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Genetics in Bone Diseases
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Genetics in Bone Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 13002

Special Issue Editor

Prof. Dr. Toshifumi Azuma

E-Mail Website
Guest Editor
Faculty of Dentistry, Tokyo Dental College, Tokyo 101-0061, Japan
Interests: odontoblast; osteoblast; Gorlin syndrome; bone regeneration

Special Issue Information

Dear Colleagues, 

The discovery of the Runx2 gene paved the way for the harmonic expression cascade of genes in bone tissue and their complex regulatory mechanisms during bone tissue development. Numerous studies elucidating the mechanisms of inherited bone diseases have shed light on new aspects of bone tissue development and bone remodeling, revealing many unexplored facts. These facts continue to be applied as breakthrough diagnostic techniques and new treatments for bone diseases. Furthermore, new technologies for genetic analysis, as exemplified by genome analysis using next-generation sequencers, are advancing dramatically. Today, it is applied not only to exome analysis, but also to coding and non-coding RNA analysis, epigenome analysis, and gene regulation analysis. In addition, with advances in more precise cell separation techniques, single cell analysis techniques are being developed and the pathways of differentiation of single cells in niche environments are being elucidated. The overall picture of bone tissue development and differentiation is gradually being elucidated. In the mechanism of gene regulation of bone tissue as mechanosensory-responsive tissue, we will focus on the membrane-cytoskeleton-nuclear membrane and LINC complex-chromosome-gene regulatory pathway axes. New areas such as bone cell chromosome dynamics are also discussed. Taken together, this special issue summarizes new findings in bone tissue genetics and related research today and identifies important issues for the future.

Prof. Dr. Toshifumi Azuma
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • odontoblast
  • osteoblast
  • Gorlin syndrome
  • bone regeneration
  • genes in bone tissue
  • bone tissue development
  • bone disease

Published Papers (7 papers)

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Research

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16 pages, 1572 KiB  
Article
A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis
by Vivia Khosasih, Kai-Ming Liu, Chung-Ming Huang, Lieh-Bang Liou, Ming-Shium Hsieh, Chian-Her Lee, Chang-Youh Tsai, San-Yuan Kuo, Su-Yang Hwa, Chia-Li Yu, Chih-Hao Chang, Cheng-Jyh Lin, Song-Chou Hsieh, Chun-Ying Cheng, Wei-Ming Chen, Liang-Kuang Chen, Hui-Ping Chuang, Ying-Ting Chen, Pei-Chun Tsai, Liang-Suei Lu, Weng-Siong H’ng, Yanfei Zhang, Hsiang-Cheng Chen, Chien-Hsiun Chen, Ming Ta Michael Lee and Jer-Yuarn Wuadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2023, 24(3), 3021; https://doi.org/10.3390/ijms24033021 - 03 Feb 2023
Cited by 1 | Viewed by 2000
Abstract
While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population [...] Read more.
While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger’s hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10−7–7.31 × 10−6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10−7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10−6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D’ = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis. Full article
(This article belongs to the Special Issue Genetics in Bone Diseases)
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Review

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14 pages, 1582 KiB  
Review
Current Status of Next-Generation Sequencing in Bone Genetic Diseases
by Natsuko Aida, Akiko Saito and Toshifumi Azuma
Int. J. Mol. Sci. 2023, 24(18), 13802; https://doi.org/10.3390/ijms241813802 - 07 Sep 2023
Viewed by 1059
Abstract
The development of next-generation sequencing (NGS) has dramatically increased the speed and volume of genetic analysis. Furthermore, the range of applications of NGS is rapidly expanding to include genome, epigenome (such as DNA methylation), metagenome, and transcriptome analyses (such as RNA sequencing and [...] Read more.
The development of next-generation sequencing (NGS) has dramatically increased the speed and volume of genetic analysis. Furthermore, the range of applications of NGS is rapidly expanding to include genome, epigenome (such as DNA methylation), metagenome, and transcriptome analyses (such as RNA sequencing and single-cell RNA sequencing). NGS enables genetic research by offering various sequencing methods as well as combinations of methods. Bone tissue is the most important unit supporting the body and is a reservoir of calcium and phosphate ions, which are important for physical activity. Many genetic diseases affect bone tissues, possibly because metabolic mechanisms in bone tissue are complex. For instance, the presence of specialized immune cells called osteoclasts in the bone tissue, which absorb bone tissue and interact with osteoblasts in complex ways to support normal vital functions. Moreover, the many cell types in bones exhibit cell-specific proteins for their respective activities. Mutations in the genes encoding these proteins cause a variety of genetic disorders. The relationship between age-related bone tissue fragility (also called frailty) and genetic factors has recently attracted attention. Herein, we discuss the use of genomic, epigenomic, transcriptomic, and metagenomic analyses in bone genetic disorders. Full article
(This article belongs to the Special Issue Genetics in Bone Diseases)
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17 pages, 1347 KiB  
Review
Hedgehog-Related Mutation Causes Bone Malformations with or without Hereditary Gene Mutations
by Shoko Onodera and Toshifumi Azuma
Int. J. Mol. Sci. 2023, 24(16), 12903; https://doi.org/10.3390/ijms241612903 - 17 Aug 2023
Viewed by 1057
Abstract
The hedgehog (Hh) family consists of numerous signaling mediators that play important roles at various stages of development. Thus, the Hh pathway is essential for bone tissue development and tumorigenesis. Gorlin syndrome is a skeletal and tumorigenic disorder caused by gain-of-function mutations in [...] Read more.
The hedgehog (Hh) family consists of numerous signaling mediators that play important roles at various stages of development. Thus, the Hh pathway is essential for bone tissue development and tumorigenesis. Gorlin syndrome is a skeletal and tumorigenic disorder caused by gain-of-function mutations in Hh signaling. In this review, we first present the phenotype of Gorlin syndrome and the relationship between genotype and phenotype in bone and craniofacial tissues, including the causative gene as well as other Hh-related genes. Next, the importance of new diagnostic methods using next-generation sequencing and multiple gene panels will be discussed. We summarize Hh-related genetic disorders, including cilia disease, and the genetics of Hh-related bone diseases. Full article
(This article belongs to the Special Issue Genetics in Bone Diseases)
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14 pages, 1177 KiB  
Review
Single-Cell RNA-Sequencing Reveals the Skeletal Cellular Dynamics in Bone Repair and Osteoporosis
by Sixun Wu, Shinsuke Ohba and Yuki Matsushita
Int. J. Mol. Sci. 2023, 24(12), 9814; https://doi.org/10.3390/ijms24129814 - 06 Jun 2023
Cited by 1 | Viewed by 2743
Abstract
The bone is an important organ that performs various functions, and the bone marrow inside the skeleton is composed of a complex intermix of hematopoietic, vascular, and skeletal cells. Current single-cell RNA sequencing (scRNA-seq) technology has revealed heterogeneity and sketchy differential hierarchy of [...] Read more.
The bone is an important organ that performs various functions, and the bone marrow inside the skeleton is composed of a complex intermix of hematopoietic, vascular, and skeletal cells. Current single-cell RNA sequencing (scRNA-seq) technology has revealed heterogeneity and sketchy differential hierarchy of skeletal cells. Skeletal stem and progenitor cells (SSPCs) are located upstream of the hierarchy and differentiate into chondrocytes, osteoblasts, osteocytes, and bone marrow adipocytes. In the bone marrow, multiple types of bone marrow stromal cells (BMSCs), which have the potential of SSPCs, are spatiotemporally located in distinct areas, and SSPCs’ potential shift of BMSCs may occur with the advancement of age. These BMSCs contribute to bone regeneration and bone diseases, such as osteoporosis. In vivo lineage-tracing technologies show that various types of skeletal lineage cells concomitantly gather and contribute to bone regeneration. In contrast, these cells differentiate into adipocytes with aging, leading to senile osteoporosis. scRNA-seq analysis has revealed that alteration in the cell-type composition is a major cause of tissue aging. In this review, we discuss the cellular dynamics of skeletal cell populations in bone homeostasis, regeneration, and osteoporosis. Full article
(This article belongs to the Special Issue Genetics in Bone Diseases)
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14 pages, 1723 KiB  
Review
Emerging RUNX2-Mediated Gene Regulatory Mechanisms Consisting of Multi-Layered Regulatory Networks in Skeletal Development
by Hironori Hojo
Int. J. Mol. Sci. 2023, 24(3), 2979; https://doi.org/10.3390/ijms24032979 - 03 Feb 2023
Cited by 6 | Viewed by 2402
Abstract
Skeletal development is tightly coordinated by chondrocytes and osteoblasts, which are derived from skeletal progenitors, and distinct cell-type gene regulatory programs underlie the specification and differentiation of cells. Runt-related transcription factor 2 (Runx2) is essential to chondrocyte hypertrophy and osteoblast differentiation. Genetic studies [...] Read more.
Skeletal development is tightly coordinated by chondrocytes and osteoblasts, which are derived from skeletal progenitors, and distinct cell-type gene regulatory programs underlie the specification and differentiation of cells. Runt-related transcription factor 2 (Runx2) is essential to chondrocyte hypertrophy and osteoblast differentiation. Genetic studies have revealed the biological functions of Runx2 and its involvement in skeletal genetic diseases. Meanwhile, molecular biology has provided a framework for our understanding of RUNX2-mediated transactivation at a limited number of cis-regulatory elements. Furthermore, studies using next-generation sequencing (NGS) have provided information on RUNX2-mediated gene regulation at the genome level and novel insights into the multiple layers of gene regulatory mechanisms, including the modes of action of RUNX2, chromatin accessibility, the concept of pioneer factors and phase separation, and three-dimensional chromatin organization. In this review, I summarize the emerging RUNX2-mediated regulatory mechanism from a multi-layer perspective and discuss future perspectives for applications in the treatment of skeletal diseases. Full article
(This article belongs to the Special Issue Genetics in Bone Diseases)
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19 pages, 1150 KiB  
Review
Kruppel-like Factors in Skeletal Physiology and Pathologies
by Makoto Abe, Naoya Saeki, Yuki Ikeda and Shinsuke Ohba
Int. J. Mol. Sci. 2022, 23(23), 15174; https://doi.org/10.3390/ijms232315174 - 02 Dec 2022
Cited by 5 | Viewed by 1880
Abstract
Kruppel-like factors (KLFs) belong to a large group of zinc finger-containing transcription factors with amino acid sequences resembling the Drosophila gap gene Krüppel. Since the first report of molecular cloning of the KLF family gene, the number of KLFs has increased rapidly. [...] Read more.
Kruppel-like factors (KLFs) belong to a large group of zinc finger-containing transcription factors with amino acid sequences resembling the Drosophila gap gene Krüppel. Since the first report of molecular cloning of the KLF family gene, the number of KLFs has increased rapidly. Currently, 17 murine and human KLFs are known to play crucial roles in the regulation of transcription, cell proliferation, cellular differentiation, stem cell maintenance, and tissue and organ pathogenesis. Recent evidence has shown that many KLF family molecules affect skeletal cells and regulate their differentiation and function. This review summarizes the current understanding of the unique roles of each KLF in skeletal cells during normal development and skeletal pathologies. Full article
(This article belongs to the Special Issue Genetics in Bone Diseases)
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9 pages, 439 KiB  
Review
Progress and Current Status in Hajdu-Cheney Syndrome with Focus on Novel Genetic Research
by Natsuko Aida, Tatsukuni Ohno and Toshifumi Azuma
Int. J. Mol. Sci. 2022, 23(19), 11374; https://doi.org/10.3390/ijms231911374 - 27 Sep 2022
Cited by 3 | Viewed by 1278
Abstract
Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant manifestation of a congenital genetic disorder caused by a mutation in the NOTCH2 gene. NOTCH signaling has variations from NOTCH 1 to 4 and maintains homeostasis by determining and regulating the proliferation and differentiation of [...] Read more.
Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant manifestation of a congenital genetic disorder caused by a mutation in the NOTCH2 gene. NOTCH signaling has variations from NOTCH 1 to 4 and maintains homeostasis by determining and regulating the proliferation and differentiation of various cells. In HCS, the over-accumulated NOTCH2 causes abnormal bone resorption due to its continuous excessive signaling. HCS is characterized by progressive bone destruction, has complex wide-range clinical manifestations, and significantly impacts the patient’s quality of life. However, no effective treatment has been established for HCS to date. There are genetic variants of NOTCH2 that have been reported in the ClinVar database of the U.S. National Institutes of Health. In total, 26 mutant variants were detected based on the American College of Medical Genetics and Genomics (ACMC). To date, there has been no comprehensive compilation of HCS mutations. In this review, we provide the most comprehensive list possible of HCS variants, nucleotide changes, amino acid definitions, and molecular consequences reported to date, following the ACMC guidelines. Full article
(This article belongs to the Special Issue Genetics in Bone Diseases)
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