Cleidocranial dysplasia with decreased bone density and biochemical findings of hypophosphatasia

Morava, Éva; Kárteszi, Judit; Weisenbach, J; Caliebe, Almuth; Mundlos, Stefan; Méhes, K

doi:10.1007/s00431-002-0977-x

Cited by 32 publications

(22 citation statements)

References 15 publications

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“…Studies to identify the mechanisms by which RUNX2 and TNSALP interact will provide important molecular evidence to support our clinical hypothesis. In the interim, recognition of the hypophosphatasia phenocopy in some CCD patients [9] should help prevent misdiagnosis and clarify the varying natural history of this disorder.…”

Section: Discussionmentioning

confidence: 98%

Severe cleidocranial dysplasia can mimic hypophosphatasia

Unger

Mornet

Mundlos

et al. 2002

European Journal of Pediatrics

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Section: Discussionmentioning

confidence: 98%

Severe cleidocranial dysplasia can mimic hypophosphatasia

Unger

Mornet

Mundlos

et al. 2002

European Journal of Pediatrics

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“…(12) Abnormalities in RUNX2 function can lead to cleidocranial dysplasia (CCD), in which there is defective ossification of the cranial bones with large fontanels and delayed closing of the sutures with complete or partial absence of the clavicles. (13)(14)(15)(16)(17)(18)(19) Mice with homozygous mutations in RUNX2 cannot survive after birth owing to breathing defects caused by the absence of ossification of the ribs. (20,21) The functions of RUNX2 and SOX9 are controlled by transcriptional and posttranscriptional regulation, including ubiquitination, phosphorylation, and acetylation.…”

Section: Introductionmentioning

confidence: 99%

SOX9 determines RUNX2 transactivity by directing intracellular degradation

Cheng

Genever

2010

Journal of Bone and Mineral Research

133

112

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Mesenchymal stem cell differentiation is controlled by the cooperative activity of a network of signaling mechanisms. Among these, RUNX2 and SOX9 are the major transcription factors for osteogenesis and chondrogenesis, respectively. Their expression is overlapped both temporally and spatially during embryogenesis. Here we have demonstrated that RUNX2 and SOX9 physically interact in intact cells and have confirmed that SOX9 can inhibit the transactivation of RUNX2. In addition, RUNX2 exerts reciprocal inhibition on SOX9 transactivity. In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dosedependent degradation of RUNX2. Although RUNX2 is normally degraded by the ubiquitin-proteasome pathway, we found that SOX9-mediated degradation was proteasome-independent but phosphorylation-dependent and required the presence of the RUNX2 Cterminal domain, which contains a nuclear matrix targeting sequence (NMTS). Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed b-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown. Consequently, the mechanisms by which SOX9 regulates RUNX2 function may underlie broader signaling pathways that can influence osteochondrogenesis and mesenchymal fate. ß

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“…On the other hand, although the patient has the complete heterozygous deletion of Runx2 , master gene of OB differentiation, we found that serum markers of OB activity as bone alkaline phosphatase and osteocalcin are in the control range. According to our results, other authors demonstrated that alkaline phosphatase function is disturbed in only serious cases, in which CCD is also associated to hypophosphatasia 32, 33. The major limitation of our study is that the results refer to a single patient, seeing as the CCD is a rare skeletal dysplasia.…”

Section: Discussionmentioning

confidence: 55%

Osteoclastogenic Potential of Peripheral Blood Mononuclear Cells in Cleidocranial Dysplasia

et al. 2014

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Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia characterized by hypoplastic or aplastic clavicles, dental abnormalities, and delayed closure of the cranial sutures. In addition, mid-face hypoplasia, short stature, skeletal anomalies and osteoporosis are common. We aimed to evaluate osteoclastogenesis in a child (4 years old), who presented with clinical signs of CCD and who have been diagnosed as affected by deletion of RUNX2, master gene in osteoblast differentiation, but also affecting T cell development and indirectly osteoclastogenesis. The results of this study may help to understand whether in this disease is present an alteration in the bone-resorptive cells, the osteoclasts (OCs). Unfractionated and T cell-depleted Peripheral Blood Mononuclear Cells (PBMCs) from patient were cultured in presence/absence of recombinant human M-CSF and RANKL. At the end of the culture period, OCs only developed following the addition of M-CSF and RANKL. Moreover, real-time PCR experiment showed that freshly isolated T cells expressed the osteoclastogenic cytokines (RANKL and TNFα) at very low level, as in controls. This is in accordance with results arising from flow cytometry experiments demonstrating an high percentage of circulating CD4+CD28+ and CD4+CD27+ T cells, not able to produce osteoclastogenic cytokines. Also RANKL, OPG and CTX serum levels in CCD patient are similar to controls, whereas QUS measurements showed an osteoporotic status (BTT-Z score -3.09) in the patient. In conclusions, our findings suggest that the heterozygous deletion of RUNX2 in this CCD patient did not alter the osteoclastogenic potential of PBMCs in vitro.

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Cleidocranial dysplasia with decreased bone density and biochemical findings of hypophosphatasia

Abstract: we suggest that the observed metabolic alterations are secondary to the RUNX2 gene mutation affecting early bone maturation and turnover. This is the first description of biochemical findings of hypophosphatasia in patients with cleidocranial dysplasia.

Cited by 32 publications

References 15 publications

Severe cleidocranial dysplasia can mimic hypophosphatasia

Severe cleidocranial dysplasia can mimic hypophosphatasia

SOX9 determines RUNX2 transactivity by directing intracellular degradation

Osteoclastogenic Potential of Peripheral Blood Mononuclear Cells in Cleidocranial Dysplasia

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