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New Insights into the Use of Mouse Models for the Study of Musculoskeletal Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 8210

Special Issue Editor

Dr. Giuseppina Storlino

E-Mail Website
Guest Editor
Department of Clinical and Experimental Medicine (DMCS), University of Foggia, 71122 Foggia, Italy
Interests: musculoskeletal system; mouse model; osteosarcopenia; musculoskeletal disease; ageing model; genetic engineering; hind limb unloading; surgical mice model; sarcopenia; osteoporosis; osteoarthritis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Musculoskeletal disorders include a wide variety of pathologies characterised by the loss of muscle tissue often associated with bone loss. The study of these diseases and preclinical developments of therapeutic approaches require the use of well-characterised mouse models that reproduce the effects of human pathology and are crucial for understanding the molecular mechanisms underlying the onset of these diseases. Some examples of mouse models used for the study of musculoskeletal disorders are hind limb suspended mice, ovariectomised or orchidectomised mice, menischectomised mice and others. Furthermore, with advances in genetic engineering, various transgenic mouse models are available that reproduce musculoskeletal pathologies.

Leading by Dr. Giuseppina Storlino and assisting by our Topical Advisory Panel Member Dr. Roberta Zerlotin (University of Bari), in this special issue, we invite authors to submit original articles and reviews that contribute to a better understanding of the following topics: use of murine models in understanding the physiology of the musculoskeletal system, new murine models for the study of the musculoskeletal system, murine models for therapeutic approaches to osteoporosis, sarcopenia, muscle atrophy, osteoarthritis, and many others. The authors are also invited to contribute new emerging research on the use of cellular models, with particular focus, but not exclusive, on the study of co-culture cellular systems involving cell (or organoid) interactions that mimic the musculoskeletal system.

Dr. Giuseppina Storlino
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

  • mouse models
  • musculoskeletal
  • bone
  • muscle
  • cartilage
  • osteoporosis
  • muscle atrophy
  • muscle cachexia
  • muscle wasting
  • sarcopenia
  • osteoarthritis
  • rheumatoid arthritis
  • inflammation
  • pain

Published Papers (7 papers)

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Research

20 pages, 13351 KiB  
Article
Studying the Effect of MBNL1 and MBNL2 Loss in Skeletal Muscle Regeneration
by Ramesh S. Yadava, Mahua Mandal and Mani S. Mahadevan
Int. J. Mol. Sci. 2024, 25(5), 2687; https://doi.org/10.3390/ijms25052687 - 26 Feb 2024
Viewed by 742
Abstract
Loss of function of members of the muscleblind-like (MBNL) family of RNA binding proteins has been shown to play a key role in the spliceopathy of RNA toxicity in myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children. [...] Read more.
Loss of function of members of the muscleblind-like (MBNL) family of RNA binding proteins has been shown to play a key role in the spliceopathy of RNA toxicity in myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children. MBNL1 and MBNL2 are the most abundantly expressed members in skeletal muscle. A key aspect of DM1 is poor muscle regeneration and repair, leading to dystrophy. We used a BaCl2-induced damage model of muscle injury to study regeneration and effects on skeletal muscle satellite cells (MuSCs) in Mbnl1∆E3/∆E3 and Mbnl2∆E2/∆E2 knockout mice. Similar experiments have previously shown deleterious effects on these parameters in mouse models of RNA toxicity. Muscle regeneration in Mbnl1 and Mbnl2 knockout mice progressed normally with no obvious deleterious effects on MuSC numbers or increased expression of markers of fibrosis. Skeletal muscles in Mbnl1∆E3/∆E3/ Mbnl2∆E2/+ mice showed increased histopathology but no deleterious reductions in MuSC numbers and only a slight increase in collagen deposition. These results suggest that factors beyond the loss of MBNL1/MBNL2 and the associated spliceopathy are likely to play a key role in the defects in skeletal muscle regeneration and deleterious effects on MuSCs that are seen in mouse models of RNA toxicity due to expanded CUG repeats. Full article
(This article belongs to the Special Issue New Insights into the Use of Mouse Models for the Study of Musculoskeletal Diseases)
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19 pages, 5504 KiB  
Article
Utilization of the Rat Tibial Nerve Transection Model to Evaluate Cellular and Molecular Mechanisms Underpinning Denervation-Mediated Muscle Injury
by Christina Doherty, Monika Lodyga, Judy Correa, Caterina Di Ciano-Oliveira, Pamela J. Plant, James R. Bain and Jane Batt
Int. J. Mol. Sci. 2024, 25(3), 1847; https://doi.org/10.3390/ijms25031847 - 03 Feb 2024
Viewed by 1152
Abstract
Peripheral nerve injury denervates muscle, resulting in muscle paralysis and atrophy. This is reversible if timely muscle reinnervation occurs. With delayed reinnervation, the muscle’s reparative ability declines, and muscle-resident fibro-adipogenic progenitor cells (FAPs) proliferate and differentiate, inducing fibro-fatty muscle degradation and thereby physical [...] Read more.
Peripheral nerve injury denervates muscle, resulting in muscle paralysis and atrophy. This is reversible if timely muscle reinnervation occurs. With delayed reinnervation, the muscle’s reparative ability declines, and muscle-resident fibro-adipogenic progenitor cells (FAPs) proliferate and differentiate, inducing fibro-fatty muscle degradation and thereby physical disability. The mechanisms by which the peripheral nerve regulates FAPs expansion and differentiation are incompletely understood. Using the rat tibial neve transection model, we demonstrated an increased FAPs content and a changing FAPs phenotype, with an increased capacity for adipocyte and fibroblast differentiation, in gastrocnemius muscle post-denervation. The FAPs response was inhibited by immediate tibial nerve repair with muscle reinnervation via neuromuscular junctions (NMJs) and sensory organs (e.g., muscle spindles) or the sensory protection of muscle (where a pure sensory nerve is sutured to the distal tibial nerve stump) with reinnervation by muscle spindles alone. We found that both procedures reduced denervation-mediated increases in glial-cell-line-derived neurotrophic factor (GDNF) in muscle and that GDNF promoted FAPs adipogenic and fibrogenic differentiation in vitro. These results suggest that the peripheral nerve controls FAPs recruitment and differentiation via the modulation of muscle GDNF expression through NMJs and muscle spindles. GDNF can serve as a therapeutic target in the management of denervation-induced muscle injury. Full article
(This article belongs to the Special Issue New Insights into the Use of Mouse Models for the Study of Musculoskeletal Diseases)
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15 pages, 2786 KiB  
Article
Generating Bone Marrow Chimeric Mouse Using GPR120 Deficient Mouse for the Study of DHA Inhibitory Effect on Osteoclast Formation and Bone Resorption
by Jinghan Ma, Hideki Kitaura, Fumitoshi Ohori, Takahiro Noguchi, Aseel Marahleh, Ria Kinjo, Kayoko Kanou, Jiayi Ren, Mariko Miura, Kohei Narita and Itaru Mizoguchi
Int. J. Mol. Sci. 2023, 24(23), 17000; https://doi.org/10.3390/ijms242317000 - 30 Nov 2023
Viewed by 757
Abstract
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that exerts physiological effects via G protein-coupled receptor 120 (GPR120). In our previous studies, we figured out the inhibitory effects of DHA on TNF-α (Tumor necrosis factor-α)-induced osteoclastogenesis via GPR120 in vivo. Moreover, DHA directly [...] Read more.
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that exerts physiological effects via G protein-coupled receptor 120 (GPR120). In our previous studies, we figured out the inhibitory effects of DHA on TNF-α (Tumor necrosis factor-α)-induced osteoclastogenesis via GPR120 in vivo. Moreover, DHA directly suppressed RANKL expression in osteoblasts via GPR120 in vitro. In this study, we generated bone marrow chimeric mice using GPR120 deficient mice (GPR120-KO) to study the inhibitory effects of DHA on bone resorption and osteoclast formation. Bone marrow cells of wild-type (WT) or GPR120-KO mice were transplanted into irradiated recipient mice, which were WT or GPR120 deficient mice. The resulting chimeric mice contained stromal cells from the recipient and bone marrow cells, including osteoclast precursors, from the donor. These chimeric mice were used to perform a series of histological and microfocus computed tomography (micro-CT) analyses after TNF-α injection for induction of osteoclast formation with or without DHA. Osteoclast number and bone resorption were found to be significantly increased in chimeric mice, which did not express GPR120 in stromal cells, compared to chimeric mice, which expressed GPR120 in stromal cells. DHA was also found to suppress specific signaling pathways. We summarized that DHA suppressed TNF-α-induced stromal-dependent osteoclast formation and bone resorption via GPR120. Full article
(This article belongs to the Special Issue New Insights into the Use of Mouse Models for the Study of Musculoskeletal Diseases)
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14 pages, 6348 KiB  
Article
Heterotypic Cell Culture from Mouse Bone Marrow under Simulated Microgravity: Lessons for Stromal Lineage Functions
by Elena Markina, Ekaterina Tyrina, Andrey Ratushnyy, Elena Andreeva and Ludmila Buravkova
Int. J. Mol. Sci. 2023, 24(18), 13746; https://doi.org/10.3390/ijms241813746 - 06 Sep 2023
Cited by 1 | Viewed by 766
Abstract
Muscle and skeleton structures are considered most susceptible to negative factors of spaceflights, namely microgravity. Three-dimensional clinorotation is a ground-based simulation of microgravity. It provides an opportunity to elucidate the effects of microgravity at the cellular level. The extracellular matrix (ECM) content, transcriptional [...] Read more.
Muscle and skeleton structures are considered most susceptible to negative factors of spaceflights, namely microgravity. Three-dimensional clinorotation is a ground-based simulation of microgravity. It provides an opportunity to elucidate the effects of microgravity at the cellular level. The extracellular matrix (ECM) content, transcriptional profiles of genes encoding ECM and remodelling molecules, and secretory profiles were investigated in a heterotypic primary culture of bone marrow cells after 14 days of 3D clinorotation. Simulated microgravity negatively affected stromal lineage cells, responsible for bone tissue formation. This was evidenced by the reduced ECM volume and stromal cell numbers, including multipotent mesenchymal stromal cells (MSCs). ECM genes encoding proteins responsible for matrix stiffness and cell-ECM contacts were downregulated. In a heterotypic population of bone marrow cells, the upregulation of genes encoding ECM degrading molecules and the formation of a paracrine profile that can stimulate ECM degradation, may be mechanisms of osteodegenerative events that develop in real spaceflight. Full article
(This article belongs to the Special Issue New Insights into the Use of Mouse Models for the Study of Musculoskeletal Diseases)
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16 pages, 4253 KiB  
Article
Characterization of the Cardiac Structure and Function of Conscious D2.B10-Dmdmdx/J (D2-mdx) mice from 16–17 to 24–25 Weeks of Age
by Daria De Giorgio, Deborah Novelli, Francesca Motta, Marianna Cerrato, Davide Olivari, Annasimon Salama, Francesca Fumagalli, Roberto Latini, Lidia Staszewsky, Luca Crippa, Christian Steinkühler and Simonetta Andrea Licandro
Int. J. Mol. Sci. 2023, 24(14), 11805; https://doi.org/10.3390/ijms241411805 - 22 Jul 2023
Cited by 1 | Viewed by 1293
Abstract
Duchenne muscular dystrophy (DMD) is the most common form of muscle degenerative hereditary disease. Muscular replacement by fibrosis and calcification are the principal causes of progressive and severe musculoskeletal, respiratory, and cardiac dysfunction. To date, the D2.B10-Dmdmdx/J (D2-mdx) [...] Read more.
Duchenne muscular dystrophy (DMD) is the most common form of muscle degenerative hereditary disease. Muscular replacement by fibrosis and calcification are the principal causes of progressive and severe musculoskeletal, respiratory, and cardiac dysfunction. To date, the D2.B10-Dmdmdx/J (D2-mdx) model is proposed as the closest to DMD, but the results are controversial. In this study, the cardiac structure and function was characterized in D2-mdx mice from 16–17 up to 24–25 weeks of age. Echocardiographic assessment in conscious mice, gross pathology, and histological and cardiac biomarker analyses were performed. At 16–17 weeks of age, D2-mdx mice presented mild left ventricular function impairment and increased pulmonary vascular resistance. Cardiac fibrosis was more extended in the right ventricle, principally on the epicardium. In 24–25-week-old D2-mdx mice, functional and structural alterations increased but with large individual variation. High-sensitivity cardiac Troponin T, but not N-terminal pro-atrial natriuretic peptide, plasma levels were increased. In conclusion, left ventricle remodeling was mild to moderate in both young and adult mice. We confirmed that right ventricle epicardial fibrosis is the most outstanding finding in D2-mdx mice. Further long-term studies are needed to evaluate whether this mouse model can also be considered a model of DMD cardiomyopathy. Full article
(This article belongs to the Special Issue New Insights into the Use of Mouse Models for the Study of Musculoskeletal Diseases)
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21 pages, 7696 KiB  
Article
Irisin Protects against Loss of Trabecular Bone Mass and Strength in Adult Ovariectomized Mice by Stimulating Osteoblast Activity
by Giuseppina Storlino, Manuela Dicarlo, Roberta Zerlotin, Patrizia Pignataro, Lorenzo Sanesi, Clelia Suriano, Angela Oranger, Giorgio Mori, Giovanni Passeri, Silvia Colucci, Maria Grano and Graziana Colaianni
Int. J. Mol. Sci. 2023, 24(12), 9896; https://doi.org/10.3390/ijms24129896 - 08 Jun 2023
Cited by 3 | Viewed by 1383
Abstract
Irisin is a peptide secreted by skeletal muscle that plays a major role in bone metabolism. Experiments in mouse models have shown that administration of recombinant irisin prevents disuse-induced bone loss. In this study, we aimed to evaluate the effects of irisin treatment [...] Read more.
Irisin is a peptide secreted by skeletal muscle that plays a major role in bone metabolism. Experiments in mouse models have shown that administration of recombinant irisin prevents disuse-induced bone loss. In this study, we aimed to evaluate the effects of irisin treatment for the prevention of bone loss in the ovariectomized (Ovx) mouse, the animal model commonly used to investigate osteoporosis caused by estrogen deficiency. Micro-Ct analysis conducted on Sham mice (Sham-veh) and Ovx mice treated with vehicle (Ovx-veh) or recombinant irisin (Ovx-irisn) showed bone volume fraction (BV/TV) decreases in femurs (Ovx-veh 1.39± 0.71 vs. Sham-veh 2.84 ± 1.23; p = 0.02) and tibia at both proximal condyles (Ovx-veh 1.97 ± 0.68 vs. Sham-veh 3.48 ± 1.26; p = 0.03) and the subchondral plate (Ovx-veh 6.33 ± 0.36 vs. Sham-veh 8.18 ± 0.41; p = 0.01), which were prevented by treatment with a weekly dose of irisin for 4 weeks. Moreover, histological analysis of trabecular bone showed that irisin increased the number of active osteoblasts per bone perimeter (Ovx-irisin 32.3 ± 3.9 vs. Ovx-veh 23.5 ± 3.6; p = 0.01), while decreasing osteoclasts (Ovx-irisin 7.6 ± 2.4 vs. Ovx-veh 12.9 ± 3.04; p = 0.05). The possible mechanism by which irisin enhances osteoblast activity in Ovx mice is upregulation of the transcription factor Atf4, one of the key markers of osteoblast differentiation, and osteoprotegerin, thereby inhibiting osteoclast formation. Full article
(This article belongs to the Special Issue New Insights into the Use of Mouse Models for the Study of Musculoskeletal Diseases)
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16 pages, 2541 KiB  
Article
Stromal Lineage Precursors from Rodent Femur and Tibia Bone Marrows after Hindlimb Unloading: Functional Ex Vivo Analysis
by Elena Markina, Elena Andreeva and Ludmila Buravkova
Int. J. Mol. Sci. 2023, 24(10), 8594; https://doi.org/10.3390/ijms24108594 - 11 May 2023
Viewed by 1165
Abstract
Rodent hindlimb unloading (HU) model was developed to elucidate responses/mechanisms of adverse consequences of space weightlessness. Multipotent mesenchymal stromal cells (MMSCs) were isolated from rat femur and tibia bone marrows and examined ex vivo after 2 weeks of HU and subsequent 2 weeks [...] Read more.
Rodent hindlimb unloading (HU) model was developed to elucidate responses/mechanisms of adverse consequences of space weightlessness. Multipotent mesenchymal stromal cells (MMSCs) were isolated from rat femur and tibia bone marrows and examined ex vivo after 2 weeks of HU and subsequent 2 weeks of restoration of load (HU + RL). In both bones, decrease of fibroblast colony forming units (CFU-f) after HU with restoration after HU + RL detected. In CFU-f and MMSCs, levels of spontaneous/induced osteocommitment were similar. MMSCs from tibia initially had greater spontaneous mineralization of extracellular matrix but were less sensitive to osteoinduction. There was no recovery of initial levels of mineralization in MMSCs from both bones during HU + RL. After HU, most bone-related genes were downregulated in tibia or femur MMSCs. After HU + RL, the initial level of transcription was restored in femur, while downregulation persisted in tibia MMSCs. Therefore, HU provoked a decrease of osteogenic activity of BM stromal precursors at transcriptomic and functional levels. Despite unidirectionality of changes, the negative effects of HU were more pronounced in stromal precursors from distal limb—tibia. These observations appear to be on demand for elucidation of mechanisms of skeletal disorders in astronauts in prospect of long-term space missions. Full article
(This article belongs to the Special Issue New Insights into the Use of Mouse Models for the Study of Musculoskeletal Diseases)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Utilization of the Rat Tibial Nerve Transection Model to evaluate cellular mechanisms underpinning denervation-mediated muscle injury
Author: Batt
Highlights: 1. Rat tibial nerve transection model is ideal for mechanistic study of traumatic muscle denervation injury 2. Both tibial nerve repair and sensory protection of denervated muscle mitigate fibrosis and modulate FAPs expansion 3. The neurotrophic factor GDNF is decreased to baseline expression in denervated muscle provided sensory protection 4.GDNF stimulates FAPs proliferation/differentiation to adipocytes and fibroblasts in vitro.

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