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Bone Development and Regeneration—4th Edition
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Bone Development and Regeneration—4th Edition

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

Deadline for manuscript submissions: 30 September 2026 | Viewed by 5993

Special Issue Editor

Prof. Dr. Kazuo Yudoh

E-Mail Website
Guest Editor
Department of Frontier Medicine, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Japan
Interests: articular cartilage; chondrocytes; polychondritis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The bone is a fascinating tissue conferring structural body support, mechanical integrity, and organ protection. A more holistic perspective sees the bone as an integral organ that, together with other tissues, not only regulates mineral homeostasis and maintains the hematopoietic niche but also plays endocrine functions, contributing to and regulating numerous metabolic processes independent of the mineral metabolism.

Bone formation is orchestrated by multiple stimuli and processes, and based on their embryological origin, the ossification of collagenous tissues is regulated by different paths. Compared to other musculoskeletal tissues, the bone has a high regenerative potential, with the skeleton being fully remodeled multiple times throughout the human lifespan. However, with a continuous extension of life expectancy, aging-related bone issues and pathologies have become more prominent, negatively impacting the quality of life of an increasing number of individuals.

While several mechanisms and pathways, such as the WNT, BMP2, or PTH signaling pathways, have been thoroughly studied over the last few decades, new scientific capabilities and perspectives allow for a more integrative and comprehensive view of bone development and regeneration. With the revolutionary rise of the omics field and the latest advances in cell lineage-tracing models and single-cell analysis, new molecular mechanisms are being elucidated, and important novel players are being recognized. For example, our understanding of epigenetic processes or metabolites that control bone integrity is growing at a rapid pace. In concert with the progress made recently in the development and design of new scaffolds and biomaterials, all these advances generate novel and alternative approaches to target bone regeneration and are under investigation, with the potential to increase the quality of life for many people.

This Special Issue of IJMS provides a platform for high-quality publications exploring novel insights on bone development and/or presenting new molecular and conceptual approaches for the manipulation of osteogenesis, bone regeneration, and bone homeostasis. This will provide a representative picture of the latest advances in bone research and serve as a road map for the future of the bone field.

Prof. Dr. Kazuo Yudoh
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 250 words) can be sent to the Editorial Office for assessment.

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

  • osteoblast
  • osteocyte
  • osteoclast
  • mesenchymal stem cell
  • cell differentiation
  • epigenetics
  • omics
  • integrative analysis
  • biomaterials

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Published Papers (4 papers)

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Research

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16 pages, 6693 KB  
Article
Runx2 in the Perichondrial Osteoblasts Enhances Terminal Differentiation of Chondrocytes Through Nell1 Induction
by Xin Qin, Qing Jiang, Longfei Wu, Suemi Yabuta, Chiharu Sakane, Yuki Matsuo, Ziheng Zhang, Hisato Komori, Manyu Zhang, Kosei Ito and Toshihisa Komori
Int. J. Mol. Sci. 2026, 27(3), 1266; https://doi.org/10.3390/ijms27031266 - 27 Jan 2026
Viewed by 425
Abstract
Runx2 plays essential roles in osteoblast differentiation and chondrocyte maturation. Runx2 in the perichondrium has been reported to inhibit chondrocyte maturation through Fgf18 induction. To further investigate the functions of Runx2 in the perichondrium, we generated Runx2fl/−Cre mice by crossing Runx2fl/+ [...] Read more.
Runx2 plays essential roles in osteoblast differentiation and chondrocyte maturation. Runx2 in the perichondrium has been reported to inhibit chondrocyte maturation through Fgf18 induction. To further investigate the functions of Runx2 in the perichondrium, we generated Runx2fl/−Cre mice by crossing Runx2fl/+, Runx2+/−, and 2.3-kb Col1a1 Cre mice and compared them with Runx2fl/− mice at E15.5, when the endochondral bones were cartilaginous. Skeletal preparation of the upper limbs in Runx2fl/−Cre mice showed reduced mineralization of the humerus and scapula, and histological analysis of the femurs showed delays in the terminal differentiation of chondrocytes, as indicated by the absence of mineralization and Spp1 expression in the cartilage and osteoblast differentiation in the perichondrium, compared to those in Runx2fl/− mice. mRNA sequence analysis showed that the expression of Nell1, which encodes a secreted protein that enhances chondrocyte maturation, in Runx2fl/−Cre femurs was more than two-fold lower than that in Runx2fl/− femurs. Nell1 expression was reduced in the perichondrium of Runx2fl/−Cre femurs compared to that in Runx2fl/− femurs. Nell1 expression was upregulated by Runx2 overexpression and downregulated by Runx2 siRNA. These findings indicate that Runx2 in perichondrial osteoblasts enhances the terminal differentiation of chondrocytes by inducing Nell1 expression. Full article
(This article belongs to the Special Issue Bone Development and Regeneration—4th Edition)
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14 pages, 2075 KB  
Article
(D-Ala2)GIP Inhibits TNF-α-Induced Osteoclast Formation and Bone Resorption, and Orthodontic Tooth Movement
by Angyi Lin, Hideki Kitaura, Jinghan Ma, Fumitoshi Ohori, Aseel Marahleh, Kayoko Kanou, Kohei Narita, Ziqiu Fan, Kou Murakami and Hiroyasu Kanetaka
Int. J. Mol. Sci. 2026, 27(1), 199; https://doi.org/10.3390/ijms27010199 - 24 Dec 2025
Viewed by 623
Abstract
The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) promotes insulin secretion, lowers blood glucose levels, and is increasingly linked to bone remodeling. Native GIP is quickly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), whereas (D-Ala2)GIP is a novel GIP analog engineered to [...] Read more.
The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) promotes insulin secretion, lowers blood glucose levels, and is increasingly linked to bone remodeling. Native GIP is quickly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), whereas (D-Ala2)GIP is a novel GIP analog engineered to resist DPP-4 degradation. Tumor necrosis factor-alpha (TNF-α), a key proinflammatory cytokine, promotes osteoclastogenesis and is notably upregulated during orthodontic tooth movement (OTM). This study aimed to evaluate the effects of (D-Ala2)GIP on TNF-α-induced osteoclast formation and bone resorption in vivo, as well as on OTM and related root resorption. Mice received daily supracalvarial injections of TNF-α with or without (D-Ala2)GIP for 5 days. The (D-Ala2)GIP-treated group showed significantly reduced osteoclast formation, bone resorption, and expression of osteoclastic markers TRAP and cathepsin K, compared to the group that received TNF-α alone. OTM was induced in mice by applying a nickel-titanium closed-coil spring, and mice were treated with either phosphate-buffered saline (PBS) or (D-Ala2)GIP every 2 days. After 12 days, the (D-Ala2)GIP-treated group showed significantly reduced tooth movement and fewer osteoclasts and odontoclasts on the compression side compared to the PBS control. These findings suggest that (D-Ala2)GIP inhibits OTM, potentially by suppressing TNF-α-driven osteoclastogenesis and bone resorption. Full article
(This article belongs to the Special Issue Bone Development and Regeneration—4th Edition)
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20 pages, 5374 KB  
Article
Repetitive Compressive Loading Downregulates Mitochondria Function and Upregulates the Cartilage Matrix Degrading Enzyme MMP-13 Through the Coactivation of NAD-Dependent Sirtuin 1 and Runx2 in Osteoarthritic Chondrocytes
by Masahiro Takemoto, Yodo Sugishita, Yuki Takahashi-Suzuki, Hiroto Fujiya, Hisateru Niki and Kazuo Yudoh
Int. J. Mol. Sci. 2025, 26(11), 4967; https://doi.org/10.3390/ijms26114967 - 22 May 2025
Cited by 3 | Viewed by 1692
Abstract
Mechanical stress is known to be a pivotal risk factor in the development of OA. However, the involvement of repetitive compressive loading in mitochondrial dysfunction in chondrocytes remains unclear. The aim of this study was to investigate whether physiologic levels of repetitive mechanical [...] Read more.
Mechanical stress is known to be a pivotal risk factor in the development of OA. However, the involvement of repetitive compressive loading in mitochondrial dysfunction in chondrocytes remains unclear. The aim of this study was to investigate whether physiologic levels of repetitive mechanical force affect the regulation of energy metabolism and activities of mitochondrial function regulators, sirtuin 1 and nicotinamide adenine dinucleotide (NAD) in chondrocytes, and to clarify any correlation with chondrocyte catabolic activity. Repetitive physiological mechanical stress was applied in a 3D chondrocyte-collagen scaffold construct, and the 3D cultured tissues were collected at different time points by collagenase treatment to collect cellular proteins. Changes in chondrocyte activity (cell proliferation, MMP-13 production), energy metabolism regulator levels (sirtuin 1), mitochondrial function (ATP production, NAD level), and the expression level of the osteogenic and hypertrophic chondrogenic transcription factor, runt-related transcription factor 2 (Runx2), were measured. Treatment with repetitive compressive loading resulted in no significant change in the cell viability of chondrocytes. In the repetitive mechanical loading group, there were statistically significant increases in MMP-13 production and expression of both sirtuin 1 and Runx2 in chondrocytes relative to the non-loading control group. Furthermore, ATP production and NAD activity in mitochondria decreased in the repetitive mechanical loading group. Our present study reveals that in chondrocytes, repetitive compressive loading accelerated sirtuin activation, which requires and consumes NAD within mitochondria, leading to a decrease of NAD and ultimately in reduced mitochondrial ATP production. Additionally, since sirtuin 1 is known to positively regulate Runx2 activity in chondrocytes, the activation of sirtuin 1 by repetitive load stimulation may induce an increase in the expression of Runx2, which promotes the expression of MMP-13, and subsequently enhances MMP-13 production. Our findings indicate that repetitive compression loading-mediated mitochondrial dysfunction plays a pivotal role in the progression of OA, primarily by driving the downregulation of ATP production and promoting the expression of the matrix-degrading enzyme MMP-13. Full article
(This article belongs to the Special Issue Bone Development and Regeneration—4th Edition)
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Review

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16 pages, 852 KB  
Review
Recent Advances in the Role of Osteocytes in Orthodontic Tooth Movement
by Aseel Marahleh, Fumitoshi Ohori, Jinghan Ma, Ziqiu Fan, Angyi Lin, Kohei Narita, Kou Murakami and Hideki Kitaura
Int. J. Mol. Sci. 2025, 26(19), 9396; https://doi.org/10.3390/ijms26199396 - 26 Sep 2025
Cited by 2 | Viewed by 2743
Abstract
Orthodontic tooth movement (OTM) is a biologically orchestrated process involving the dynamic interplay of mechanical force, inflammatory signaling, and bone remodeling. Osteocytes, the most abundant cells within the bone matrix, serve as mechanosensitive regulators that transduce mechanical cues into biochemical signals in response [...] Read more.
Orthodontic tooth movement (OTM) is a biologically orchestrated process involving the dynamic interplay of mechanical force, inflammatory signaling, and bone remodeling. Osteocytes, the most abundant cells within the bone matrix, serve as mechanosensitive regulators that transduce mechanical cues into biochemical signals in response to orthodontic force. This review delineates the multifaceted role of osteocytes in facilitating bone resorption required for OTM. The role of osteocytes is examined in inflammation, mechanical adaptation, and cell death. Additionally, we discuss the evidence on how aging alters osteocyte function, with senescence-associated changes disrupting mechanosensory networks and attenuating bone remodeling. Finally, the possibility that osteocytes themselves undergo morphological adaptation during force application is explored. This structural plasticity may impact individual variability in orthodontic outcomes. Advancing our understanding of osteocyte signaling in OTM holds significant promise for optimizing treatment outcomes across diverse patient populations. Full article
(This article belongs to the Special Issue Bone Development and Regeneration—4th Edition)
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