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Musculoskeletal Development and Skeletal Pathophysiologies

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: closed (31 January 2022) | Viewed by 49549

Special Issue Editor

Dr. Elizabeth W. Bradley

E-Mail Website
Guest Editor
Orthpedic Surgery and Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
Interests: osteoimmunology; bone; osteoclast; chondrocyte; cartilage development; osteoporosis; osteoarthritis; fracture repair
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

We are excited to announce a Special Issue of the Journal of International Molecular Sciences that focuses on Musculoskeletal Development and Skeletal Pathophysiologies. Musculoskeletal problems are one of the leading reasons for physician visits each year.  As such, diseases such as osteoporosis and osteoarthritis impart a major social and economic burden and are associated with significant morbidity and mortality.  This burden will grow as the population ages, unless treatment modalities are expanded; thus, new knowledge is needed to provide a better understanding of musculoskeletal generation and degeneration, and to identify new therapeutic approaches. 

We are seeking submissions of original research articles as well as manuscripts that review a relevant field of research. All papers will undergo peer review.

Dr. Elizabeth W. Bradley
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

  • musculoskeletal development
  • growth plate
  • endochondral ossification
  • intramembranous ossification
  • osteoporosis
  • osteoarthritis
  • bone
  • cartilage
  • osteoblast
  • osteoclast
  • chondrocyte

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Published Papers (16 papers)

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Editorial

Jump to: Research, Review

3 pages, 190 KiB  
Editorial
Musculoskeletal Development and Skeletal Pathophysiology’s
by Elizabeth W. Bradley
Int. J. Mol. Sci. 2022, 23(16), 9092; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169092 - 13 Aug 2022
Cited by 1 | Viewed by 953
Abstract
Musculoskeletal (MSK) disorders are one of the leading causes of disability for people of all ages and impart significant socio-economic burdens on society [...] Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)

Research

Jump to: Editorial, Review

19 pages, 3756 KiB  
Article
Fatty Acid Fingerprints and Hyaluronic Acid in Extracellular Vesicles from Proliferating Human Fibroblast-like Synoviocytes
by Anne-Mari Mustonen, Tommi Paakkonen, Johanna Matilainen, Kirsi Rilla, Reijo Käkelä, Marjo Malinen, Piia Takabe, Sanna Oikari, Janne Capra, Sanna P. Sihvo, Pauliina Ryökäs and Petteri Nieminen
Int. J. Mol. Sci. 2022, 23(10), 5613; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105613 - 17 May 2022
Cited by 4 | Viewed by 2137
Abstract
Extracellular vesicles (EVs) function as conveyors of fatty acids (FAs) and other bioactive lipids and can modulate the gene expression and behavior of target cells. EV lipid composition influences the fluidity and stability of EV membranes and reflects the availability of lipid mediator [...] Read more.
Extracellular vesicles (EVs) function as conveyors of fatty acids (FAs) and other bioactive lipids and can modulate the gene expression and behavior of target cells. EV lipid composition influences the fluidity and stability of EV membranes and reflects the availability of lipid mediator precursors. Fibroblast-like synoviocytes (FLSs) secrete EVs that transport hyaluronic acid (HA). FLSs play a central role in inflammation, pannus formation, and cartilage degradation in joint diseases, and EVs have recently emerged as potential mediators of these effects. The aim of the present study was to follow temporal changes in HA and EV secretion by normal FLSs, and to characterize the FA profiles of FLSs and EVs during proliferation. The methods used included nanoparticle tracking analysis, confocal laser scanning microscopy, sandwich-type enzyme-linked sorbent assay, quantitative PCR, and gas chromatography. The expression of hyaluronan synthases 1–3 in FLSs and HA concentrations in conditioned media decreased during cell proliferation. This was associated with elevated proportions of 20:4n-6 and total n-6 polyunsaturated FAs (PUFAs) in high-density cells, reductions in n-3/n-6 PUFA ratios, and up-regulation of cluster of differentiation 44, tumor necrosis factor α, peroxisome proliferator-activated receptor (PPAR)-α, and PPAR-γ. Compared to the parent FLSs, 16:0, 18:0, and 18:1n-9 were enriched in the EV fraction. EV counts decreased during cell growth, and 18:2n-6 in EVs correlated with the cell count. To conclude, FLS proliferation was featured by increased 20:4n-6 proportions and reduced n-3/n-6 PUFA ratios, and FAs with a low degree of unsaturation were selectively transferred from FLSs into EVs. These FA modifications have the potential to affect membrane fluidity, biosynthesis of lipid mediators, and inflammatory processes in joints, and could eventually provide tools for translational studies to counteract cartilage degradation in inflammatory joint diseases. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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13 pages, 5816 KiB  
Article
Myeloid Lineage Ablation of Phlpp1 Regulates M-CSF Signaling and Tempers Bone Resorption in Female Mice
by Ismael Y. Karkache, Jeyaram R. Damodaran, David H. H. Molstad, Kim C. Mansky and Elizabeth W. Bradley
Int. J. Mol. Sci. 2021, 22(18), 9702; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189702 - 08 Sep 2021
Cited by 3 | Viewed by 1924
Abstract
Prior work demonstrated that Phlpp1 deficiency alters trabecular bone mass and enhances M-CSF responsiveness, but the cell types and requirement of Phlpp1 for this effect were unclear. To understand the function of Phlpp1 within myeloid lineage cells, we crossed Phlpp1 floxed mice with [...] Read more.
Prior work demonstrated that Phlpp1 deficiency alters trabecular bone mass and enhances M-CSF responsiveness, but the cell types and requirement of Phlpp1 for this effect were unclear. To understand the function of Phlpp1 within myeloid lineage cells, we crossed Phlpp1 floxed mice with mice harboring LysM-Cre. Micro-computed tomography of the distal femur of 12-week-old mice revealed a 30% increase in bone volume per total volume of Phlpp1 female conditional knockouts, but we did not observe significant changes within male Phlpp1 cKOLysM mice. Bone histomorphmetry of the proximal tibia further revealed that Phlpp1 cKOLysM females exhibited elevated osteoclast numbers, but conversely had reduced levels of serum markers of bone resorption as compared to littermate controls. Osteoblast number and serum markers of bone formation were unchanged. In vitro assays confirmed that Phlpp1 ablation enhanced osteoclast number and area, but limited bone resorption. Additionally, reconstitution with exogenous Phlpp1 suppressed osteoclast numbers. Dose response assays demonstrated that Phlpp1−/− cells are more responsive to M-CSF, but reconstitution with Phlpp1 abrogated this effect. Furthermore, small molecule-mediated Phlpp inhibition enhanced osteoclast numbers and size. Enhanced phosphorylation of Phlpp substrates—including Akt, ERK1/2, and PKCζ—accompanied these observations. In contrast, actin cytoskeleton disruption occurred within Phlpp inhibitor treated osteoclasts. Moreover, Phlpp inhibition reduced resorption of cells cultured on bovine bone slices in vitro. Our results demonstrate that Phlpp1 deficiency within myeloid lineage cells enhances bone mass by limiting bone resorption while leaving osteoclast numbers intact; moreover, we show that Phlpp1 represses osteoclastogenesis and controls responses to M-CSF. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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13 pages, 4042 KiB  
Article
Caspase-1 Inhibition Impacts the Formation of Chondrogenic Nodules, and the Expression of Markers Related to Osteogenic Differentiation and Lipid Metabolism
by Alice Ramesova, Barbora Vesela, Eva Svandova, Herve Lesot and Eva Matalova
Int. J. Mol. Sci. 2021, 22(17), 9576; https://doi.org/10.3390/ijms22179576 - 03 Sep 2021
Cited by 5 | Viewed by 2526
Abstract
Caspase-1, as the main pro-inflammatory cysteine protease, was investigated mostly with respect to inflammation-related processes. Interestingly, caspase-1 was identified as being involved in lipid metabolism, which is extremely important for the proper differentiation of chondrocytes. Based on a screening investigation, general caspase inhibition [...] Read more.
Caspase-1, as the main pro-inflammatory cysteine protease, was investigated mostly with respect to inflammation-related processes. Interestingly, caspase-1 was identified as being involved in lipid metabolism, which is extremely important for the proper differentiation of chondrocytes. Based on a screening investigation, general caspase inhibition impacts the expression of Cd36 in chondrocytes, the fatty acid translocase with a significant impact on lipid metabolism. However, the engagement of individual caspases in the effect has not yet been identified. Therefore, the hypothesis that caspase-1 might be a candidate here appears challenging. The primary aim of this study thus was to find out whether the inhibition of caspase-1 activity would affect Cd36 expression in a chondrogenic micromass model. The expression of Pparg, a regulator Cd36, was examined as well. In the caspase-1 inhibited samples, both molecules were significantly downregulated. Notably, in the treated group, the formation of the chondrogenic nodules was apparently disrupted, and the subcellular deposition of lipids and polysaccharides showed an abnormal pattern. To further investigate this observation, the samples were subjected to an osteogenic PCR array containing selected markers related to cartilage/bone cell differentiation. Among affected molecules, Bmp7 and Gdf10 showed a significantly increased expression, while Itgam, Mmp9, Vdr, and Rankl decreased. Notably, Rankl is a key marker in bone remodeling/homeostasis and thus is a target in several treatment strategies, including a variety of fatty acids, and is balanced by its decoy receptor Opg (osteoprotegerin). To evaluate the effect of Cd36 downregulation on Rankl and Opg, Cd36 silencing was performed using micromass cultures. After Cd36 silencing, the expression of Rankl was downregulated and Opg upregulated, which was an inverse effect to caspase-1 inhibition (and Cd36 upregulation). These results demonstrate new functions of caspase-1 in chondrocyte differentiation and lipid metabolism-related pathways. The effect on the Rankl/Opg ratio, critical for bone maintenance and pathology, including osteoarthritis, is particularly important here as well. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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14 pages, 1330 KiB  
Article
Global Deletion of 11β-HSD1 Prevents Muscle Wasting Associated with Glucocorticoid Therapy in Polyarthritis
by Justine M. Webster, Michael S. Sagmeister, Chloe G. Fenton, Alex P. Seabright, Yu-Chiang Lai, Simon W. Jones, Andrew Filer, Mark S. Cooper, Gareth G. Lavery, Karim Raza, Ramon Langen and Rowan S. Hardy
Int. J. Mol. Sci. 2021, 22(15), 7828; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157828 - 22 Jul 2021
Cited by 10 | Viewed by 2828
Abstract
Glucocorticoids provide indispensable anti-inflammatory therapies. However, metabolic adverse effects including muscle wasting restrict their use. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) modulates peripheral glucocorticoid responses through pre-receptor metabolism. This study investigates how 11β-HSD1 influences skeletal muscle responses to glucocorticoid therapy for chronic [...] Read more.
Glucocorticoids provide indispensable anti-inflammatory therapies. However, metabolic adverse effects including muscle wasting restrict their use. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) modulates peripheral glucocorticoid responses through pre-receptor metabolism. This study investigates how 11β-HSD1 influences skeletal muscle responses to glucocorticoid therapy for chronic inflammation. We assessed human skeletal muscle biopsies from patients with rheumatoid arthritis and osteoarthritis for 11β-HSD1 activity ex vivo. Using the TNF-α-transgenic mouse model (TNF-tg) of chronic inflammation, we examined the effects of corticosterone treatment and 11β-HSD1 global knock-out (11βKO) on skeletal muscle, measuring anti-inflammatory gene expression, muscle weights, fiber size distribution, and catabolic pathways. Muscle 11β-HSD1 activity was elevated in patients with rheumatoid arthritis and correlated with inflammation markers. In murine skeletal muscle, glucocorticoid administration suppressed IL6 expression in TNF-tg mice but not in TNF-tg11βKO mice. TNF-tg mice exhibited reductions in muscle weight and fiber size with glucocorticoid therapy. In contrast, TNF-tg11βKO mice were protected against glucocorticoid-induced muscle atrophy. Glucocorticoid-mediated activation of catabolic mediators (FoxO1, Trim63) was also diminished in TNF-tg11βKO compared to TNF-tg mice. In summary, 11β-HSD1 knock-out prevents muscle atrophy associated with glucocorticoid therapy in a model of chronic inflammation. Targeting 11β-HSD1 may offer a strategy to refine the safety of glucocorticoids. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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25 pages, 4153 KiB  
Article
Proteomic Analysis of Synovial Fibroblasts and Articular Chondrocytes Co-Cultures Reveals Valuable VIP-Modulated Inflammatory and Degradative Proteins in Osteoarthritis
by Selene Pérez-García, Valentina Calamia, Tamara Hermida-Gómez, Irene Gutiérrez-Cañas, Mar Carrión, Raúl Villanueva-Romero, David Castro, Carmen Martínez, Yasmina Juarranz, Francisco J. Blanco and Rosa P. Gomariz
Int. J. Mol. Sci. 2021, 22(12), 6441; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126441 - 16 Jun 2021
Cited by 7 | Viewed by 2975
Abstract
Osteoarthritis (OA) is the most common musculoskeletal disorder causing a great disability and a reduction in the quality of life. In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) [...] Read more.
Osteoarthritis (OA) is the most common musculoskeletal disorder causing a great disability and a reduction in the quality of life. In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) degradation. Given the lack of therapies for the treatment of OA, in this study, we explore biomarkers that enable the development of new therapeutical approaches. We analyze the set of secreted proteins in AC and SF co-cultures by stable isotope labeling with amino acids (SILAC). We describe, for the first time, 115 proteins detected in SF-AC co-cultures stimulated by fibronectin fragments (Fn-fs). We also study the role of the vasoactive intestinal peptide (VIP) in this secretome, providing new proteins involved in the main events of OA, confirmed by ELISA and multiplex analyses. VIP decreases proteins involved in the inflammatory process (CHI3L1, PTX3), complement activation (C1r, C3), and cartilage ECM degradation (DCN, CTSB and MMP2), key events in the initiation and progression of OA. Our results support the anti-inflammatory and anti-catabolic properties of VIP in rheumatic diseases and provide potential new targets for OA treatment. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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12 pages, 2742 KiB  
Article
Intra-Articular Administration of Cramp into Mouse Knee Joint Exacerbates Experimental Osteoarthritis Progression
by Moon-Chang Choi, Jiwon Jo, Myeongjin Lee, Jonggwan Park and Yoonkyung Park
Int. J. Mol. Sci. 2021, 22(7), 3429; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073429 - 26 Mar 2021
Cited by 4 | Viewed by 2941
Abstract
Osteoarthritis (OA) is the most common type of arthritis and is associated with wear and tear, aging, and inflammation. Previous studies revealed that several antimicrobial peptides are up-regulated in the knee synovium of patients with OA or rheumatoid arthritis. Here, we investigated the [...] Read more.
Osteoarthritis (OA) is the most common type of arthritis and is associated with wear and tear, aging, and inflammation. Previous studies revealed that several antimicrobial peptides are up-regulated in the knee synovium of patients with OA or rheumatoid arthritis. Here, we investigated the functional effects of cathelicidin-related antimicrobial peptide (Cramp) on OA pathogenesis. We found that Cramp is highly induced by IL-1β via the NF-κB signaling pathway in mouse primary chondrocytes. Elevated Cramp was also detected in the cartilage and synovium of mice suffering from OA cartilage destruction. The treatment of chondrocytes with Cramp stimulated the expression of catabolic factors, and the knockdown of Cramp by small interfering RNA reduced chondrocyte catabolism mediated by IL-1β. Moreover, intra-articular injection of Cramp into mouse knee joints at a low dose accelerated traumatic OA progression. At high doses, Cramp affected meniscal ossification and tears, leading to cartilage degeneration. These findings demonstrate that Cramp is associated with OA pathophysiology. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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19 pages, 1838 KiB  
Article
β-Hydroxy-β-Methylbutyrate (HMB) Supplementation Prevents Bone Loss during Pregnancy—Novel Evidence from a Spiny Mouse (Acomys cahirinus) Model
by Ewa Tomaszewska, Janine Donaldson, Jakub Kosiński, Piotr Dobrowolski, Agnieszka Tomczyk-Warunek, Monika Hułas-Stasiak, Krzysztof Lamorski, Dorota Laskowska-Woźniak, Siemowit Muszyński, Rudolf Blicharski and Tomasz Blicharski
Int. J. Mol. Sci. 2021, 22(6), 3047; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063047 - 17 Mar 2021
Cited by 3 | Viewed by 2601
Abstract
The aim of this study was to determine the effects of ß-hydroxy-ß-methylbutyrate (HMB) supplementation during pregnancy on postpartum bone tissue quality by assessing changes in trabecular and compact bone as well as in hyaline and epiphyseal cartilage. The experiment was carried out on [...] Read more.
The aim of this study was to determine the effects of ß-hydroxy-ß-methylbutyrate (HMB) supplementation during pregnancy on postpartum bone tissue quality by assessing changes in trabecular and compact bone as well as in hyaline and epiphyseal cartilage. The experiment was carried out on adult 6-month-old female spiny mice (Acomys cahirinus) divided into three groups: pregnant control (PregCont), pregnant HMB-treated (supplemented with 0.02 g/kg b.w of HMB during the second trimester of pregnancy, PregHMB), and non-pregnant females (NonPreg). Cross-sectional area and cortical index of the femoral mid-shaft, stiffness, and Young modulus were significantly greater in the PregHMB group. Whole-bone mineral density was similar in all groups, and HMB supplementation increased trabecular number. Growth plate cartilage was the thinnest, while the articular cartilage was the thickest in the PregHMB group. HMB supplementation increased the content of proteoglycans in the articular cartilage and the percentage of immature collagen content in metaphyseal trabeculae and compact bone. In summary, dietary HMB supplementation during the second trimester of pregnancy intensifies bone metabolic processes and prevents bone loss during pregnancy. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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34 pages, 6035 KiB  
Article
In Vitro Macrophage Immunomodulation by Poly(ε-caprolactone) Based-Coated AZ31 Mg Alloy
by Andreea-Mariana Negrescu, Madalina-Georgiana Necula, Adi Gebaur, Florentina Golgovici, Cristina Nica, Filis Curti, Horia Iovu, Marieta Costache and Anisoara Cimpean
Int. J. Mol. Sci. 2021, 22(2), 909; https://doi.org/10.3390/ijms22020909 - 18 Jan 2021
Cited by 16 | Viewed by 3220
Abstract
Due to its excellent bone-like mechanical properties and non-toxicity, magnesium (Mg) and its alloys have attracted great interest as biomaterials for orthopaedic applications. However, their fast degradation rate in physiological environments leads to an acute inflammatory response, restricting their use as biodegradable metallic [...] Read more.
Due to its excellent bone-like mechanical properties and non-toxicity, magnesium (Mg) and its alloys have attracted great interest as biomaterials for orthopaedic applications. However, their fast degradation rate in physiological environments leads to an acute inflammatory response, restricting their use as biodegradable metallic implants. Endowing Mg-based biomaterials with immunomodulatory properties can help trigger a desired immune response capable of supporting a favorable healing process. In this study, electrospun poly(ε-caprolactone) (PCL) fibers loaded with coumarin (CM) and/or zinc oxide nanoparticles (ZnO) were used to coat the commercial AZ31 Mg alloy as single and combined formulas, and their effects on the macrophage inflammatory response and osteoclastogenic process were investigated by indirect contact studies. Likewise, the capacity of the analyzed samples to generate reactive oxygen species (ROS) has been investigated. The data obtained by attenuated total reflection Fourier-transform infrared (FTIR-ATR) and X-ray photoelectron spectroscopy (XPS) analyses indicate that AZ31 alloy was perfectly coated with the PCL fibers loaded with CM and ZnO, which had an important influence on tuning the release of the active ingredient. Furthermore, in terms of degradation in phosphate-buffered saline (PBS) solution, the PCL-ZnO- and secondary PCL-CM-ZnO-coated samples exhibited the best corrosion behaviour. The in vitro results showed the PCL-CM-ZnO and, to a lower extent, PCL-ZnO coated sample exhibited the best behaviour in terms of inflammatory response and receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated differentiation of RAW 264.7 macrophages into osteoclasts. Altogether, the results obtained suggest that the coating of Mg alloys with fibrous PCL containing CM and/or ZnO can constitute a feasible strategy for biomedical applications. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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12 pages, 2112 KiB  
Article
CTLA-4Ig Improves Hyperalgesia in a Mouse Model of Osteoporosis
by Nobuto Nagao, Hiroki Wakabayashi, Gaku Miyamura, Sho Kato, Yohei Naito and Akihiro Sudo
Int. J. Mol. Sci. 2020, 21(24), 9479; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249479 - 13 Dec 2020
Cited by 4 | Viewed by 1739
Abstract
This study aimed to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effects of cytotoxic T lymphocyte-associated antigen-4Ig (CTLA-4Ig) administration in ovariectomized (OVX) mice. Eight-week-old female ddY mice were assigned to three groups: sham-operated mice (SHAM) treated with vehicle, OVX [...] Read more.
This study aimed to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effects of cytotoxic T lymphocyte-associated antigen-4Ig (CTLA-4Ig) administration in ovariectomized (OVX) mice. Eight-week-old female ddY mice were assigned to three groups: sham-operated mice (SHAM) treated with vehicle, OVX mice treated with vehicle (OVX), and OVX mice treated with CTLA-4Ig (CTLA-4Ig). Vehicle or CTLA-4Ig was injected intraperitoneally, starting immediately after surgery. After 4 weeks of treatment, mechanical sensitivity was examined, and the bilateral hind limbs were removed and evaluated by micro-computed tomography, immunohistochemical analyses, and messenger RNA expression analysis. Ovariectomy induced bone loss and mechanical hyperalgesia in the hindlimbs. CTLA-4Ig treatment prevented bone loss in the hindlimbs compared to vehicle administration in the OVX group. Moreover, mechanical hyperalgesia was significantly decreased in the CTLA-4Ig treatment group in comparison to the OVX group. The expression levels of tumor necrosis factor-α (TNF-α) and sclerostin (SOST), as well as the number of osteoclasts, were increased, and the expression level of Wnt-10b was decreased in the OVX group compared with the SHAM group, whereas these parameters were improved in the CTLA-4Ig group compared with the OVX group. The novelty of this research is that CTLA-4Ig administration prevented bone loss and mechanical hyperalgesia induced by ovariectomy in the hindlimbs. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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Review

Jump to: Editorial, Research

24 pages, 430 KiB  
Review
Osteonecrosis of the Jaws in Patients with Hereditary Thrombophilia/Hypofibrinolysis—From Pathophysiology to Therapeutic Implications
by Minerva Codruta Badescu, Elena Rezus, Manuela Ciocoiu, Oana Viola Badulescu, Lacramioara Ionela Butnariu, Diana Popescu, Ioana Bratoiu and Ciprian Rezus
Int. J. Mol. Sci. 2022, 23(2), 640; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020640 - 07 Jan 2022
Cited by 6 | Viewed by 2053
Abstract
Osteonecrosis of the jaws (ONJ) usually has a clear etiology. Local infection or trauma, radiotherapy and drugs that disrupt the vascular supply or bone turnover in the jaws are its major contributors. The thrombotic occlusion of the bone’s venous outflow that occurs in [...] Read more.
Osteonecrosis of the jaws (ONJ) usually has a clear etiology. Local infection or trauma, radiotherapy and drugs that disrupt the vascular supply or bone turnover in the jaws are its major contributors. The thrombotic occlusion of the bone’s venous outflow that occurs in individuals with hereditary thrombophilia and/or hypofibrinolysis has a less known impact on jaw health and healing capability. Our research provides the most comprehensive, up-to-date and systematized information on the prevalence and significance of hereditary thrombophilia and/or hypofibrinolysis states in ONJ. We found that hereditary prothrombotic abnormalities are common in patients with ONJ refractory to conventional medical and dental treatments. Thrombophilia traits usually coexist with hypofibrinolysis traits. We also found that frequently acquired prothrombotic abnormalities coexist with hereditary ones and enhance their negative effect on the bone. Therefore, we recommend a personalized therapeutic approach that addresses, in particular, the modifiable risk factors of ONJ. Patients will have clear benefits, as they will be relieved of persistent pain and repeated dental procedures. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
20 pages, 354 KiB  
Review
Osteonecrosis of the Femoral Head in Patients with Hypercoagulability—From Pathophysiology to Therapeutic Implications
by Elena Rezus, Bogdan Ionel Tamba, Minerva Codruta Badescu, Diana Popescu, Ioana Bratoiu and Ciprian Rezus
Int. J. Mol. Sci. 2021, 22(13), 6801; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136801 - 24 Jun 2021
Cited by 18 | Viewed by 4188
Abstract
Osteonecrosis of the femoral head (ONFH) is a debilitating disease with major social and economic impacts. It frequently affects relatively young adults and has a predilection for rapid progression to femoral head collapse and end-stage hip arthritis. If not diagnosed and treated properly [...] Read more.
Osteonecrosis of the femoral head (ONFH) is a debilitating disease with major social and economic impacts. It frequently affects relatively young adults and has a predilection for rapid progression to femoral head collapse and end-stage hip arthritis. If not diagnosed and treated properly in the early stages, ONFH has devastating consequences and leads to mandatory total hip arthroplasty. The pathophysiology of non-traumatic ONFH is very complex and not fully understood. While multiple risk factors have been associated with secondary ONFH, there are still many cases in which a clear etiology cannot be established. Recognition of the prothrombotic state as part of the etiopathogeny of primary ONFH provides an opportunity for early medical intervention, with implications for both prophylaxis and therapy aimed at slowing or stopping the progression of the disease. Hereditary thrombophilia and hypofibrinolysis are associated with thrombotic occlusion of bone vessels. Anticoagulant treatment can change the natural course of the disease and improve patients’ quality of life. The present work focused on highlighting the association between hereditary thrombophilia/hypofibrinolysis states and ONFH, emphasizing the importance of identifying this condition. We have also provided strong arguments to support the efficiency and safety of anticoagulant treatment in the early stages of the disease, encouraging etiological diagnosis and prompt therapeutic intervention. In the era of direct oral anticoagulants, new therapeutic options have become available, enabling better long-term compliance. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
19 pages, 652 KiB  
Review
Effects of Incretin-Related Diabetes Drugs on Bone Formation and Bone Resorption
by Hideki Kitaura, Saika Ogawa, Fumitoshi Ohori, Takahiro Noguchi, Aseel Marahleh, Yasuhiko Nara, Adya Pramusita, Ria Kinjo, Jinghan Ma, Kayoko Kanou and Itaru Mizoguchi
Int. J. Mol. Sci. 2021, 22(12), 6578; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126578 - 19 Jun 2021
Cited by 12 | Viewed by 3920
Abstract
Patients with type 2 diabetes have an increased risk of fracture compared to the general population. Glucose absorption is accelerated by incretin hormones, which induce insulin secretion from the pancreas. The level of the incretin hormone, glucagon-like peptide-1 (GLP-1), shows an immediate postprandial [...] Read more.
Patients with type 2 diabetes have an increased risk of fracture compared to the general population. Glucose absorption is accelerated by incretin hormones, which induce insulin secretion from the pancreas. The level of the incretin hormone, glucagon-like peptide-1 (GLP-1), shows an immediate postprandial increase, and the circulating level of intact GLP-1 is reduced rapidly by dipeptidyl peptidase-4 (DPP-4)-mediated inactivation. Therefore, GLP-1 receptor agonists and DPP-4 inhibitors are effective in the treatment of type 2 diabetes. However, these incretin-related diabetic agents have been reported to affect bone metabolism, including bone formation and resorption. These agents enhance the expression of bone markers, and have been applied to improve bone quality and bone density. In addition, they have been reported to suppress chronic inflammation and reduce the levels of inflammatory cytokine expression. Previously, we reported that these incretin-related agents inhibited both the expression of inflammatory cytokines and inflammation-induced bone resorption. This review presents an overview of current knowledge regarding the effects of incretin-related diabetes drugs on osteoblast differentiation and bone formation as well as osteoclast differentiation and bone resorption. The mechanisms by which incretin-related diabetes drugs regulate bone formation and bone resorption are also discussed. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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11 pages, 2273 KiB  
Review
Factors Involved in Morphogenesis in the Muscle–Tendon–Bone Complex
by Shinichi Abe and Masahito Yamamoto
Int. J. Mol. Sci. 2021, 22(12), 6365; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126365 - 14 Jun 2021
Cited by 14 | Viewed by 2444
Abstract
A decline in the body’s motor functions has been linked to decreased muscle mass and function in the oral cavity and throat; however, aging of the junctions of the muscles and bones has also been identified as an associated factor. Basic and clinical [...] Read more.
A decline in the body’s motor functions has been linked to decreased muscle mass and function in the oral cavity and throat; however, aging of the junctions of the muscles and bones has also been identified as an associated factor. Basic and clinical studies on the muscles, tendons and bones, each considered independently, have been published. In recent years, however, research has focused on muscle attachment as the muscle–tendon–bone complex from various perspectives, and there is a growing body of knowledge on SRY-box9 (Sox9) and Mohawk(Mkx), which has been identified as a common controlling factor and a key element. Myostatin, a factor that inhibits muscle growth, has been identified as a potential key element in the mechanisms of lifetime structural maintenance of the muscle–tendon–bone complex. Findings in recent studies have also uncovered aspects of the mechanisms of motor organ complex morphostasis in the superaged society of today and will lay the groundwork for treatments to prevent motor function decline in older adults. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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16 pages, 964 KiB  
Review
Small Noncoding RNAs in Knee Osteoarthritis: The Role of MicroRNAs and tRNA-Derived Fragments
by Julian Zacharjasz, Anna M. Mleczko, Paweł Bąkowski, Tomasz Piontek and Kamilla Bąkowska-Żywicka
Int. J. Mol. Sci. 2021, 22(11), 5711; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115711 - 27 May 2021
Cited by 14 | Viewed by 3522
Abstract
Knee osteoarthritis (OA) is a degenerative knee joint disease that results from the breakdown of joint cartilage and underlying bone, affecting about 3.3% of the world’s population. As OA is a multifactorial disease, the underlying pathological process is closely associated with genetic changes [...] Read more.
Knee osteoarthritis (OA) is a degenerative knee joint disease that results from the breakdown of joint cartilage and underlying bone, affecting about 3.3% of the world’s population. As OA is a multifactorial disease, the underlying pathological process is closely associated with genetic changes in articular cartilage and bone. Many studies have focused on the role of small noncoding RNAs in OA and identified numbers of microRNAs that play important roles in regulating bone and cartilage homeostasis. The connection between other types of small noncoding RNAs, especially tRNA-derived fragments and knee osteoarthritis is still elusive. The observation that there is limited information about small RNAs different than miRNAs in knee OA was very surprising to us, especially given the fact that tRNA fragments are known to participate in a plethora of human diseases and a portion of them are even more abundant than miRNAs. Inspired by these findings, in this review we have summarized the possible involvement of microRNAs and tRNA-derived fragments in the pathology of knee osteoarthritis. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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13 pages, 527 KiB  
Review
The Effect of Platelet-Rich Plasma on the Intra-Articular Microenvironment in Knee Osteoarthritis
by Dawid Szwedowski, Joanna Szczepanek, Łukasz Paczesny, Jan Zabrzyński, Maciej Gagat, Ali Mobasheri and Sławomir Jeka
Int. J. Mol. Sci. 2021, 22(11), 5492; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115492 - 23 May 2021
Cited by 51 | Viewed by 8168
Abstract
Knee osteoarthritis (KOA) represents a clinical challenge due to poor potential for spontaneous healing of cartilage lesions. Several treatment options are available for KOA, including oral nonsteroidal anti-inflammatory drugs, physical therapy, braces, activity modification, and finally operative treatment. Intra-articular (IA) injections are usually [...] Read more.
Knee osteoarthritis (KOA) represents a clinical challenge due to poor potential for spontaneous healing of cartilage lesions. Several treatment options are available for KOA, including oral nonsteroidal anti-inflammatory drugs, physical therapy, braces, activity modification, and finally operative treatment. Intra-articular (IA) injections are usually used when the non-operative treatment is not effective, and when the surgery is not yet indicated. More and more studies suggesting that IA injections are as or even more efficient and safe than NSAIDs. Recently, research to improve intra-articular homeostasis has focused on biologic adjuncts, such as platelet-rich plasma (PRP). The catabolic and inflammatory intra-articular processes that exists in knee osteoarthritis (KOA) may be influenced by the administration of PRP and its derivatives. PRP can induce a regenerative response and lead to the improvement of metabolic functions of damaged structures. However, the positive effect on chondrogenesis and proliferation of mesenchymal stem cells (MSC) is still highly controversial. Recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, significant progress has been made in understanding the mechanism of PRP action. In this review, we will discuss mechanisms related to inflammation and chondrogenesis in cartilage repair and regenerative processes after PRP administration in in vitro and animal studies. Furthermore, we review clinical trials of PRP efficiency in changing the OA biomarkers in knee joint. Full article
(This article belongs to the Special Issue Musculoskeletal Development and Skeletal Pathophysiologies)
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