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Special Issue "Biological Basis of Musculoskeletal Regeneration"

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 (30 June 2018).

Special Issue Editors

Guest Editor
Prof. Dr. Britt Wildemann

Julius Wolff Institute, Berlin Brandenburg Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany
Website | E-Mail
Interests: bone healing; osteomyelitis prophylaxis and treatment; tendon biology; osteoblast, osteoclast and tenocyte biology; animal models for musculoskeletal regeneration; biomaterials
Guest Editor
Dr. Franka Klatte-Schulz

Julius Wolff Institute, Berlin Brandenburg Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany
Website | E-Mail
Interests: tendon healing; tenocyte cell biology; tendon stem cells; growth factors; platelet based blood products; bursa subacromialis

Special Issue Information

Dear Colleagues,

Disabilities due to musculoskeletal disorders increased dramatically within the last few decades, and will further increase in the future. Due to the aging population and increasing recreational activities, especially for the elderly, musculoskeletal disorders are becoming one of the main reasons for seeking medical care. Hence, they represent a major personal and socioeconomic burden. Identifying the mechanisms responsible for promoting or hindering tissue regeneration is important for the development of new treatments strategies. This Special Issue will cover all aspects of molecular and cellular mechanisms of bone, cartilage, tendon/ligament, and muscle regeneration. We are inviting contributions describing novel findings based on in vitro and in vivo studies, and also welcome clinical studies employing molecular methods to address aspects of musculoskeletal regeneration. In addition, studies elucidating the interaction of musculoskeletal tissue with other tissues or cells during regeneration are of high interest for this Special Issue.

Prof. Dr. Britt Wildemann
Dr. Franka Klatte-Schulz
Guest Editors

Manuscript Submission Information

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Keywords

  • Musculoskeletal tissue
  • Mechanism of regeneration
  • Molecular and cellular pathways
  • Interaction with surrounding tissue and cells
  • Preclinical models: in vitro and in vivo
  • Regenerative therapies
  • Translational studies

Related Special Issue

Published Papers (23 papers)

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Research

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Open AccessArticle
Improved Chondrogenic Differentiation of rAAV SOX9-Modified Human MSCs Seeded in Fibrin-Polyurethane Scaffolds in a Hydrodynamic Environment
Int. J. Mol. Sci. 2018, 19(9), 2635; https://doi.org/10.3390/ijms19092635
Received: 23 July 2018 / Revised: 30 August 2018 / Accepted: 3 September 2018 / Published: 5 September 2018
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Abstract
The repair of focal articular cartilage defects remains a problem. Combining gene therapy with tissue engineering approaches using bone marrow-derived mesenchymal stem cells (MSCs) may allow the development of improved options for cartilage repair. Here, we examined whether a three-dimensional fibrin-polyurethane scaffold provides [...] Read more.
The repair of focal articular cartilage defects remains a problem. Combining gene therapy with tissue engineering approaches using bone marrow-derived mesenchymal stem cells (MSCs) may allow the development of improved options for cartilage repair. Here, we examined whether a three-dimensional fibrin-polyurethane scaffold provides a favorable environment for the effective chondrogenic differentiation of human MSCs (hMSCs) overexpressing the cartilage-specific SOX9 transcription factor via recombinant adeno-associated virus (rAAV) -mediated gene transfer cultured in a hydrodynamic environment in vitro. Sustained SOX9 expression was noted in the constructs for at least 21 days, the longest time point evaluated. Such spatially defined SOX9 overexpression enhanced proliferative, metabolic, and chondrogenic activities compared with control (reporter lacZ gene transfer) treatment. Of further note, administration of the SOX9 vector was also capable of delaying premature hypertrophic and osteogenic differentiation in the constructs. This enhancement of chondrogenesis by spatially defined overexpression of human SOX9 demonstrate the potential benefits of using rAAV-modified hMSCs seeded in fibrin-polyurethane scaffolds as a promising approach for implantation in focal cartilage lesions to improve cartilage repair. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Tenogenic Properties of Mesenchymal Progenitor Cells Are Compromised in an Inflammatory Environment
Int. J. Mol. Sci. 2018, 19(9), 2549; https://doi.org/10.3390/ijms19092549
Received: 31 July 2018 / Revised: 22 August 2018 / Accepted: 23 August 2018 / Published: 28 August 2018
PDF Full-text (5740 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Transplantation of multipotent mesenchymal progenitor cells is a valuable option for treating tendon disease. Tenogenic differentiation leading to cell replacement and subsequent matrix modulation may contribute to the regenerative effects of these cells, but it is unclear whether this occurs in the inflammatory [...] Read more.
Transplantation of multipotent mesenchymal progenitor cells is a valuable option for treating tendon disease. Tenogenic differentiation leading to cell replacement and subsequent matrix modulation may contribute to the regenerative effects of these cells, but it is unclear whether this occurs in the inflammatory environment of acute tendon disease. Equine adipose-derived stromal cells (ASC) were cultured as monolayers or on decellularized tendon scaffolds in static or dynamic conditions, the latter represented by cyclic stretching. The impact of different inflammatory conditions, as represented by supplementation with interleukin-1β and/or tumor necrosis factor-α or by co-culture with allogeneic peripheral blood leukocytes, on ASC functional properties was investigated. High cytokine concentrations increased ASC proliferation and osteogenic differentiation, but decreased chondrogenic differentiation and ASC viability in scaffold culture, as well as tendon scaffold repopulation, and strongly influenced musculoskeletal gene expression. Effects regarding the latter differed between the monolayer and scaffold cultures. Leukocytes rather decreased ASC proliferation, but had similar effects on viability and musculoskeletal gene expression. This included decreased expression of the tenogenic transcription factor scleraxis by an inflammatory environment throughout culture conditions. The data demonstrate that ASC tenogenic properties are compromised in an inflammatory environment, with relevance to their possible mechanisms of action in acute tendon disease. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Autologous Mesenchymal Stroma Cells Are Superior to Allogeneic Ones in Bone Defect Regeneration
Int. J. Mol. Sci. 2018, 19(9), 2526; https://doi.org/10.3390/ijms19092526
Received: 22 June 2018 / Revised: 10 August 2018 / Accepted: 22 August 2018 / Published: 25 August 2018
Cited by 2 | PDF Full-text (3745 KB) | HTML Full-text | XML Full-text
Abstract
The application of autologous mesenchymal stem cells (MSC) for the treatment of bone defects requires two invasive procedures and several weeks of ex vivo cell expansion. To overcome these limitations, the administration of allogeneic MSC may be attractive, because they are anticipated to [...] Read more.
The application of autologous mesenchymal stem cells (MSC) for the treatment of bone defects requires two invasive procedures and several weeks of ex vivo cell expansion. To overcome these limitations, the administration of allogeneic MSC may be attractive, because they are anticipated to be immunoprivileged. Because preclinical studies using various animal models are conflicting with respect to the efficacy of allogeneic MSC, we investigated whether autologous and allogeneic human MSC (hMSC) are equally effective in regenerating bone in a humanized mouse model resembling the human immune system. Applying autologous and allogeneic hMSC in critically sized femoral defects, we found that allogeneic hMSC elicited a mild immune response early after implantation, whereas early angiogenic processes were similar in both treatments. At later healing time points, the transplantation of allogeneic hMSC resulted in less bone formation than autologous hMSC, associated with a reduced expression of the osteogenic factor Runx2 and impaired angiogenesis. We found by species-specific staining for collagen-type-1α2 that MSCs of either source did not synthesize new bone matrix, indicating an indirect contribution of transplanted hMSC to bone regeneration. In conclusion, our data suggest that the application of autologous hMSC is superior to that of allogeneic cells for bone defect treatment. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
In Vitro Comparison of 2D-Cell Culture and 3D-Cell Sheets of Scleraxis-Programmed Bone Marrow Derived Mesenchymal Stem Cells to Primary Tendon Stem/Progenitor Cells for Tendon Repair
Int. J. Mol. Sci. 2018, 19(8), 2272; https://doi.org/10.3390/ijms19082272
Received: 21 June 2018 / Revised: 23 July 2018 / Accepted: 27 July 2018 / Published: 2 August 2018
Cited by 1 | PDF Full-text (8525 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The poor and slow healing capacity of tendons requires novel strategies to speed up the tendon repair process. Hence, new and promising developments in tendon tissue engineering have become increasingly relevant. Previously, we have established a tendon progenitor cell line via ectopic expression [...] Read more.
The poor and slow healing capacity of tendons requires novel strategies to speed up the tendon repair process. Hence, new and promising developments in tendon tissue engineering have become increasingly relevant. Previously, we have established a tendon progenitor cell line via ectopic expression of the tendon-related basic helix-loop-helix (bHLH) transcription factor Scleraxis (Scx) in human bone marrow mesenchymal stem cells (hMSC-Scx). The aim of this study was to directly compare the characteristics of hMSC-Scx cells to that of primary human tendon stem/progenitors cells (hTSPCs) via assessment of self-renewal and multipotency, gene marker expression profiling, in vitro wound healing assay and three-dimensional cell sheet formation. As expected, hTSPCs were more naive than hMSC-Scx cells because of higher clonogenicity, trilineage differentiation potential, and expression of stem cell markers, as well as higher mRNA levels of several gene factors associated with early tendon development. Interestingly, with regards to wound healing, both cell types demonstrate a comparable speed of scratch closure, as well as migratory velocity and distance in various migration experiments. In the three-dimensional cell sheet model, hMSC-Scx cells and hTSPCs form compact tendinous sheets as histological staining, and transmission electron microscopy shows spindle-shaped cells and collagen type I fibrils with similar average diameter size and distribution. Taken together, hTSPCs exceed hMSC-Scx cells in several characteristics, namely clonogenicity, multipotentiality, gene expression profile and rates of tendon-like sheet formation, whilst in three-dimensional cell sheets, both cell types have comparable in vitro healing potential and collagenous composition of their three-dimensional cell sheets, making both cell types a suitable cell source for tendon tissue engineering and healing. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Immune Cell Induced Migration of Osteoprogenitor Cells Is Mediated by TGF-β Dependent Upregulation of NOX4 and Activation of Focal Adhesion Kinase
Int. J. Mol. Sci. 2018, 19(8), 2239; https://doi.org/10.3390/ijms19082239
Received: 27 June 2018 / Revised: 24 July 2018 / Accepted: 27 July 2018 / Published: 31 July 2018
Cited by 1 | PDF Full-text (8961 KB) | HTML Full-text | XML Full-text
Abstract
The cytokines secreted by immune cells have a large impact on the tissue, surrounding a fracture, e.g., by attraction of osteoprogenitor cells. However, the underlying mechanisms are not yet fully understood. Thus, this study aims at investigating molecular mechanisms of the immune cell-mediated [...] Read more.
The cytokines secreted by immune cells have a large impact on the tissue, surrounding a fracture, e.g., by attraction of osteoprogenitor cells. However, the underlying mechanisms are not yet fully understood. Thus, this study aims at investigating molecular mechanisms of the immune cell-mediated migration of immature primary human osteoblasts (phOBs), with transforming growth factor beta (TGF-β), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and focal adhesion kinase (FAK) as possible regulators. Monocyte- and macrophage (THP-1 cells ± phorbol 12-myristate 13-acetate (PMA) treatment)-conditioned media, other than the granulocyte-conditioned medium (HL-60 cells + dimethyl sulfoxide (DMSO) treatment), induce migration of phOBs. Monocyte- and macrophage (THP-1 cells)-conditioned media activate Smad3-dependent TGF-β signaling in the phOBs. Stimulation with TGF-β promotes migration of phOBs. Furthermore, TGF-β treatment strongly induces NOX4 expression on both mRNA and protein levels. The associated reactive oxygen species (ROS) accumulation results in phosphorylation (Y397) of FAK. Blocking TGF-β signaling, NOX4 activity and FAK signaling effectively inhibits the migration of phOBs towards TGF-β. In summary, our data suggest that monocytic- and macrophage-like cells induce migration of phOBs in a TGF-β-dependent manner, with TGF-β-dependent induction of NOX4, associated production of ROS and resulting activation of FAK as key mediators. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Chemokine CCL25 Induces Migration and Extracellular Matrix Production of Anulus Fibrosus-Derived Cells
Int. J. Mol. Sci. 2018, 19(8), 2207; https://doi.org/10.3390/ijms19082207
Received: 30 June 2018 / Revised: 23 July 2018 / Accepted: 26 July 2018 / Published: 28 July 2018
Cited by 1 | PDF Full-text (3650 KB) | HTML Full-text | XML Full-text
Abstract
Intervertebral disc degeneration is a major source of back pain. For intervertebral disc regeneration after herniation a fast closure of anulus fibrosus (AF) defects is crucial. Here, the use of the C-C motif chemokine ligand 25 (CCL)25 in comparison to differentiation factors such [...] Read more.
Intervertebral disc degeneration is a major source of back pain. For intervertebral disc regeneration after herniation a fast closure of anulus fibrosus (AF) defects is crucial. Here, the use of the C-C motif chemokine ligand 25 (CCL)25 in comparison to differentiation factors such as transforming growth factor (TGF)β3, bone morphogenetic protein (BMP)2, BMP7, BMP12, and BMP14 (all in concentrations of 10, 50 and 100 ng/mL) was tested in an in vitro micro mass pellet model with isolated and cultivated human AF-cells (n = 3) to induce and enhance AF-matrix formation. The pellets were differentiated (serum-free) with supplementation of the factors. After 28 days all used factors induced proteoglycan production (safranin O staining) and collagen type I production (immunohistochemical staining) in at least one of the tested concentrations. Histomorphometric scoring revealed that TGFβ3 delivered the strongest induction of proteoglycan production in all three concentrations. Furthermore, it was the only factor able to facilitate collagen type II production, even higher than in native tissue samples. CCL25 was also able to induce proteoglycan and collagen type I production comparable to several BMPs. CCL25 could additionally induce migration of AF-cells in a chemotaxis assay and therefore possibly aid in regeneration processes after disc herniation by recruiting AF-cells. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Evaluation of Mesenchymal Stem Cell Sheets Overexpressing BMP-7 in Canine Critical-Sized Bone Defects
Int. J. Mol. Sci. 2018, 19(7), 2073; https://doi.org/10.3390/ijms19072073
Received: 21 May 2018 / Revised: 13 July 2018 / Accepted: 15 July 2018 / Published: 17 July 2018
Cited by 2 | PDF Full-text (5198 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this study was to investigate the in vitro osteogenic capacity of bone morphogenetic protein 7 (BMP-7) overexpressing adipose-derived (Ad-) mesenchymal stem cells (MSCs) sheets (BMP-7-CS). In addition, BMP-7-CS were transplanted into critical-sized bone defects and osteogenesis was assessed. BMP-7 gene [...] Read more.
The aim of this study was to investigate the in vitro osteogenic capacity of bone morphogenetic protein 7 (BMP-7) overexpressing adipose-derived (Ad-) mesenchymal stem cells (MSCs) sheets (BMP-7-CS). In addition, BMP-7-CS were transplanted into critical-sized bone defects and osteogenesis was assessed. BMP-7 gene expressing lentivirus particles were transduced into Ad-MSCs. BMP-7, at the mRNA and protein level, was up-regulated in BMP-7-MSCs compared to expression in Ad-MSCs. Osteogenic and vascular-related gene expressions were up-regulated in BMP-7-CS compared to Ad-MSCs and Ad-MSC sheets. In a segmental bone-defect model, newly formed bone and neovascularization were enhanced with BMP-7-CS, or with a combination of BMP-7-CS and demineralized bone matrix (DBM), compared to those in control groups. These results demonstrate that lentiviral-mediated gene transfer of BMP-7 into Ad-MSCs allows for stable BMP-7 production. BMP-7-CS displayed higher osteogenic capacity than Ad-MSCs and Ad-MSC sheets. In addition, BMP-7-CS combined with demineralized bone matrix (DBM) stimulated new bone and blood vessel formation in a canine critical-sized bone defect. The BMP-7-CS not only provides BMP-7 producing MSCs but also produce osteogenic and vascular trophic factors. Thus, BMP-7-CS and DBM have therapeutic potential for the treatment of critical-sized bone defects and could be used to further enhance clinical outcomes during bone-defect treatment. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Influence of Menopause on Inflammatory Cytokines during Murine and Human Bone Fracture Healing
Int. J. Mol. Sci. 2018, 19(7), 2070; https://doi.org/10.3390/ijms19072070
Received: 21 June 2018 / Revised: 12 July 2018 / Accepted: 15 July 2018 / Published: 16 July 2018
Cited by 2 | PDF Full-text (7087 KB) | HTML Full-text | XML Full-text
Abstract
Postmenopausal females display a chronic inflammatory phenotype with higher levels of circulating pro-inflammatory cytokines. Furthermore, the inflammatory response to injury may be altered under estrogen-deficiency, because it was shown previously that estrogen-deficient mice displayed increased levels of the inflammatory cytokines Midkine (Mdk) and [...] Read more.
Postmenopausal females display a chronic inflammatory phenotype with higher levels of circulating pro-inflammatory cytokines. Furthermore, the inflammatory response to injury may be altered under estrogen-deficiency, because it was shown previously that estrogen-deficient mice displayed increased levels of the inflammatory cytokines Midkine (Mdk) and Interleukin-6 (IL-6) in the early fracture hematoma. Because a balanced immune response to fracture is required for successful bone regeneration, this might contribute to the delayed fracture healing frequently observed in osteoporotic, postmenopausal fracture patients. In this study, we aimed to investigate whether further cytokines in addition to Mdk and IL-6 might be affected by estrogen-deficiency after fracture in mice and whether these cytokines are also relevant during human fracture healing. Additionally, we aimed to investigate whether serum from male vs. female fracture patients affects osteogenic differentiation of human mesenchymal stem cells (MSCs). To address these questions, female mice were either sham-operated or ovariectomized (OVX) and subjected to standardized femur osteotomy. A broad panel of pro- and anti-inflammatory cytokines was determined systemically and locally in the fracture hematoma. In a translational approach, serum was collected from healthy controls and patients with an isolated fracture. Mdk and IL-6 serum levels were determined at day 0, day 14 and day 42 after fracture. Subgroup analysis was performed to investigate differences between male and female fracture patients after menopause. In an in vitro approach, human MSCs were cultured with the collected patient serum and osteogenic differentiation was assessed by qPCR and alkaline-phosphatase staining. Our results suggest an important role for the pro-inflammatory cytokines Mdk and IL-6 in the response to fracture in estrogen-deficient mice among all of the measured inflammatory mediators. Notably, both cytokines were also significantly increased in the serum of patients after fracture. However, only Mdk serum levels differed significantly between male and female fracture patients after menopause. MSCs cultivated with serum from female fracture patients displayed significantly reduced osteogenic differentiation, which was attenuated by Mdk-antibody treatment. In conclusion, our study demonstrated increased Mdk levels after fracture in OVX mice and female fracture patients after menopause. Because Mdk is a negative regulator of bone formation, this might contribute to impaired osteoporotic fracture healing. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Tenogenesis of Decellularized Porcine Achilles Tendon Matrix Reseeded with Human Tenocytes in the Nude Mice Xenograft Model
Int. J. Mol. Sci. 2018, 19(7), 2059; https://doi.org/10.3390/ijms19072059
Received: 12 May 2018 / Revised: 4 July 2018 / Accepted: 6 July 2018 / Published: 15 July 2018
Cited by 1 | PDF Full-text (2315 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Cultivation of autologous human tenocytes in a cell-free xenogenic extracellular tendon matrix (xECM) could present an approach for tendon reconstruction. The aim of this study was to achieve tendon-like tissue formation by implanting decellularized porcine Achilles tendons recellularized with human hamstring tendon-derived tenocytes [...] Read more.
Cultivation of autologous human tenocytes in a cell-free xenogenic extracellular tendon matrix (xECM) could present an approach for tendon reconstruction. The aim of this study was to achieve tendon-like tissue formation by implanting decellularized porcine Achilles tendons recellularized with human hamstring tendon-derived tenocytes into nude mice. The structure of decellularized xECM was histologically monitored before being dynamically reseeded with human tenocytes. After 6–12 weeks in vivo, construct quality was monitored using macroscopical and histological scoring systems, vitality assay and quantitative DNA and glycosaminoglycan (GAG) assays. For comparison to tendon xECM, a synthetic polyglycolic acid (PGA) polymer was implanted in a similar manner. Despite decellularized xECM lost some GAGs and structure, it could be recellularized in vitro with human tenocytes, but the cell distribution remained inhomogeneous, with accumulations at the margins of the constructs. In vivo, the xECM constructs revealed in contrast to the PGA no altered size, no inflammation and encapsulation and a more homogeneous cell distribution. xECM reseeded with tenocytes showed superior histological quality than cell-free implanted constructs and contained surviving human cells. Their DNA content after six and 12 weeks in vivo resembled that of native tendon and xECM recellularized in vitro. Results suggest that reseeded decellularized xECM formed a tendon-like tissue in vivo. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Quality Assessment of Surgical Disc Samples Discriminates Human Annulus Fibrosus and Nucleus Pulposus on Tissue and Molecular Level
Int. J. Mol. Sci. 2018, 19(6), 1761; https://doi.org/10.3390/ijms19061761
Received: 29 May 2018 / Revised: 11 June 2018 / Accepted: 11 June 2018 / Published: 13 June 2018
Cited by 4 | PDF Full-text (3878 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A discrimination of the highly specialised annulus fibrosus (AF) and nucleus pulposus (NP) cells in the mature human intervertebral disc (IVD) is thus far still not possible in a reliable way. The aim of this study was to identify molecular markers that distinguish [...] Read more.
A discrimination of the highly specialised annulus fibrosus (AF) and nucleus pulposus (NP) cells in the mature human intervertebral disc (IVD) is thus far still not possible in a reliable way. The aim of this study was to identify molecular markers that distinguish AF and NP cells in human disc tissue using microarray analysis as a screening tool. AF and NP samples were obtained from 28 cervical discs. First, all samples underwent quality sorting using two novel scoring systems for small-sized disc tissue samples including macroscopic, haptic and histological evaluation. Subsequently, samples with clear disc characteristics of either AF or NP that were free from impurities of foreign tissue (IVD score) and with low signs of disc degeneration on cellular level (DD score) were selected for GeneChip analysis (HGU1332P). The 11 AF and 9 NP samples showed distinctly different genome-wide transcriptomes. The majority of differentially expressed genes (DEGs) could be specifically assigned to the AF, whereas no DEG was exclusively expressed in the NP. Nevertheless, we identified 11 novel marker genes that clearly distinguished AF and NP, as confirmed by quantitative gene expression analysis. The novel established scoring systems and molecular markers showed the identity of AF and NP in disc starting material and are thus of great importance in the quality assurance of cell-based therapeutics in regenerative treatment of disc degeneration. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Insulin-Like Growth Factor-1 as a Possible Alternative to Bone Morphogenetic Protein-7 to Induce Osteogenic Differentiation of Human Mesenchymal Stem Cells in Vitro
Int. J. Mol. Sci. 2018, 19(6), 1674; https://doi.org/10.3390/ijms19061674
Received: 4 May 2018 / Revised: 1 June 2018 / Accepted: 2 June 2018 / Published: 5 June 2018
Cited by 5 | PDF Full-text (1308 KB) | HTML Full-text | XML Full-text
Abstract
Growth factors and mesenchymal stem cells (MSC) support consolidation of bone defects. Bone Morphogenetic Protein-7 (BMP-7) has been used clinically and experimentally, but the outcomes remain controversial. Increased systemic expression of Insulin-like Growth Factor-1 (IGF-1) significantly correlates with successful regeneration of bone healing [...] Read more.
Growth factors and mesenchymal stem cells (MSC) support consolidation of bone defects. Bone Morphogenetic Protein-7 (BMP-7) has been used clinically and experimentally, but the outcomes remain controversial. Increased systemic expression of Insulin-like Growth Factor-1 (IGF-1) significantly correlates with successful regeneration of bone healing disorders, making IGF-1 a promising alternative to BMP-7. There is no experimental data comparing the osteoinductive potential of IGF-1 and BMP-7. Therefore, in this study, the influence of IGF-1 and BMP-7 in different concentrations on the osteogenic differentiation of two human MSC-subtypes, isolated from reaming debris (RMSC) and iliac crest bone marrow (BMSC) has been assessed. A more sensitive reaction of BMSC towards stimulation with IGF-1 in concentrations of 400–800 ng/mL was found, leading to a significantly higher degree of osteogenic differentiation compared to stimulation with BMP-7. RMSC react more sensitively to stimulation with BMP-7 compared to BMSC. Lower concentrations of IGF-1 were necessary to significantly increase osteogenic differentiation of RMSC and BMSC compared to BMP-7. Therefore, IGF-1 should be considered as a valuable option to improve osteogenic differentiation of MSC and merits further experimental consideration. The MSC subtype and method of differentiation factor application also have to be considered, as they affect the outcome of osteogenic differentiation. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Hyaluronic Acid Influence on Normal and Osteoarthritic Tissue-Engineered Cartilage
Int. J. Mol. Sci. 2018, 19(5), 1519; https://doi.org/10.3390/ijms19051519
Received: 25 April 2018 / Revised: 8 May 2018 / Accepted: 15 May 2018 / Published: 19 May 2018
Cited by 3 | PDF Full-text (4251 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The aim of this study is to identify gene expression profiles associated with hyaluronic acid (HA) treatment of normal and osteoarthritis (OA)-like tissue-engineered cartilage. 3D cartilage micromasses were treated with tumour necrosis factor-α (TNF-α) (OA-inducer) and/or HA for 7 days. Viability was examined [...] Read more.
The aim of this study is to identify gene expression profiles associated with hyaluronic acid (HA) treatment of normal and osteoarthritis (OA)-like tissue-engineered cartilage. 3D cartilage micromasses were treated with tumour necrosis factor-α (TNF-α) (OA-inducer) and/or HA for 7 days. Viability was examined by PI/FDA staining. To document extracellular matrix (ECM) formation, glycosaminoglycans (GAG) were stained with Safranin-O and cartilage-specific type II collagen was detected immunohistochemically. Genome-wide gene expression was determined using microarray analysis. Normal and OA-like micromasses remained vital and showed a spherical morphology and homogenous cell distribution regardless of the treatment. There was no distinct difference in immunolabeling for type II collagen. Safranin-O staining demonstrated a typical depletion of GAG in TNF-α-treated micromasses (−73%), although the extent was limited in the presence of HA (−39%). The microarray data showed that HA can influence the cartilage metabolism via upregulation of TIMP3 in OA-like condition. The upregulation of VEGFA and ANKRD37 genes implies a supportive role of HA in cartilage maturation and survival. The results of this study validate the feasibility of the in vitro OA model for the investigation of HA. On the cellular level, no inhibiting or activating effect of HA was shown. Microarray data demonstrated a minor impact of HA on gene expression level. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessCommunication
Reproduction of Characteristics of Extracellular Matrices in Specific Longitudinal Depth Zone Cartilage within Spherical Organoids in Response to Changes in Osmotic Pressure
Int. J. Mol. Sci. 2018, 19(5), 1507; https://doi.org/10.3390/ijms19051507
Received: 17 April 2018 / Revised: 12 May 2018 / Accepted: 15 May 2018 / Published: 18 May 2018
Cited by 2 | PDF Full-text (2374 KB) | HTML Full-text | XML Full-text
Abstract
Articular cartilage is compressed with joint-loading and weight-bearing stresses, followed by a bulging of the tissue during times of off-loading. This loading and off-loading causes changes in water content, and thus alterations in osmotic pressure. Another unique characteristic of articular cartilage is that [...] Read more.
Articular cartilage is compressed with joint-loading and weight-bearing stresses, followed by a bulging of the tissue during times of off-loading. This loading and off-loading causes changes in water content, and thus alterations in osmotic pressure. Another unique characteristic of articular cartilage is that it has longitudinal depth: surface, middle, and deep zones. Since each zone is composed of unique components of highly negative extracellular matrices, each zone has a different level of osmotic pressure. It was unclear how changes in osmotic pressure affected chondrocyte matrix turnover in specific longitudinal zones. Therefore, we hypothesized that a change in extrinsic osmotic pressure would alter the production of extracellular matrices by zone-specific chondrocytes. We incubated spheroidal cartilage organoids, formed by specific longitudinal depth zone-derived chondrocytes, under different levels of osmotic pressure. We compared the gene expression and the immunohistology of the matrix proteins produced by the zone-specific chondrocytes. We found that high osmotic pressure significantly upregulated the transient expression of aggrecan and collagen type-II by all zone-derived chondrocytes (p < 0.05). At a high osmotic pressure, surface-zone chondrocytes significantly upregulated the expression of collagen type-I (p < 0.05), and middle- and deep-zone chondrocytes significantly upregulated matrix metalloproteinase-13 (p < 0.05). The spheroids, once exposed to high osmotic pressure, accumulated extracellular matrices with empty spaces. Our findings show that chondrocytes have zone-specific turnover of extracellular matrices in response to changes in osmotic pressure. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Osteogenic Differentiation Modulates the Cytokine, Chemokine, and Growth Factor Profile of ASCs and SHED
Int. J. Mol. Sci. 2018, 19(5), 1454; https://doi.org/10.3390/ijms19051454
Received: 16 April 2018 / Revised: 11 May 2018 / Accepted: 11 May 2018 / Published: 14 May 2018
Cited by 3 | PDF Full-text (3640 KB) | HTML Full-text | XML Full-text
Abstract
Great efforts have been made to improve bone regeneration techniques owing to a growing variety of sources of stem cells suitable for autologous transplants. Specifically, adipose-derived stem cells (ASCs) and stems cells from human exfoliated deciduous teeth (SHED) hold great potential for bone [...] Read more.
Great efforts have been made to improve bone regeneration techniques owing to a growing variety of sources of stem cells suitable for autologous transplants. Specifically, adipose-derived stem cells (ASCs) and stems cells from human exfoliated deciduous teeth (SHED) hold great potential for bone tissue engineering and cell therapy. After a preliminary characterization of the main biomolecules ASCs and SHED released in their conditioned media, cells were kept both in normal and osteo-inducing conditions. Conventional assays were performed to prove their osteogenic potential such as quantitative real-time polymerase chain reaction (qRT-PCR) (for RUNX-2, collagen type I, osteopontin and osteonectin), alkaline phosphatase activity, osteocalcin production, and von Kossa staining. Conditioned media were tested again after the osteogenic induction and compared to maintaining condition both at base line and after 14 days of culture. The osteogenic condition inhibited the release of all the biomolecules, with the exception, concerning SHED, of growth-regulated alpha protein precursor (GROα), and, to a lesser extent, interleukin (IL)-8. In conclusion, our data support that undifferentiated ASCs and SHED may be preferable to committed ones for general cell therapy approaches, due to their higher paracrine activity. Osteoinduction significantly affects the cytokine, chemokine, and growth factor profile in a differential way, as SHED kept a more pronounced pro-angiogenic signature than ASCs. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Different Achilles Tendon Pathologies Show Distinct Histological and Molecular Characteristics
Int. J. Mol. Sci. 2018, 19(2), 404; https://doi.org/10.3390/ijms19020404
Received: 10 January 2018 / Revised: 25 January 2018 / Accepted: 26 January 2018 / Published: 30 January 2018
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Abstract
Reasons for the development of chronic tendon pathologies are still under debate and more basic knowledge is needed about the different diseases. The aim of the present study was therefore to characterize different acute and chronic Achilles tendon disorders. Achilles tendon samples from [...] Read more.
Reasons for the development of chronic tendon pathologies are still under debate and more basic knowledge is needed about the different diseases. The aim of the present study was therefore to characterize different acute and chronic Achilles tendon disorders. Achilles tendon samples from patients with chronic tendinopathy (n = 7), chronic ruptures (n = 6), acute ruptures (n = 13), and intact tendons (n = 4) were analyzed. The histological score investigating pathological changes was significantly increased in tendinopathy and chronic ruptures compared to acute ruptures. Inflammatory infiltration was detected by immunohistochemistry in all tendon pathology groups, but was significantly lower in tendinopathy compared to chronic ruptures. Quantitative real-time PCR (qRT-PCR) analysis revealed significantly altered expression of genes related to collagens and matrix modeling/remodeling (matrix metalloproteinases, tissue inhibitors of metalloproteinases) in tendinopathy and chronic ruptures compared to intact tendons and/or acute ruptures. In all three tendon pathology groups markers of inflammation (interleukin (IL) , tumor necrosis factor α, IL6, IL10, IL33, soluble ST2, transforming growth factor β1, cyclooxygenase 2), inflammatory cells (cluster of differentaition (CD) 3, CD68, CD80, CD206), fat metabolism (fatty acid binding protein 4, peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, adiponectin), and innervation (protein gene product 9.5, growth associated protein 43, macrophage migration inhibitory factor) were detectable, but only in acute ruptures significantly regulated compared to intact tendons. The study gives an insight into structural and molecular changes of pathological processes in tendons and might be used to identify targets for future therapy of tendon pathologies. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle
Comparative Analysis of Different Platelet Lysates and Platelet Rich Preparations to Stimulate Tendon Cell Biology: An In Vitro Study
Int. J. Mol. Sci. 2018, 19(1), 212; https://doi.org/10.3390/ijms19010212
Received: 13 December 2017 / Revised: 5 January 2018 / Accepted: 8 January 2018 / Published: 10 January 2018
Cited by 7 | PDF Full-text (2253 KB) | HTML Full-text | XML Full-text
Abstract
The poor healing potential of tendons is still a clinical problem, and the use of Platelet Rich Plasma (PRP) was hypothesized to stimulate healing. As the efficacy of PRPs remains unproven, platelet lysate (PL) could be an alternative with its main advantages of [...] Read more.
The poor healing potential of tendons is still a clinical problem, and the use of Platelet Rich Plasma (PRP) was hypothesized to stimulate healing. As the efficacy of PRPs remains unproven, platelet lysate (PL) could be an alternative with its main advantages of storage and characterization before use. Five different blood products were prepared from 16 male donors: human serum, two PRPs (Arthrex, (PRP-ACP); RegenLab (PRP-BCT)), platelet concentrate (apheresis, PC), and PL (freezing-thawing destruction of PC). Additionally, ten commercial allogenic PLs (AlloPL) from pooled donors were tested. The highest concentration of most growth factors was found in AlloPL, whereas the release of growth factors lasted longer in the other products. PRP-ACP, PRP-BCT, and PC significantly increased cell viability of human tenocyte-like cells, whereas PC and AlloPL increased Col1A1 expression and PRP-BCT increased Col3A1 expression. MMP-1, IL-1β, and HGF expression was significantly increased and Scleraxis expression decreased by most blood products. COX1 expression significantly decreased by PC and AlloPL. No clear positive effects on tendon cell biology could be shown, which might partially explain the weak outcome results in clinical practice. Pooled PL seemed to have the most beneficial effects and might be the future in using blood products for tendon tissue regeneration. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Review

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Open AccessReview
Anabolic Therapies in Osteoporosis and Bone Regeneration
Int. J. Mol. Sci. 2019, 20(1), 83; https://doi.org/10.3390/ijms20010083
Received: 16 November 2018 / Revised: 9 December 2018 / Accepted: 18 December 2018 / Published: 26 December 2018
Cited by 3 | PDF Full-text (729 KB) | HTML Full-text | XML Full-text
Abstract
Osteoporosis represents the most common bone disease worldwide and results in a significantly increased fracture risk. Extrinsic and intrinsic factors implicated in the development of osteoporosis are also associated with delayed fracture healing and impaired bone regeneration. Based on a steadily increasing life [...] Read more.
Osteoporosis represents the most common bone disease worldwide and results in a significantly increased fracture risk. Extrinsic and intrinsic factors implicated in the development of osteoporosis are also associated with delayed fracture healing and impaired bone regeneration. Based on a steadily increasing life expectancy in modern societies, the global implications of osteoporosis and impaired bone healing are substantial. Research in the last decades has revealed several molecular pathways that stimulate bone formation and could be targeted to treat both osteoporosis and impaired fracture healing. The identification and development of therapeutic approaches modulating bone formation, rather than bone resorption, fulfils an essential clinical need, as treatment options for reversing bone loss and promoting bone regeneration are limited. This review focuses on currently available and future approaches that may have the potential to achieve these aims. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessReview
The Role of Physical Stimuli on Calcium Channels in Chondrogenic Differentiation of Mesenchymal Stem Cells
Int. J. Mol. Sci. 2018, 19(10), 2998; https://doi.org/10.3390/ijms19102998
Received: 3 August 2018 / Revised: 4 September 2018 / Accepted: 22 September 2018 / Published: 1 October 2018
Cited by 3 | PDF Full-text (822 KB) | HTML Full-text | XML Full-text
Abstract
Human mesenchymal stem cells (hMSC) are becoming increasingly popular in tissue engineering. They are the most frequently used stem cell source for clinical applications due to their high potential to differentiate into several lineages. Cartilage is known for its low capacity for self-maintenance [...] Read more.
Human mesenchymal stem cells (hMSC) are becoming increasingly popular in tissue engineering. They are the most frequently used stem cell source for clinical applications due to their high potential to differentiate into several lineages. Cartilage is known for its low capacity for self-maintenance and currently there are no efficient methods to improve cartilage repair. Chondrogenic differentiation of hMSC isolated from different tissues is widely employed due to a high clinical demand for the improvement of cartilage regeneration. Calcium channels that are regulated by physical stimuli seem to play a pivotal role in chondrogenic differentiation of MSCs. These channels increase intracellular calcium concentration, which leads to the initiation of the relevant cellular processes that are required for differentiation. This review will focus on the impact of different physical stimuli, including electrical, electromagnetic/magnetic and mechanical on various calcium channels and calcium signaling mechanisms during chondrogenic differentiation of hMSC. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessReview
Repair of Damaged Articular Cartilage: Current Approaches and Future Directions
Int. J. Mol. Sci. 2018, 19(8), 2366; https://doi.org/10.3390/ijms19082366
Received: 29 June 2018 / Revised: 7 August 2018 / Accepted: 7 August 2018 / Published: 11 August 2018
Cited by 7 | PDF Full-text (1130 KB) | HTML Full-text | XML Full-text
Abstract
Articular hyaline cartilage is extensively hydrated, but it is neither innervated nor vascularized, and its low cell density allows only extremely limited self-renewal. Most clinical and research efforts currently focus on the restoration of cartilage damaged in connection with osteoarthritis or trauma. Here, [...] Read more.
Articular hyaline cartilage is extensively hydrated, but it is neither innervated nor vascularized, and its low cell density allows only extremely limited self-renewal. Most clinical and research efforts currently focus on the restoration of cartilage damaged in connection with osteoarthritis or trauma. Here, we discuss current clinical approaches for repairing cartilage, as well as research approaches which are currently developing, and those under translation into clinical practice. We also describe potential future directions in this area, including tissue engineering based on scaffolding and/or stem cells as well as a combination of gene and cell therapy. Particular focus is placed on cell-based approaches and the potential of recently characterized chondro-progenitors; progress with induced pluripotent stem cells is also discussed. In this context, we also consider the ability of different types of stem cell to restore hyaline cartilage and the importance of mimicking the environment in vivo during cell expansion and differentiation into mature chondrocytes. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessReview
From the Clinical Problem to the Basic Research—Co-Culture Models of Osteoblasts and Osteoclasts
Int. J. Mol. Sci. 2018, 19(8), 2284; https://doi.org/10.3390/ijms19082284
Received: 28 June 2018 / Revised: 26 July 2018 / Accepted: 31 July 2018 / Published: 3 August 2018
Cited by 3 | PDF Full-text (1845 KB) | HTML Full-text | XML Full-text
Abstract
Bone tissue undergoes constant remodeling and healing when fracture happens, in order to ensure its structural integrity. In order to better understand open biological and clinical questions linked to various bone diseases, bone cell co-culture technology is believed to shed some light into [...] Read more.
Bone tissue undergoes constant remodeling and healing when fracture happens, in order to ensure its structural integrity. In order to better understand open biological and clinical questions linked to various bone diseases, bone cell co-culture technology is believed to shed some light into the dark. Osteoblasts/osteocytes and osteoclasts dominate the metabolism of bone by a multitude of connections. Therefore, it is widely accepted that a constant improvement of co-culture models with both cell types cultured on a 3D scaffold, is aimed to mimic an in vivo environment as closely as possible. Although in recent years a considerable knowledge of bone co-culture models has been accumulated, there are still many open questions. We here try to summarize the actual knowledge and address open questions. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessReview
Cartilage Regeneration in Humans with Adipose Tissue-Derived Stem Cells and Adipose Stromal Vascular Fraction Cells: Updated Status
Int. J. Mol. Sci. 2018, 19(7), 2146; https://doi.org/10.3390/ijms19072146
Received: 27 June 2018 / Revised: 18 July 2018 / Accepted: 21 July 2018 / Published: 23 July 2018
Cited by 6 | PDF Full-text (533 KB) | HTML Full-text | XML Full-text
Abstract
Adipose tissue-derived stem cells (ASCs) in the form of stromal vascular fraction (SVF) and cultured expansion have been applied in clinical settings in some countries to treat osteoarthritis (OA) of knees, one of the most common debilitating, incurable disorders. Since the first report [...] Read more.
Adipose tissue-derived stem cells (ASCs) in the form of stromal vascular fraction (SVF) and cultured expansion have been applied in clinical settings in some countries to treat osteoarthritis (OA) of knees, one of the most common debilitating, incurable disorders. Since the first report of successful cartilage-like tissue regeneration with autologous adipose SVF containing ASCs, there has been a gradual increase in the number of publications confirming such results. Thus far, most of the reports have been limited to treatments of OA of knees. Recently, successful applications of adipose SVF in treating OA of ankles and hips have been reported. In addition, several groups have reported modified methods of applying adipose SVF, such as combining bone marrow stimulation with adipose SVF or adding additional extracellular matrix (ECM) in treating OA. Here, we present an updated, systematic review of clinical effectiveness and safety in treating OA of knees, ankles, and one hip since 2016 using ASCs in the form of adipose SVF or in cultured expansion, along with a description and suggestion of potential biological mechanisms of cartilage regeneration. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessReview
Immunology Guides Skeletal Muscle Regeneration
Int. J. Mol. Sci. 2018, 19(3), 835; https://doi.org/10.3390/ijms19030835
Received: 31 January 2018 / Revised: 7 March 2018 / Accepted: 9 March 2018 / Published: 13 March 2018
Cited by 6 | PDF Full-text (2098 KB) | HTML Full-text | XML Full-text
Abstract
Soft tissue trauma of skeletal muscle is one of the most common side effects in surgery. Muscle injuries are not only caused by accident-related injuries but can also be of an iatrogenic nature as they occur during surgical interventions when the anatomical region [...] Read more.
Soft tissue trauma of skeletal muscle is one of the most common side effects in surgery. Muscle injuries are not only caused by accident-related injuries but can also be of an iatrogenic nature as they occur during surgical interventions when the anatomical region of interest is exposed. If the extent of trauma surpasses the intrinsic regenerative capacities, signs of fatty degeneration and formation of fibrotic scar tissue can occur, and, consequentially, muscle function deteriorates or is diminished. Despite research efforts to investigate the physiological healing cascade following trauma, our understanding of the early onset of healing and how it potentially determines success or failure is still only fragmentary. This review focuses on the initial physiological pathways following skeletal muscle trauma in comparison to bone and tendon trauma and what conclusions can be drawn from new scientific insights for the development of novel therapeutic strategies. Strategies to support regeneration of muscle tissue after injury are scarce, even though muscle trauma has a high incidence. Based on tissue specific differences, possible clinical treatment options such as local immune-modulatory and cell therapeutic approaches are suggested that aim to support the endogenous regenerative potential of injured muscle tissues. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessReview
Mustn1: A Developmentally Regulated Pan-Musculoskeletal Cell Marker and Regulatory Gene
Int. J. Mol. Sci. 2018, 19(1), 206; https://doi.org/10.3390/ijms19010206
Received: 4 December 2017 / Revised: 26 December 2017 / Accepted: 6 January 2018 / Published: 12 January 2018
PDF Full-text (1986 KB) | HTML Full-text | XML Full-text
Abstract
The Mustn1 gene encodes a small nuclear protein (~9.6 kDa) that does not belong to any known family. Its genomic organization consists of three exons interspersed by two introns and it is highly homologous across vertebrate species. Promoter analyses revealed that its expression [...] Read more.
The Mustn1 gene encodes a small nuclear protein (~9.6 kDa) that does not belong to any known family. Its genomic organization consists of three exons interspersed by two introns and it is highly homologous across vertebrate species. Promoter analyses revealed that its expression is regulated by the AP family of transcription factors, especially c-Fos, Fra-2 and JunD. Mustn1 is predominantly expressed in the major tissues of the musculoskeletal system: bone, cartilage, skeletal muscle and tendon. Its expression has been associated with normal embryonic development, postnatal growth, exercise, and regeneration of bone and skeletal muscle. Moreover, its expression has also been detected in various musculoskeletal pathologies, including arthritis, Duchenne muscular dystrophy, other skeletal muscle myopathies, clubfoot and diabetes associated muscle pathology. In vitro and in vivo functional perturbation revealed that Mustn1 is a key regulatory molecule in myogenic and chondrogenic lineages. This comprehensive review summarizes our current knowledge of Mustn1 and proposes that it is a new developmentally regulated pan-musculoskeletal marker as well as a key regulatory protein for cell differentiation and tissue growth. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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