important roles in angiogenic-osteogenic coupling. The research in this field might help limiting the disability associated with the disease.

show abstract

Hajdu-Cheney syndrome: a review

Cited by 80 publications

References 83 publications

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

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

NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis

Acroosteolysis in systemic sclerosis: An insight into hypoxia-related pathogenesis

Contact Info

Product

Resources

About