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From Molecular Mechanisms to Therapy: Novel Insight on Musculoskeletal System

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

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 19440

Special Issue Editors

Dr. Gianluigi Pasta

E-Mail Website
Guest Editor
Department of Orthopedic Surgery, IRCCS Fondazione Policlinico San Matteo, 27100 Pavia, Italy
Interests: orthopedic surgery; regenerative medicine; rare diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Antonio Pompilio Gigante

E-Mail Website
Guest Editor
Clinical Orthopaedics, Department of Clinical and Molecular Science DISCLIMO, Università Politecnica Delle Marche, 60126 Ancona, Italy
Interests: orthopedic surgery; replacement surgery; precision medicine; regenerative medicine

Special Issue Information

Dear Colleagues, 

Advancements in fields such as stem cell biology, genomics, developmental biology, and molecular genetics are all contributing to advancements in our understanding of basic pathological conditions involving musculoskeletal system. 

Mainly, regenerative medicine and its applications for the musculoskeletal system in order to replace, repair, and promote tissue regeneration have received increased interest over the last decade. Special attention has been dedicated to mesenchymal stem cells (MSCs), which are adult stem cells that can be isolated from various tissues. These cells were able to adhere and proliferate on different substrates in presence of specific culture medium factors, can be easily maintained or expand in vitro and have the ability to assume osteogenic, adipogenic, and chondrogenic, phenotypes. By virtue of their multipotency, MSCs are a source for clinical applications, mainly tissue injury and immune disorders. Recently, special emphasis has been paid to therapies using MSCs encapsulated in hydrogels. Actually, several recent studies have demonstrated how targeted therapies using cell-encapsulated hydrogels, are able to reduce inflammation and increase regenerative potential in different tissues.

Furthermore, recent literature data have focused the attention to several bioactive factors produced by MSCs including cytokines, growth factors, microRNAs, proteasomes, and exosomes that play an important role in the regulation of numerous physiological processes. 

Experimental and clinical studies suggest that MSC-derived secretome represents a promising cell-free therapeutic tool in order to treat degenerative and inflammatory diseases. However, further studies both in vitro than in vivo are needed to clarify molecular bases.

This Special Issue will focus on recent advances that aim to understand better the molecular processes underlying the available technologies and the development of new therapeutic approaches. Original research articles, comprehensive reviews. and short communications related to this topic are all welcome.

Dr. Gianluigi Pasta
Dr. Antonio Pompilio Gigante
Guest Editors

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 system
  • regeneration
  • regenerative medicine
  • mesenchymal stem cells
  • MSCs
  • multipotent mesenchymal cells
  • tissue
  • chondral lesions
  • bone healing
  • tendon lesions
  • bioactive factors
  • MSC-derived secretome

Published Papers (6 papers)

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Research

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19 pages, 5811 KiB  
Article
Inflammatory Treatment Used to Mimic Osteoarthritis and Patients’ Synovial Fluid Have Divergent Molecular Impact on Chondrocytes In Vitro
by Enrico Ragni, Paola De Luca, Federico Valli, Luigi Zagra and Laura de Girolamo
Int. J. Mol. Sci. 2023, 24(3), 2625; https://doi.org/10.3390/ijms24032625 - 30 Jan 2023
Cited by 3 | Viewed by 1392
Abstract
Osteoarthritis (OA) is a chronic disease characterized by joint tissue disruption and inflammation with a paucity of therapeutic options. Chondrocyte in vitro models are commonly used as the first step in evaluating new approaches and rely on the stimulation of an OA-like phenotype [...] Read more.
Osteoarthritis (OA) is a chronic disease characterized by joint tissue disruption and inflammation with a paucity of therapeutic options. Chondrocyte in vitro models are commonly used as the first step in evaluating new approaches and rely on the stimulation of an OA-like phenotype with inflammation often the method of choice. Inflammatory priming is frequently based on cytokines used at concentrations very far from the reality in the patients’ synovial fluid (SF). The aim of this work was to compare the transcriptional response of chondrocytes to different inflammatory conditions: the high levels of IL1β that are used for standardized inflammation protocols, OA-SF, IL1β, IL6 and IFNγ at SF-like concentrations both individually and simultaneously to mimic a simplified “in vitro” SF. Both high IL1β and OA-SF strongly influenced chondrocytes, while SF-like concentrations of cytokines gave weak (IL1β alone or in combination) or no (IL6 and IFNγ alone) outcomes. Chondrocytes under the two most powerful polarizing conditions had a clearly distinct fingerprint, with only a shared albeit molecularly divergent effect on ECM stability, with IL1β mainly acting on ECM degrading enzymes and OA-SF accounting for a higher turnover in favor of fibrous collagens. Moreover, OA-SF did not induce the inflammatory response observed with IL1β. In conclusion, although partially similar in the endpoint phenotype, this work intends to encourage reflection on the robustness of inflammation-based in vitro OA models for molecular studies on chondrocytes. Full article
(This article belongs to the Special Issue From Molecular Mechanisms to Therapy: Novel Insight on Musculoskeletal System)
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12 pages, 2450 KiB  
Article
Optimization of the Alizarin Red S Assay by Enhancing Mineralization of Osteoblasts
by Aline Bernar, Jennifer Viktoria Gebetsberger, Monika Bauer, Werner Streif and Michael Schirmer
Int. J. Mol. Sci. 2023, 24(1), 723; https://doi.org/10.3390/ijms24010723 - 31 Dec 2022
Cited by 14 | Viewed by 5322
Abstract
The alizarin red S assay is considered the gold standard for quantification of osteoblast mineralization and is thus widely used among scientists. However, there are several restrictions to this method, e.g., moderate sensitivity makes it difficult to uncover slight but significant effects of [...] Read more.
The alizarin red S assay is considered the gold standard for quantification of osteoblast mineralization and is thus widely used among scientists. However, there are several restrictions to this method, e.g., moderate sensitivity makes it difficult to uncover slight but significant effects of potentially clinically relevant substances. Therefore, an adaptation of the staining method is appropriate and might be obtained by increasing the mineralization ability of osteoblasts. In this study, cell culture experiments with human (SaOs-2) and murine (MC3T3-E1) osteoblasts were performed under the addition of increasing concentrations of calcium chloride (1, 2.5, 5, and 10 mM) or calcitonin (1, 2.5, 5, and 10 nM). After three or four weeks, the mineralization matrix was stained with alizarin red S and the concentration was quantified photometrically. Only calcium chloride was able to significantly increase mineralization, and therefore enhanced the sensitivity of the alizarin red S staining in a dose-dependent manner in both osteoblastic cell lines as well as independent of the cell culture well surface area. This cost- and time-efficient optimization enables a more sensitive analysis of potentially clinically relevant substances in future bone research. Full article
(This article belongs to the Special Issue From Molecular Mechanisms to Therapy: Novel Insight on Musculoskeletal System)
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Review

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24 pages, 2140 KiB  
Review
Achilles’ Heel—The Significance of Maintaining Microenvironmental Homeostasis in the Nucleus Pulposus for Intervertebral Discs
by Zhangbin Luo, Ziyan Wei, Guangzhi Zhang, Haiwei Chen, Lei Li and Xuewen Kang
Int. J. Mol. Sci. 2023, 24(23), 16592; https://doi.org/10.3390/ijms242316592 - 22 Nov 2023
Viewed by 1019
Abstract
The dysregulation of intracellular and extracellular environments as well as the aberrant expression of ion channels on the cell membrane are intricately linked to a diverse array of degenerative disorders, including intervertebral disc degeneration. This condition is a significant contributor to low back [...] Read more.
The dysregulation of intracellular and extracellular environments as well as the aberrant expression of ion channels on the cell membrane are intricately linked to a diverse array of degenerative disorders, including intervertebral disc degeneration. This condition is a significant contributor to low back pain, which poses a substantial burden on both personal quality of life and societal economics. Changes in the number and function of ion channels can disrupt the water and ion balance both inside and outside cells, thereby impacting the physiological functions of tissues and organs. Therefore, maintaining ion homeostasis and stable expression of ion channels within the cellular microenvironment may prove beneficial in the treatment of disc degeneration. Aquaporin (AQP), calcium ion channels, and acid-sensitive ion channels (ASIC) play crucial roles in regulating water, calcium ions, and hydrogen ions levels. These channels have significant effects on physiological and pathological processes such as cellular aging, inflammatory response, stromal decomposition, endoplasmic reticulum stress, and accumulation of cell metabolites. Additionally, Piezo 1, transient receptor potential vanilloid type 4 (TRPV4), tension response enhancer binding protein (TonEBP), potassium ions, zinc ions, and tungsten all play a role in the process of intervertebral disc degeneration. This review endeavors to elucidate alterations in the microenvironment of the nucleus pulposus during intervertebral disc degeneration (IVDD), with a view to offer novel insights and approaches for exploring therapeutic interventions against disc degeneration. Full article
(This article belongs to the Special Issue From Molecular Mechanisms to Therapy: Novel Insight on Musculoskeletal System)
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12 pages, 865 KiB  
Review
Polydeoxyribonucleotide in the Treatment of Tendon Disorders, from Basic Science to Clinical Practice: A Systematic Review
by Davide Bizzoca, Giovanni Brunetti, Lorenzo Moretti, Andrea Piazzolla, Giovanni Vicenti, Francesco Luca Moretti, Giuseppe Solarino and Biagio Moretti
Int. J. Mol. Sci. 2023, 24(5), 4582; https://doi.org/10.3390/ijms24054582 - 26 Feb 2023
Cited by 4 | Viewed by 4635
Abstract
Polydeoxyribonucleotide (PDRN) is a proprietary and registered drug with several beneficial effects, including tissue repairing, anti-ischemic action, and anti-inflammatory properties. The present study aims to summarize the current evidence about PRDN’s clinical effectiveness in the management of tendon disorders. From January 2015 to [...] Read more.
Polydeoxyribonucleotide (PDRN) is a proprietary and registered drug with several beneficial effects, including tissue repairing, anti-ischemic action, and anti-inflammatory properties. The present study aims to summarize the current evidence about PRDN’s clinical effectiveness in the management of tendon disorders. From January 2015 to November 2022, OVID-MEDLINE®, EMBASE, Cochrane Library, SCOPUS, Web of Science, Google Scholar and PubMed were searched to identify relevant studies. The methodological quality of the studies was evaluated, and relevant data were extracted. Nine studies (two in vivo studies and seven clinical studies) were finally included in this systematic review. Overall, 169 patients (male: 103) were included in the present study. The effectiveness and safeness of PDRN has been investigated in the management of the following diseases: plantar fasciitis; epicondylitis; Achilles tendinopathy; pes anserine bursitis; chronic rotator cuff disease. No adverse effects have been recorded in the included studies and all the patients showed an improvement in clinical symptoms during the follow-up. PDRN are a valid emerging therapeutic drug in the treatment of tendinopathies. Further multicentric randomized clinical studies are needed to better define the therapeutic role of PDRN, especially in combined clinical protocols. Full article
(This article belongs to the Special Issue From Molecular Mechanisms to Therapy: Novel Insight on Musculoskeletal System)
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23 pages, 981 KiB  
Review
Intra-Articular Mesenchymal Stem Cell Injection for Knee Osteoarthritis: Mechanisms and Clinical Evidence
by Pengxu Wei and Ruixue Bao
Int. J. Mol. Sci. 2023, 24(1), 59; https://doi.org/10.3390/ijms24010059 - 21 Dec 2022
Cited by 16 | Viewed by 3975
Abstract
Knee osteoarthritis presents higher incidences than other joints, with increased prevalence during aging. It is a progressive process and may eventually lead to disability. Mesenchymal stem cells (MSCs) are expected to repair damaged issues due to trilineage potential, trophic effects, and immunomodulatory properties [...] Read more.
Knee osteoarthritis presents higher incidences than other joints, with increased prevalence during aging. It is a progressive process and may eventually lead to disability. Mesenchymal stem cells (MSCs) are expected to repair damaged issues due to trilineage potential, trophic effects, and immunomodulatory properties of MSCs. Intra-articular MSC injection was reported to treat knee osteoarthritis in many studies. This review focuses on several issues of intra-articular MSC injection for knee osteoarthritis, including doses of MSCs applied for injection and the possibility of cartilage regeneration following MSC injection. Intra-articular MSC injection induced hyaline-like cartilage regeneration, which could be seen by arthroscopy in several studies. Additionally, anatomical, biomechanical, and biochemical changes during aging and other causes participate in the development of knee osteoarthritis. Conversely, appropriate intervention based on these anatomical, biomechanical, biochemical, and functional properties and their interactions may postpone the progress of knee OA and facilitate cartilage repair induced by MSC injection. Hence, post-injection rehabilitation programs and related mechanisms are discussed. Full article
(This article belongs to the Special Issue From Molecular Mechanisms to Therapy: Novel Insight on Musculoskeletal System)
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9 pages, 255 KiB  
Review
Towards Precision Medicine for Osteoarthritis: Focus on the Synovial Fluid Proteome
by Lorenzo Moretti, Davide Bizzoca, Alessandro Geronimo, Francesco Luca Moretti, Edoardo Monaco, Giuseppe Solarino and Biagio Moretti
Int. J. Mol. Sci. 2022, 23(17), 9731; https://doi.org/10.3390/ijms23179731 - 27 Aug 2022
Cited by 9 | Viewed by 2494
Abstract
Osteoarthritis (OA) is a joint degenerative disease that most affects old age. The study of proteomics in synovial fluid (SF) has the task of providing additional elements to diagnose and predict the progress of OA. This review aims to identify the most significant [...] Read more.
Osteoarthritis (OA) is a joint degenerative disease that most affects old age. The study of proteomics in synovial fluid (SF) has the task of providing additional elements to diagnose and predict the progress of OA. This review aims to identify the most significant biomarkers in the study of OA and to stimulate their routine use. Some of the major components of the ECM, such as proteoglycan aggrecan and decorin, were found considerably reduced in OA. Some biomarkers have proved useful for staging the temporality of OA: Periostin was found to be increased in early OA, while CRTA1 and MMPs were found to be increased in late OA. In its natural attempt at tissue regeneration, Collagen III was found to be increased in early OA while decreased in late OA. Some molecules studied in other areas, such as ZHX3 (oncological marker), LYVE1, and VEGF (lymph and angiogenesis markers), also have been found to be altered in OA. It also has been recorded that alteration of the hormonal pathway, using a dosage of PPAR-γ and RETN, can influence the evolution of OA. IL-1, one of the most investigated biomarkers in OA-SF, is not as reliable as a target of OA in recent studies. The study of biomarkers in SF appears to be, in combination with the clinical and radiological aspects, an additional weapon to address the diagnosis and staging of OA. Therefore, it can guide us more appropriately towards the indication of arthroplasty in patients with OA. Full article
(This article belongs to the Special Issue From Molecular Mechanisms to Therapy: Novel Insight on Musculoskeletal System)
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