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Animal Experimental Models in Bone Metabolic Disease

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: closed (10 December 2022) | Viewed by 21698

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Guest Editor
Departments of Internal Medicine and Toxicology, University Hospital Rio Hortega, University of Valladolid, Valladolid, Spain
Interests: osteoporosis; genetics and relationship with chronic disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is our pleasure to inform about the Special Issue “Animal experimental models in bone metabolic disease”. Metabolic bone disease, especially osteoporosis, has a high prevalence and causes an increase in morbidity and mortality, especially in elderly patients. It is important to understand the molecular mechanisms involved in its appearance, which allow for therapeutic targets to be established. An increased knowledge of its pathophysiology allows for a better understanding of the disease and its solutions. On the other hand, knowledge of these new therapeutic targets will allow for the design of new therapeutic options. These need to be tested in experimental models before they can be tested in humans. In addition, the therapeutic options approved for other diseases could be beneficial in metabolic bone disease and tests on animal models would facilitate their use. This Special Issue focuses on animal experimental models used to study the pathogenesis of bone metabolic diseases and will be published in the International Journal of Molecular Sciences (IJMS, https://www.mdpi.com/journal/ijms, ISSN 1422-0067). We invite researchers to submit original review articles associated with the use of animal experimental models in metabolic bone diseases.

Prof. Dr. Jose Luis Pérez-Castrillón
Guest Editor

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Keywords

  • animal experimental models
  • therapeutic targets
  • pathophysiology
  • bone metabolic disease

Published Papers (10 papers)

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Editorial

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3 pages, 198 KiB  
Editorial
Animal Experimental Models in Bone Metabolic Disease
by Ricardo Usategui-Martín and José Luis Pérez-Castrillón
Int. J. Mol. Sci. 2023, 24(11), 9534; https://doi.org/10.3390/ijms24119534 - 31 May 2023
Viewed by 884
Abstract
Bone is a highly specialized and dynamic tissue with several crucial functions, including support, movement support, protection of vital organs, and mineral storage [...] Full article
(This article belongs to the Special Issue Animal Experimental Models in Bone Metabolic Disease)

Research

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11 pages, 1657 KiB  
Article
Analysis of Bone Histomorphometry in Rat and Guinea Pig Animal Models Subject to Hypoxia
by Ricardo Usategui-Martín, Álvaro Del Real, José A. Sainz-Aja, Jesús Prieto-Lloret, Elena Olea, Asunción Rocher, Ricardo J. Rigual, José A. Riancho and José Luis Pérez-Castrillón
Int. J. Mol. Sci. 2022, 23(21), 12742; https://doi.org/10.3390/ijms232112742 - 22 Oct 2022
Cited by 2 | Viewed by 1386
Abstract
Hypoxia may be associated with alterations in bone remodeling, but the published results are contradictory. The aim of this study was to characterize the bone morphometry changes subject to hypoxia for a better understanding of the bone response to hypoxia and its possible [...] Read more.
Hypoxia may be associated with alterations in bone remodeling, but the published results are contradictory. The aim of this study was to characterize the bone morphometry changes subject to hypoxia for a better understanding of the bone response to hypoxia and its possible clinical consequences on the bone metabolism. This study analyzed the bone morphometry parameters by micro-computed tomography (μCT) in rat and guinea pig normobaric hypoxia models. Adult male and female Wistar rats were exposed to chronic hypoxia for 7 and 15 days. Additionally, adult male guinea pigs were exposed to chronic hypoxia for 15 days. The results showed that rats exposed to chronic constant and intermittent hypoxic conditions had a worse trabecular and cortical bone health than control rats (under a normoxic condition). Rats under chronic constant hypoxia were associated with a more deteriorated cortical tibia thickness, trabecular femur and tibia bone volume over the total volume (BV/TV), tibia trabecular number (Tb.N), and trabecular femur and tibia bone mineral density (BMD). In the case of chronic intermittent hypoxia, rats subjected to intermittent hypoxia had a lower cortical femur tissue mineral density (TMD), lower trabecular tibia BV/TV, and lower trabecular thickness (Tb.Th) of the tibia and lower tibia Tb.N. The results also showed that obese rats under a hypoxic condition had worse values for the femur and tibia BV/TV, tibia trabecular separation (Tb.Sp), femur and tibia Tb.N, and BMD for the femur and tibia than normoweight rats under a hypoxic condition. In conclusion, hypoxia and obesity may modify bone remodeling, and thus bone microarchitecture, and they might lead to reductions in the bone strength and therefore increase the risk of fragility fracture. Full article
(This article belongs to the Special Issue Animal Experimental Models in Bone Metabolic Disease)
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17 pages, 3612 KiB  
Article
Erythropoietin Receptor (EPOR) Signaling in the Osteoclast Lineage Contributes to EPO-Induced Bone Loss in Mice
by Zamzam Awida, Sahar Hiram-Bab, Almog Bachar, Hussam Saed, Dan Zyc, Anton Gorodov, Nathalie Ben-Califa, Sewar Omari, Jana Omar, Liana Younis, Jennifer Ana Iden, Liad Graniewitz Visacovsky, Ida Gluzman, Tamar Liron, Bitya Raphael-Mizrahi, Albert Kolomansky, Martina Rauner, Ben Wielockx, Yankel Gabet and Drorit Neumann
Int. J. Mol. Sci. 2022, 23(19), 12051; https://doi.org/10.3390/ijms231912051 - 10 Oct 2022
Cited by 5 | Viewed by 2159
Abstract
Erythropoietin (EPO) is a pleiotropic cytokine that classically drives erythropoiesis but can also induce bone loss by decreasing bone formation and increasing resorption. Deletion of the EPO receptor (EPOR) on osteoblasts or B cells partially mitigates the skeletal effects of EPO, thereby implicating [...] Read more.
Erythropoietin (EPO) is a pleiotropic cytokine that classically drives erythropoiesis but can also induce bone loss by decreasing bone formation and increasing resorption. Deletion of the EPO receptor (EPOR) on osteoblasts or B cells partially mitigates the skeletal effects of EPO, thereby implicating a contribution by EPOR on other cell lineages. This study was designed to define the role of monocyte EPOR in EPO-mediated bone loss, by using two mouse lines with conditional deletion of EPOR in the monocytic lineage. Low-dose EPO attenuated the reduction in bone volume (BV/TV) in Cx3cr1Cre EPORf/f female mice (27.05%) compared to controls (39.26%), but the difference was not statistically significant. To validate these findings, we increased the EPO dose in LysMCre model mice, a model more commonly used to target preosteoclasts. There was a significant reduction in both the increase in the proportion of bone marrow preosteoclasts (CD115+) observed following high-dose EPO administration and the resulting bone loss in LysMCre EPORf/f female mice (44.46% reduction in BV/TV) as compared to controls (77.28%), without interference with the erythropoietic activity. Our data suggest that EPOR in the monocytic lineage is at least partially responsible for driving the effect of EPO on bone mass. Full article
(This article belongs to the Special Issue Animal Experimental Models in Bone Metabolic Disease)
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10 pages, 3644 KiB  
Article
A Novel Ex Vivo Bone Culture Model for Regulation of Collagen/Apatite Preferential Orientation by Mechanical Loading
by Ryota Watanabe, Aira Matsugaki, Takuya Ishimoto, Ryosuke Ozasa, Takuya Matsumoto and Takayoshi Nakano
Int. J. Mol. Sci. 2022, 23(13), 7423; https://doi.org/10.3390/ijms23137423 - 4 Jul 2022
Cited by 2 | Viewed by 1747
Abstract
The anisotropic microstructure of bone, composed of collagen fibers and biological apatite crystallites, is an important determinant of its mechanical properties. Recent studies have revealed that the preferential orientation of collagen/apatite composites is closely related to the direction and magnitude of in vivo [...] Read more.
The anisotropic microstructure of bone, composed of collagen fibers and biological apatite crystallites, is an important determinant of its mechanical properties. Recent studies have revealed that the preferential orientation of collagen/apatite composites is closely related to the direction and magnitude of in vivo principal stress. However, the mechanism of alteration in the collagen/apatite microstructure to adapt to the mechanical environment remains unclear. In this study, we established a novel ex vivo bone culture system using embryonic mouse femurs, which enabled artificial control of the mechanical environment. The mineralized femur length significantly increased following cultivation; uniaxial mechanical loading promoted chondrocyte hypertrophy in the growth plates of embryonic mouse femurs. Compressive mechanical loading using the ex vivo bone culture system induced a higher anisotropic microstructure than that observed in the unloaded femur. Osteocytes in the anisotropic bone microstructure were elongated and aligned along the long axis of the femur, which corresponded to the principal loading direction. The ex vivo uniaxial mechanical loading successfully induced the formation of an oriented collagen/apatite microstructure via osteocyte mechano-sensation in a manner quite similar to the in vivo environment. Full article
(This article belongs to the Special Issue Animal Experimental Models in Bone Metabolic Disease)
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13 pages, 2849 KiB  
Article
PRDX2 Knockdown Inhibits Extracellular Matrix Synthesis of Chondrocytes by Inhibiting Wnt5a/YAP1/CTGF and Activating IL-6/JAK2/STAT3 Pathways in Deer Antler
by Xuyang Sun, Xiaoying Gu, Jingna Peng, Liguo Yang, Xinxin Zhang, Zaohong Ran and Jiajun Xiong
Int. J. Mol. Sci. 2022, 23(9), 5232; https://doi.org/10.3390/ijms23095232 - 7 May 2022
Cited by 1 | Viewed by 1976
Abstract
Although peroxiredoxin 2 (PRDX2) plays a vital role in relieving oxidative stress, its physiological function in cartilage development remains almost unknown. In this study, we found that the expression of PRDX2 significantly increased in the chondrocytes compared with pre-chondrocytes. PRDX2 knockdown significantly decreased [...] Read more.
Although peroxiredoxin 2 (PRDX2) plays a vital role in relieving oxidative stress, its physiological function in cartilage development remains almost unknown. In this study, we found that the expression of PRDX2 significantly increased in the chondrocytes compared with pre-chondrocytes. PRDX2 knockdown significantly decreased the expression of extracellular matrix (ECM) protein (Col2a and Aggrecan), which led to blocked cartilage formation. Moreover, PRDX2 knockdown also inhibited the expression of connective tissue growth factor (CTGF). CTGF is an important growth factor that regulates synthesis of ECM proteins. We explored the possible regulatory mechanism by which PRDX2 regulated the expression of CTGF. Our results demonstrated that PRDX2 knockdown downregulated the expression of CTGF by inhibiting Wnt5a/Yes-associated protein 1 (YAP1) pathway. In addition, PRDX2 knockdown promoted the expression of interleukin 6 (IL-6), indicating PRDX2 expression had an anti-inflammatory function during antler growth. Mechanistically, PRDX2 knockdown promoted cartilage matrix degradation by activating the IL-6-mediated Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway. These results reveal that PRDX2 is a potential regulator that promotes cartilage extracellular matrix synthesis. Full article
(This article belongs to the Special Issue Animal Experimental Models in Bone Metabolic Disease)
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10 pages, 1377 KiB  
Article
Sprague Dawley Rats Show More Severe Bone Loss, Osteophytosis and Inflammation Compared toWistar Han Rats in a High-Fat, High-Sucrose Diet Model of Joint Damage
by Kelly Warmink, Jaqueline L. Rios, Devin R. van Valkengoed, Nicoline M. Korthagen and Harrie Weinans
Int. J. Mol. Sci. 2022, 23(7), 3725; https://doi.org/10.3390/ijms23073725 - 28 Mar 2022
Cited by 7 | Viewed by 2602
Abstract
In animal models, joint degeneration observed in response to obesogenic diet varies in nature and severity. In this study, we compare joint damage in Sprague Dawley and Wistar-Han rats in response to a high-fat, high-sucrose (HFS) diet groove model of osteoarthritis (OA). Wistar [...] Read more.
In animal models, joint degeneration observed in response to obesogenic diet varies in nature and severity. In this study, we compare joint damage in Sprague Dawley and Wistar-Han rats in response to a high-fat, high-sucrose (HFS) diet groove model of osteoarthritis (OA). Wistar Han (n = 5) and Sprague Dawley (n = 5) rats were fed an HFS diet for 24 weeks. OA was induced 12 weeks after the diet onset by groove surgery in the right knee joint. The left knee served as a control. Outcomes were OARSI histopathology scoring, bone changes by µCT imaging, local (synovial and fat pad) and systemic (blood cytokine) inflammation markers. In both rat strains, the HFS diet resulted in a similar change in metabolic parameters, but only Sprague Dawley rats showed a large, osteoporosis-like decrease in trabecular bone volume. Osteophyte count and local joint inflammation were higher in Sprague Dawley rats. In contrast, cartilage degeneration and systemic inflammatory marker levels were similar between the rat strains. The difference in bone volume loss, osteophytosis and local inflammation suggest that both rat strains show a different joint damage phenotype and could, therefore, potentially represent different OA phenotypes observed in humans. Full article
(This article belongs to the Special Issue Animal Experimental Models in Bone Metabolic Disease)
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Review

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31 pages, 1706 KiB  
Review
Murine Animal Models in Osteogenesis Imperfecta: The Quest for Improving the Quality of Life
by Natividad Alcorta-Sevillano, Arantza Infante, Iratxe Macías and Clara I. Rodríguez
Int. J. Mol. Sci. 2023, 24(1), 184; https://doi.org/10.3390/ijms24010184 - 22 Dec 2022
Cited by 3 | Viewed by 2543
Abstract
Osteogenesis imperfecta is a rare genetic disorder characterized by bone fragility, due to alterations in the type I collagen molecule. It is a very heterogeneous disease, both genetically and phenotypically, with a high variability of clinical phenotypes, ranging from mild to severe forms, [...] Read more.
Osteogenesis imperfecta is a rare genetic disorder characterized by bone fragility, due to alterations in the type I collagen molecule. It is a very heterogeneous disease, both genetically and phenotypically, with a high variability of clinical phenotypes, ranging from mild to severe forms, the most extreme cases being perinatal lethal. There is no curative treatment for OI, and so great efforts are being made in order to develop effective therapies. In these attempts, the in vivo preclinical studies are of paramount importance; therefore, serious analysis is required to choose the right murine OI model able to emulate as closely as possible the disease of the target OI population. In this review, we summarize the features of OI murine models that have been used for preclinical studies until today, together with recently developed new murine models. The bone parameters that are usually evaluated in order to determine the relevance of new developing therapies are exposed, and finally, current and innovative therapeutic strategies attempts considered in murine OI models, along with their mechanism of action, are reviewed. This review aims to summarize the in vivo studies developed in murine models available in the field of OI to date, in order to help the scientific community choose the most accurate OI murine model when developing new therapeutic strategies capable of improving the quality of life. Full article
(This article belongs to the Special Issue Animal Experimental Models in Bone Metabolic Disease)
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18 pages, 3624 KiB  
Review
Osteoporosis Preclinical Research: A Systematic Review on Comparative Studies Using Ovariectomized Sheep
by Francesca Salamanna, Deyanira Contartese, Francesca Veronesi, Lucia Martini and Milena Fini
Int. J. Mol. Sci. 2022, 23(16), 8904; https://doi.org/10.3390/ijms23168904 - 10 Aug 2022
Cited by 2 | Viewed by 2732
Abstract
Sheep ovariectomy (OVX) alone or associated to steroid therapy, deficient diet, or hypothalamic–pituitary disconnection has proven to be of critical importance for osteoporosis research in orthopedics. However, the impact of specific variables, such as breed, age, diet, time after OVX, and other variables, [...] Read more.
Sheep ovariectomy (OVX) alone or associated to steroid therapy, deficient diet, or hypothalamic–pituitary disconnection has proven to be of critical importance for osteoporosis research in orthopedics. However, the impact of specific variables, such as breed, age, diet, time after OVX, and other variables, should be monitored. Thus, the design of comparative studies is mandatory to minimize the impact of these variables or to recognize the presence of unwanted variables as well as to better characterize bone remodeling in this model. Herein, we conducted a systematic review of the last 10 years on PubMed, Scopus, and Web of Knowledge considering only studies on OVX sheep where a control group was present. Of the 123 records screened, 18 studies were included and analyzed. Results showed that (i) Merino sheep are the most exploited breed; (ii) 5–6 years of age is the most used time for inducing OVX; (iii) ventral midline laparotomy is the most common approach to induce OVX; (iv) OVX associated to steroid therapy is the most widely used osteoporosis model; and (v) success of OVX was mostly verified 12 months after surgery. In detail, starting from 12 months after OVX a significant decline in bone mineral density and in microarchitectural bone parameters as well as in biochemical markers were detected in all studies in comparison to control groups. Bone alteration was also site-specific on a pattern as follows: lumbar vertebra, femoral neck, and ribs. Before 12 months from OVX and starting from 3–5 months, microarchitectural bone changes and biochemical marker alterations were present when osteoporosis was induced by OVX associated to steroid therapy. In conclusion, OVX in sheep influence bone metabolism causing pronounced systemic bone loss and structural deterioration comparable to the situation found in osteoporosis patients. Data for treating osteoporosis patients are based not only on good planning and study design but also on a correct animal use that, as suggested by 3Rs principles and by ARRIVE guidelines, includes the use of control groups to be directly contrasted with the experimental group. Full article
(This article belongs to the Special Issue Animal Experimental Models in Bone Metabolic Disease)
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24 pages, 18786 KiB  
Review
Naturally Occurring Osteoarthritis Features and Treatments: Systematic Review on the Aged Guinea Pig Model
by Francesca Veronesi, Francesca Salamanna, Lucia Martini and Milena Fini
Int. J. Mol. Sci. 2022, 23(13), 7309; https://doi.org/10.3390/ijms23137309 - 30 Jun 2022
Cited by 6 | Viewed by 2337
Abstract
To date, several in vivo models have been used to reproduce the onset and monitor the progression of osteoarthritis (OA), and guinea pigs represent a standard model for studying naturally occurring, age-related OA. This systematic review aims to characterize the guinea pig for [...] Read more.
To date, several in vivo models have been used to reproduce the onset and monitor the progression of osteoarthritis (OA), and guinea pigs represent a standard model for studying naturally occurring, age-related OA. This systematic review aims to characterize the guinea pig for its employment in in vivo, naturally occurring OA studies and for the evaluation of specific disease-modifying agents. The search was performed in PubMed, Scopus, and Web of Knowledge in the last 10 years. Of the 233 records screened, 49 studies were included. Results showed that within a relatively short period of time, this model develops specific OA aspects, including cartilage degeneration, marginal osteophytes formation, and subchondral bone alterations. Disease severity increases with age, beginning at 3 months with mild OA and reaching moderate–severe OA at 18 months. Among the different strains, Dunkin Hartley develops OA at a relatively early age. Thus, disease-modifying agents have mainly been evaluated for this strain. As summarized herein, spontaneous development of OA in guinea pigs represents an excellent model for studying disease pathogenesis and for evaluating therapeutic interventions. In an ongoing effort at standardization, a detailed characterization of specific OA models is necessary, even considering the main purpose of these models, i.e., translatability to human OA. Full article
(This article belongs to the Special Issue Animal Experimental Models in Bone Metabolic Disease)
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12 pages, 6246 KiB  
Review
Molecular Mechanisms Involved in Hypoxia-Induced Alterations in Bone Remodeling
by Ricardo Usategui-Martín, Ricardo Rigual, Marta Ruiz-Mambrilla, José-María Fernández-Gómez, Antonio Dueñas and José Luis Pérez-Castrillón
Int. J. Mol. Sci. 2022, 23(6), 3233; https://doi.org/10.3390/ijms23063233 - 17 Mar 2022
Cited by 17 | Viewed by 2162
Abstract
Bone is crucial for the support of muscles and the protection of vital organs, and as a reservoir of calcium and phosphorus. Bone is one of the most metabolically active tissues and is continuously renewed to adapt to the changes required for healthy [...] Read more.
Bone is crucial for the support of muscles and the protection of vital organs, and as a reservoir of calcium and phosphorus. Bone is one of the most metabolically active tissues and is continuously renewed to adapt to the changes required for healthy functioning. To maintain normal cellular and physiological bone functions sufficient oxygen is required, as evidence has shown that hypoxia may influence bone health. In this scenario, this review aimed to analyze the molecular mechanisms involved in hypoxia-induced bone remodeling alterations and their possible clinical consequences. Hypoxia has been associated with reduced bone formation and reduced osteoblast matrix mineralization due to the hypoxia environment inhibiting osteoblast differentiation. A hypoxic environment is involved with increased osteoclastogenesis and increased bone resorptive capacity of the osteoclasts. Clinical studies, although with contradictory results, have shown that hypoxia can modify bone remodeling. Full article
(This article belongs to the Special Issue Animal Experimental Models in Bone Metabolic Disease)
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