Craniometaphyseal Dysplasia Mutations in ANKH Negatively Affect Human Induced Pluripotent Stem Cell Differentiation into Osteoclasts

Chen, I‐Ping; Luxmi, Raj; Kanaujiya, Jitendra Kumar; Zou, Hao; Reichenberger, Ernst

doi:10.1016/j.stemcr.2017.09.016

Cited by 16 publications

(14 citation statements)

References 33 publications

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“…Osteoclasts in mutant mice and CMD patients are reduced in numbers, have defective actin rings, and have decreased resorptive activity, which greatly contributes to the skeletal phenotype of CMD. (11,12) Despite advances in CMD research, the pathogenesis remains not fully elucidated. Treatment is still limited to surgical decompression of obstructed foramina and to plastic surgery for correcting craniofacial structures.…”

Section: Introductionmentioning

confidence: 99%

Restriction of Dietary Phosphate Ameliorates Skeletal Abnormalities in a Mouse Model for Craniometaphyseal Dysplasia

Fujii

Kozák

Dutra

et al. 2020

Journal of Bone and Mineral Research

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Craniometaphyseal dysplasia (CMD), a rare genetic bone disorder, is characterized by lifelong progressive thickening of craniofacial bones and metaphyseal flaring of long bones. The autosomal dominant form of CMD is caused by mutations in the progressive ankylosis gene ANKH (mouse ortholog Ank), encoding a pyrophosphate (PPi) transporter. We previously reported reduced formation and function of osteoblasts and osteoclasts in a knockin (KI) mouse model for CMD (Ank KI/KI) and in CMD patients. We also showed rapid protein degradation of mutant ANK/ANKH. Mutant ANK protein displays reduced PPi transport, which may alter the inorganic phosphate (Pi) and PPi ratio, an important regulatory mechanism for bone mineralization. Here we investigate whether reducing dietary Pi intake can ameliorate the CMD-like skeletal phenotype by comparing male and female Ank +/+ and Ank KI/KI mice exposed to a low (0.3%) and normal (0.7%) Pi diet for 13 weeks from birth. Serum Pi and calcium (Ca) levels were not significantly changed by diet, whereas PTH and 25-hydroxy vitamin D (25-OHD) were decreased by low Pi diet but only in male Ank +/+ mice. Importantly, the 0.3% Pi diet significantly ameliorated mandibular hyperostosis in both sexes of Ank KI/KI mice. A tendency of decreased femoral trabeculation was observed in male and female Ank +/+ mice as well as in male Ank KI/KI mice fed with the 0.3% Pi diet. In contrast, in female Ank KI/KI mice the 0.3% Pi diet resulted in increased metaphyseal trabeculation. This was also the only group that showed increased bone formation rate. Low Pi diet led to increased osteoclast numbers and increased bone resorption in all mice. We conclude that lowering but not depleting dietary Pi delays the development of craniofacial hyperostosis in CMD mice without severely compromising serum levels of Pi, Ca, PTH, and 25-OHD. These findings may have implications for better clinical care of patients with CMD.

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Section: Introductionmentioning

confidence: 99%

Restriction of Dietary Phosphate Ameliorates Skeletal Abnormalities in a Mouse Model for Craniometaphyseal Dysplasia

Fujii

Kozák

Dutra

et al. 2020

Journal of Bone and Mineral Research

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“…Similarly, ANKH protein levels were strongly reduced in osteoblast-like cells derived from bone explant cultures and in stem cells from human exfoliated deciduous teeth (SHEDs) from CMD patients with ANKH_F377del compared to cells from control individuals (Fig. 1C ) 22 . Cell lysate from Ank KO/KO osteoclasts served as negative control for antibody binding (Fig.…”

Section: Resultsmentioning

confidence: 87%

“…Furthermore, there are reports that proteasomal inhibitors and the lysosomal inhibitor bafilomycin a1 can suppress osteoclast function 39 , 40 , although other studies suggest that proteasomal inhibitors may induce osteoclast survival and formation 41 . Previously we reported deficient osteoclastogenesis in the CMD mouse model and in CMD patients, which is in part responsible for hyperostosis of craniofacial bones 18 , 22 . In addition, bortezomib has been shown to enhance bone formation, partly by modulating runt-related transcription factor 2 (Runx2) 42 .…”

Section: Discussionmentioning

confidence: 96%

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Rapid degradation of progressive ankylosis protein (ANKH) in craniometaphyseal dysplasia

Kanaujiya

Bastow

Luxmi

et al. 2018

Sci Rep

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Mutations in the progressive ankylosis protein (NP_473368, human ANKH) cause craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial bones and widened metaphyses in long bones. The pathogenesis of CMD remains largely unknown, and treatment for CMD is limited to surgical intervention. We have reported that knock-in mice (AnkKI/KI) carrying a F377del mutation in ANK (NM_020332, mouse ANK) replicate many features of CMD. Interestingly, ablation of the Ank gene in AnkKO/KO mice also leads to several CMD-like phenotypes. Mutations causing CMD led to decreased steady-state levels of ANK/ANKH protein due to rapid degradation. While wild type (wt) ANK was mostly associated with plasma membranes, endoplasmic reticulum (ER), Golgi apparatus and lysosomes, CMD-linked mutant ANK was aberrantly localized in cytoplasm. Inhibitors of proteasomal degradation significantly restored levels of overexpressed mutant ANK, whereas endogenous CMD-mutant ANK/ANKH levels were more strongly increased by inhibitors of lysosomal degradation. However, these inhibitors do not correct the mislocalization of mutant ANK. Co-expressing wt and CMD-mutant ANK in cells showed that CMD-mutant ANK does not negatively affect wt ANK expression and localization, and vice versa. In conclusion, our finding that CMD mutant ANK/ANKH protein is short-lived and mislocalized in cells may be part of the CMD pathogenesis.

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“…Cx43 are required for osteoblast and osteoclast differentiation and function [84], and the compromised Cx43 could significantly limit the cell-cell communication needed for osteoclastogenesis and bone remodeling. Studies showed that hiPSCs with ANKH mutations formed fewer osteoclasts, expressed lower levels of osteoclast specific genes, and resorbed less bone [85].…”

Section: Ipscs Derived From Patients With Skeletal Disordersmentioning

confidence: 99%

Tissue engineered bone mimetics to study bone disorders ex vivo: Role of bioinspired materials

Shih

Varghese

2019

Biomaterials

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Recent advances in materials development and tissue engineering has resulted in a substantial number of bioinspired materials that recapitulate cardinal features of bone extracellular matrix (ECM) such as dynamic inorganic and organic environment(s), hierarchical organization, and topographical features. Bone mimicking materials, as defined by its self-explanatory term, are developed based on the current understandings of the natural bone ECM during development, remodeling, and fracture repair. Compared to conventional plastic cultures, biomaterials that resemble some aspects of the native environment could elicit a more natural molecular and cellular response relevant to the bone tissue. Although current bioinspired materials are mainly developed to assist tissue repair or engineer bone tissues, such materials could nevertheless be applied to model various skeletal diseases in vitro. This review summarizes the use of bioinspired materials for bone tissue engineering, and their potential to model diseases of bone development and remodeling ex vivo. We largely focus on biomaterials, designed to re-create different aspects of the chemical and physical cues of native bone ECM. Employing these bone-inspired materials and tissue engineered bone surrogates to study bone diseases has tremendous potential and will provide a closer portrayal of disease progression and maintenance, both at the cellular and tissue level. We also briefly touch upon the application of patient-derived stem cells and introduce emerging technologies such as organ-on-chip in disease modeling. Faithful recapitulation of disease pathologies will not only offer novel insights into diseases, but also lead to enabling technologies for drug discovery and new approaches for cell-based therapies.

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Craniometaphyseal Dysplasia Mutations in ANKH Negatively Affect Human Induced Pluripotent Stem Cell Differentiation into Osteoclasts

Cited by 16 publications

References 33 publications

Restriction of Dietary Phosphate Ameliorates Skeletal Abnormalities in a Mouse Model for Craniometaphyseal Dysplasia

Restriction of Dietary Phosphate Ameliorates Skeletal Abnormalities in a Mouse Model for Craniometaphyseal Dysplasia

Rapid degradation of progressive ankylosis protein (ANKH) in craniometaphyseal dysplasia

Tissue engineered bone mimetics to study bone disorders ex vivo: Role of bioinspired materials

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