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

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 38532

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Prof. Dr. José López

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Department of Morphology and Cellular Biology, Faculty of Medicine, University of Oviedo, 33006 Oviedo, Asturias, Spain
Interests: cartilage; growth plate; chondrogenic differentiation; osteogenic differentiation; bone biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

The skeleton is a structure of elements of various shapes and origins that supports and protects the body. The development and growth of the skeleton is an ongoing, life-long process. Skeletal elements, or bones, are mainly formed by cartilage and osseous tissue. Each has a specific cell type — chondrocytes in cartilage and osteoblasts and osteoclasts in osseous tissue — with its own differentiation pathway. There have been many recent significant conceptual advances in our understanding of bone development, but the mechanisms involved are so complex that researchers have only just begun to understand them and they have not yet been fully illustrated. The aim of this Special Issue is to present an up-to-date perspective on the process of formation and maintenance of the skeleton. On this basis, this Special Issue focuses on bone development and growth, including the mechanisms of bone formation, pathways that regulate the differentiation of cartilage cells (chondrocytes), bone-forming cells (osteoblasts) and bone - destroying cells (osteoclasts), limb development, endochondral and intramembranous ossification, structural aspects of longitudinal and transverse growth of bones, the role of hormones in bone formation and microarchitecture, bone growth pathologies, heterotopic bone formation, bone repair and transplantation, and bone regenerative medicine. Thus, it is open to contributions from anyone interested in bone development and function, including anatomists, cell biologists, physiologists, biochemists, orthopedists, pathologists, clinicians and biomedical engineers.

Prof. Dr. José López
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.

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Keywords

bone development
osteogenesis
bone cells
bone matrix
intramembranous bone
endochondral bone
periosteum
mineralization
growth plate
bone structure
bone remodeling
histomorphometry
growth factors
bone morphogenic protein
bone metabolism markers
fracture repair
bone defects
bone quality
heterotopic bone formation
biograft
new bone formation

Published Papers (10 papers)

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Research

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14 pages, 2429 KiB

Open AccessArticle

Bone Mass and Osteoblast Activity Are Sex-Dependent in Mice Lacking the Estrogen Receptor α in Chondrocytes and Osteoblast Progenitor Cells

by Lena Steppe, Jasmin Bülow, Jan Tuckermann, Anita Ignatius and Melanie Haffner-Luntzer

Int. J. Mol. Sci. 2022, 23(5), 2902; https://doi.org/10.3390/ijms23052902 - 07 Mar 2022

Cited by 7 | Viewed by 3710 | Correction

Abstract

While estrogen receptor alpha (ERα) is known to be important for bone development and homeostasis, its exact function during osteoblast differentiation remains unclear. Conditional deletion of ERα during specific stages of osteoblast differentiation revealed different bone phenotypes, which were also shown to be sex-dependent. Since hypertrophic chondrocytes can transdifferentiate into osteoblasts and substantially contribute to long-bone development, we aimed to investigate the effects of ERα deletion in both osteoblast and chondrocytes on bone development and structure. Therefore, we generated mice in which the ERα gene was inactivated via a Runx2-driven cyclic recombinase (ERα^fl/fl; ^Runx2Cre). We analyzed the bones of 3-month-old ERα^fl/fl; ^Runx2Cre mice by biomechanical testing, micro-computed tomography, and cellular parameters by histology. Male ERα^fl/fl; ^Runx2Cre mice displayed a significantly increased cortical bone mass and flexural rigidity of the femurs compared to age-matched controls with no active Cre-transgene (ERα^fl/fl). By contrast, female ERα^fl/fl; ^Runx2Cre mice exhibited significant trabecular bone loss, whereas in cortical bone periosteal and endosteal diameters were reduced. Our results indicate that the ERα in osteoblast progenitors and hypertrophic chondrocytes differentially contributes to bone mass regulation in male and female mice and improves our understanding of ERα signaling in bone cells in vivo. Full article

(This article belongs to the Special Issue Bone Development and Growth)

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22 pages, 7166 KiB

Open AccessArticle

Nutritional Approaches as a Treatment for Impaired Bone Growth and Quality Following the Consumption of Ultra-Processed Food

by Shelley Griess-Fishheimer, Janna Zaretsky, Tamara Travinsky-Shmul, Irina Zaretsky, Svetlana Penn, Ron Shahar and Efrat Monsonego-Ornan

Int. J. Mol. Sci. 2022, 23(2), 841; https://doi.org/10.3390/ijms23020841 - 13 Jan 2022

Cited by 4 | Viewed by 2112

Abstract

The severe impairment of bone development and quality was recently described as a new target for unbalanced ultra-processed food (UPF). Here, we describe nutritional approaches to repair this skeletal impairment in rats: supplementation with micro-nutrients and a rescue approach and switching the UPF to balanced nutrition during the growth period. The positive effect of supplementation with multi-vitamins and minerals on bone growth and quality was followed by the formation of mineral deposits on the rats’ kidneys and modifications in the expression of genes involved in inflammation and vitamin-D metabolism, demonstrating the cost of supplementation. Short and prolonged rescue improved trabecular parameters but incompletely improved the cortical parameters and the mechanical performance of the femur. Cortical porosity and cartilaginous lesions in the growth-plate were still detected one week after rescue and were reduced to normal levels 3 weeks after rescue. These findings highlight bone as a target for the effect of UPF and emphasize the importance of a balanced diet, especially during growth. Full article

(This article belongs to the Special Issue Bone Development and Growth)

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18 pages, 3812 KiB

Open AccessArticle

The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice

by Zamzam Awida, Almog Bachar, Hussam Saed, Anton Gorodov, Nathalie Ben-Califa, Maria Ibrahim, Albert Kolomansky, Jennifer Ana Iden, Liad Graniewitz Visacovsky, Tamar Liron, Sahar Hiram-Bab, Michael Brines, Yankel Gabet and Drorit Neumann

Int. J. Mol. Sci. 2022, 23(1), 55; https://doi.org/10.3390/ijms23010055 - 21 Dec 2021

Cited by 1 | Viewed by 3017

Abstract

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin⁻CD11b⁻Ly6C^hi CD115⁺, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment. Full article

(This article belongs to the Special Issue Bone Development and Growth)

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9 pages, 1661 KiB

Open AccessArticle

GPR120 Inhibits RANKL-Induced Osteoclast Formation and Resorption by Attenuating Reactive Oxygen Species Production in RAW264.7 Murine Macrophages

by Cynthia Sithole, Carla Pieterse, Kayla Howard and Abe Kasonga

Int. J. Mol. Sci. 2021, 22(19), 10544; https://doi.org/10.3390/ijms221910544 - 29 Sep 2021

Cited by 10 | Viewed by 2271

Abstract

Osteoclasts are large, multinucleated cells that are responsible for the resorption of bone. Bone degenerative diseases, such as osteoporosis, are characterized by overactive osteoclasts. Receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) binding to its receptor on osteoclast precursors will trigger osteoclast formation and resorption. The production of reactive oxygen species (ROS) is known to play a crucial role in RANKL-induced osteoclast formation and resorption. G-protein coupled receptor 120 (GPR120) signalling has been shown to affect osteoclast formation, but the exact mechanisms of action require further investigation. RAW264.7 murine macrophages were seeded into culture plates and exposed to the GPR120 agonist, TUG-891, at varying concentrations (20–100 µM) and RANKL to induce osteoclast formation. TUG-891 was shown to inhibit osteoclast formation and resorption without affecting cell viability in RAW264.7 macrophages. TUG-891 further decreased ROS production when compared to RANKL only cells. Antioxidant proteins, Nrf2, HO-1 and NQO1 were shown to be upregulated while the ROS inducing protein, Nox1, was downregulated by TUG-891. Gene silencing revealed that TUG-891 exerted its effects specifically through GPR120. This study reveals that GPR120 signalling may inhibit osteoclast formation and resorption through inhibition on ROS production. Full article

(This article belongs to the Special Issue Bone Development and Growth)

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11 pages, 2578 KiB

Open AccessArticle

Functional Analyses of Four CYP1A1 Missense Mutations Present in Patients with Atypical Femoral Fractures

by Nerea Ugartondo, Núria Martínez-Gil, Mònica Esteve, Natàlia Garcia-Giralt, Neus Roca-Ayats, Diana Ovejero, Xavier Nogués, Adolfo Díez-Pérez, Raquel Rabionet, Daniel Grinberg and Susanna Balcells

Int. J. Mol. Sci. 2021, 22(14), 7395; https://doi.org/10.3390/ijms22147395 - 09 Jul 2021

Cited by 6 | Viewed by 2198

Abstract

Osteoporosis is the most common metabolic bone disorder and nitrogen-containing bisphosphonates (BP) are a first line treatment for it. Yet, atypical femoral fractures (AFF), a rare adverse effect, may appear after prolonged BP administration. Given the low incidence of AFF, an underlying genetic cause that increases the susceptibility to these fractures is suspected. Previous studies uncovered rare CYP1A1 mutations in osteoporosis patients who suffered AFF after long-term BP treatment. CYP1A1 is involved in drug metabolism and steroid catabolism, making it an interesting candidate. However, a functional validation for the AFF-associated CYP1A1 mutations was lacking. Here we tested the enzymatic activity of four such CYP1A1 variants, by transfecting them into Saos-2 cells. We also tested the effect of commonly used BPs on the enzymatic activity of the CYP1A1 forms. We demonstrated that the p.Arg98Trp and p.Arg136His CYP1A1 variants have a significant negative effect on enzymatic activity. Moreover, all the BP treatments decreased CYP1A1 activity, although no specific interaction with CYP1A1 variants was found. Our results provide functional support to the hypothesis that an additive effect between CYP1A1 heterozygous mutations p.Arg98Trp and p.Arg136His, other rare mutations and long-term BP exposure might generate susceptibility to AFF. Full article

(This article belongs to the Special Issue Bone Development and Growth)

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Review

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21 pages, 4927 KiB

Open AccessReview

Pathophysiology and Emerging Molecular Therapeutic Targets in Heterotopic Ossification

by Favour Felix-Ilemhenbhio, George A. E. Pickering, Endre Kiss-Toth and Jeremy Mark Wilkinson

Int. J. Mol. Sci. 2022, 23(13), 6983; https://doi.org/10.3390/ijms23136983 - 23 Jun 2022

Cited by 9 | Viewed by 2688

Abstract

The term heterotopic ossification (HO) describes bone formation in tissues where bone is normally not present. Musculoskeletal trauma induces signalling events that in turn trigger cells, probably of mesenchymal origin, to differentiate into bone. The aetiology of HO includes extremely rare but severe, generalised and fatal monogenic forms of the disease; and as a common complex disorder in response to musculoskeletal, neurological or burn trauma. The resulting bone forms through a combination of endochondral and intramembranous ossification, depending on the aetiology, initiating stimulus and affected tissue. Given the heterogeneity of the disease, many cell types and biological pathways have been studied in efforts to find effective therapeutic strategies for the disorder. Cells of mesenchymal, haematopoietic and neuroectodermal lineages have all been implicated in the pathogenesis of HO, and the emerging dominant signalling pathways are thought to occur through the bone morphogenetic proteins (BMP), mammalian target of rapamycin (mTOR), and retinoic acid receptor pathways. Increased understanding of these disease mechanisms has resulted in the emergence of several novel investigational therapeutic avenues, including palovarotene and other retinoic acid receptor agonists and activin A inhibitors that target both canonical and non-canonical signalling downstream of the BMP type 1 receptor. In this article we aim to illustrate the key cellular and molecular mechanisms involved in the pathogenesis of HO and outline recent advances in emerging molecular therapies to treat and prevent HO that have had early success in the monogenic disease and are currently being explored in the common complex forms of HO. Full article

(This article belongs to the Special Issue Bone Development and Growth)

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19 pages, 1280 KiB

Open AccessReview

Molecular Mechanism of Induction of Bone Growth by the C-Type Natriuretic Peptide

by Estera Rintz, Grzegorz Węgrzyn, Toshihito Fujii and Shunji Tomatsu

Int. J. Mol. Sci. 2022, 23(11), 5916; https://doi.org/10.3390/ijms23115916 - 25 May 2022

Cited by 10 | Viewed by 3474

Abstract

The skeletal development process in the body occurs through sequential cellular and molecular processes called endochondral ossification. Endochondral ossification occurs in the growth plate where chondrocytes differentiate from resting, proliferative, hypertrophic to calcified zones. Natriuretic peptides (NPTs) are peptide hormones with multiple functions, including regulation of blood pressure, water-mineral balance, and many metabolic processes. NPTs secreted from the heart activate different tissues and organs, working in a paracrine or autocrine manner. One of the natriuretic peptides, C-type natriuretic peptide-, induces bone growth through several mechanisms. This review will summarize the knowledge, including the newest discoveries, of the mechanism of CNP activation in bone growth. Full article

(This article belongs to the Special Issue Bone Development and Growth)

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16 pages, 1359 KiB

Open AccessReview

Cellular and Molecular Alterations Underlying Abnormal Bone Growth in X-Linked Hypophosphatemia

by Rocío Fuente, María García-Bengoa, Ángela Fernández-Iglesias, Helena Gil-Peña, Fernando Santos and José Manuel López

Int. J. Mol. Sci. 2022, 23(2), 934; https://doi.org/10.3390/ijms23020934 - 15 Jan 2022

Cited by 4 | Viewed by 2546

Abstract

X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is caused by inactivating mutations of the phosphate-regulating endopeptidase gene (PHEX). XLH is mainly characterized by short stature, bone deformities and rickets, while in hypophosphatemia, normal or low vitamin D levels and low renal phosphate reabsorption are the principal biochemical aspects. The cause of growth impairment in patients with XLH is not completely understood yet, thus making the study of the growth plate (GP) alterations necessary. New treatment strategies targeting FGF23 have shown promising results in normalizing the growth velocity and improving the skeletal effects of XLH patients. However, further studies are necessary to evaluate how this treatment affects the GP as well as its long-term effects and the impact on adult height. Full article

(This article belongs to the Special Issue Bone Development and Growth)

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25 pages, 947 KiB

Open AccessReview

Obesity and Bone: A Complex Relationship

by Giuseppe Rinonapoli, Valerio Pace, Carmelinda Ruggiero, Paolo Ceccarini, Michele Bisaccia, Luigi Meccariello and Auro Caraffa

Int. J. Mol. Sci. 2021, 22(24), 13662; https://doi.org/10.3390/ijms222413662 - 20 Dec 2021

Cited by 67 | Viewed by 9308

Abstract

There is a large literature on the relationship between obesity and bone. What we can conclude from this review is that the increase in body weight causes an increase in BMD, both for a mechanical effect and for the greater amount of estrogens present in the adipose tissue. Nevertheless, despite an apparent strengthening of the bone witnessed by the increased BMD, the risk of fracture is higher. The greater risk of fracture in the obese subject is due to various factors, which are carefully analyzed by the Authors. These factors can be divided into metabolic factors and increased risk of falls. Fractures have an atypical distribution in the obese, with a lower incidence of typical osteoporotic fractures, such as those of hip, spine and wrist, and an increase in fractures of the ankle, upper leg, and humerus. In children, the distribution is different, but it is not the same in obese and normal-weight children. Specifically, the fractures of the lower limb are much more frequent in obese children. Sarcopenic obesity plays an important role. The authors also review the available literature regarding the effects of high-fat diet, weight loss and bariatric surgery. Full article

(This article belongs to the Special Issue Bone Development and Growth)

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19 pages, 2185 KiB

Open AccessReview

Site-Specific Fracture Healing: Comparison between Diaphysis and Metaphysis in the Mouse Long Bone

by Satoshi Inoue, Jiro Takito and Masanori Nakamura

Int. J. Mol. Sci. 2021, 22(17), 9299; https://doi.org/10.3390/ijms22179299 - 27 Aug 2021

Cited by 5 | Viewed by 6342

Abstract

The process of fracture healing varies depending upon internal and external factors, such as the fracture site, mode of injury, and mechanical environment. This review focuses on site-specific fracture healing, particularly diaphyseal and metaphyseal healing in mouse long bones. Diaphyseal fractures heal by forming the periosteal and medullary callus, whereas metaphyseal fractures heal by forming the medullary callus. Bone healing in ovariectomized mice is accompanied by a decrease in the medullary callus formation both in the diaphysis and metaphysis. Administration of estrogen after fracture significantly recovers the decrease in diaphyseal healing but fails to recover the metaphyseal healing. Thus, the two bones show different osteogenic potentials after fracture in ovariectomized mice. This difference may be attributed to the heterogeneity of the skeletal stem cells (SSCs)/osteoblast progenitors of the two bones. The Hox genes that specify the patterning of the mammalian skeleton during embryogenesis are upregulated during the diaphyseal healing. Hox genes positively regulate the differentiation of osteoblasts from SSCs in vitro. During bone grafting, the SSCs in the donor’s bone express Hox with adaptability in the heterologous bone. These novel functions of the Hox genes are discussed herein with reference to the site-specificity of fracture healing. Full article

(This article belongs to the Special Issue Bone Development and Growth)

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