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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 34803

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Prof. Hechmi Toumi

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Department of Rheumatology, Translational Medicine Research Platform, PRIMMO, Regional Hospital of Orleans, 45067 Orleans, France
Interests: Arthritis & osteoarthritis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Musculoskeletal research helps to determine the biological, biochemical, and biomechanical mechanisms involved in the repair and regeneration of soft tissues and bone. It involves the training and treatment of musculoskeletal components i.e muscles, joints, tendons, ligaments, cartilage, and bones. This research aims to:

Improve human musculoskeletal conditions, including inflammatory arthritis, connective tissue disease, osteoarthritis, and pain.
Utilize advanced diagnostic methods and clinical assessments for the treatment of musculoskeletal (muscle and joint) conditions.
Study the cell and developmental biology of bone and skeletal muscle, regenerative medicine, skeletal neurobiology, and pathogenesis of common developmental, degenerative, inflammatory, and neoplastic disorders of the musculoskeletal system.
Treat musculoskeletal pain with exercise (therapeutic exercise for musculoskeletal injuries).
Explore how exercise can help maintain a healthy muscular system as the body ages.
Implement intelligent physical exercise training.

Both reviews and articles related to the topic are welcome. Since IJMS is a journal of molecular science, pure clinical studies will not be suitable for our journal. However, clinical submissions with biomolecular experiments are welcome.

Prof. Dr. Hechmi Toumi
Guest Editor

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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.

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Published Papers (7 papers)

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Research

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21 pages, 6775 KiB

Open AccessArticle

Polynucleotides Suppress Inflammation and Stimulate Matrix Synthesis in an In Vitro Cell-Based Osteoarthritis Model

by Sree Samanvitha Kuppa, Hyung-Keun Kim, Ju-Yeon Kang, Seok-Cheol Lee, Hong-Yeol Yang, Jaishree Sankaranarayanan and Jong-Keun Seon

Int. J. Mol. Sci. 2023, 24(15), 12282; https://doi.org/10.3390/ijms241512282 - 31 Jul 2023

Cited by 6 | Viewed by 3924

Abstract

Osteoarthritis (OA) is characterized by degeneration of the joint cartilage, inflammation, and a change in the chondrocyte phenotype. Inflammation also promotes cell hypertrophy in human articular chondrocytes (HC-a) by activating the NF-κB pathway. Chondrocyte hypertrophy and inflammation promote extracellular matrix degradation (ECM). Chondrocytes depend on Smad signaling to control and regulate cell hypertrophy as well as to maintain the ECM. The involvement of these two pathways is crucial for preserving the homeostasis of articular cartilage. In recent years, Polynucleotides Highly Purified Technology (PN-HPT) has emerged as a promising area of research for the treatment of OA. PN-HPT involves the use of polynucleotide-based agents with controlled natural origins and high purification levels. In this study, we focused on evaluating the efficacy of a specific polynucleotide sodium agent, known as CONJURAN, which is derived from fish sperm. Polynucleotides (PN), which are physiologically present in the matrix and function as water-soluble nucleic acids with a gel-like property, have been used to treat patients with OA. However, the specific mechanisms underlying the effect remain unclear. Therefore, we investigated the effect of PN in an OA cell model in which HC-a cells were stimulated with interleukin−1β (IL−1β) with or without PN treatment. The CCK-8 assay was used to assess the cytotoxic effects of PN. Furthermore, the enzyme-linked immunosorbent assay was utilized to detect MMP13 levels, and the nitric oxide assay was utilized to determine the effect of PN on inflammation. The anti-inflammatory effects of PN and related mechanisms were investigated using quantitative PCR, Western blot analysis, and immunofluorescence to examine and analyze relative markers. PN inhibited IL−1β induced destruction of genes and proteins by downregulating the expression of MMP3, MMP13, iNOS, and COX-2 while increasing the expression of aggrecan (ACAN) and collagen II (COL2A1). This study demonstrates, for the first time, that PN exerted anti-inflammatory effects by partially inhibiting the NF-κB pathway and increasing the Smad2/3 pathway. Based on our findings, PN can potentially serve as a treatment for OA. Full article

(This article belongs to the Special Issue Musculoskeletal Disorders (MSDs) and Osteoimmunology)

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12 pages, 1935 KiB

Open AccessArticle

Zirconia-Toughened Alumina Ceramic Wear Particles Do Not Elicit Inflammatory Responses in Human Macrophages

by Alessandro Alan Porporati, Yvonne Mödinger, Sarah Fischer, Sara Polajžer, Melanie Mettang, Ulrike Deisinger, Matejka Podlogar, Rihard Trebše and Nika Lovšin

Int. J. Mol. Sci. 2023, 24(7), 6482; https://doi.org/10.3390/ijms24076482 - 30 Mar 2023

Viewed by 1997

Abstract

Ten percent of patients undergoing total hip arthroplasty (THA) require revision surgery. One of the reasons for THA are wear particles released from the implants that can activate the immune defense and cause osteolysis and failure of the joint implant. The discrepancies between reports on toxicity and immunogenicity of the implant materials led us to this study in which we compared toxicity and immunogenicity of well-defined nanoparticles from Al₂O₃, zirconia-toughened alumina (ZTA), and cobalt chrome (CoCr), a human THP-1 macrophage cell line, human PBMCs, and therefrom-derived primary macrophages. None of the tested materials decreased the viability of THP-1 macrophages nor human primary macrophages at the 24 h time point, indicating that at concentrations from 0.05 to 50 µm³/cell the tested materials are non-toxic. Forty-eight hours of treatment of THP-1 macrophages with 5 µm³/cell of CoCr and Al₂O₃ caused 8.3-fold and 4.6-fold increases in TNF-α excretion, respectively, which was not observed for ZTA. The comparison between THP-1 macrophages and human primary macrophages revealed that THP-1 macrophages show higher activation of cytokine expression in the presence of CoCr and Al₂O₃ particles than primary macrophages. Our results indicate that ZTA is a non-toxic implant material with no immunogenic effects in vitro. Full article

(This article belongs to the Special Issue Musculoskeletal Disorders (MSDs) and Osteoimmunology)

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15 pages, 6103 KiB

Open AccessArticle

Gene Expression and Chondrogenic Potential of Cartilage Cells: Osteoarthritis Grade Differences

by Marija Mazor, Eric Lespessailles, Thomas M. Best, Mazen Ali and Hechmi Toumi

Int. J. Mol. Sci. 2022, 23(18), 10610; https://doi.org/10.3390/ijms231810610 - 13 Sep 2022

Cited by 4 | Viewed by 2428

Abstract

Recent data suggest that cells isolated from osteoarthritic (OA) cartilage express mesenchymal progenitor cell (MPC) markers that have the capacity to form hyaline-like cartilage tissue. Whether or not these cells are influenced by the severity of OA remains unexplored. Therefore, we analyzed MPC marker expression and chondrogenetic potential of cells from mild, moderate and severe OA tissue. Human osteoarthritic tibial plateaus were obtained from 25 patients undergoing total knee replacement. Each sample was classified as mild, moderate or severe OA according to OARSI scoring. mRNA expression levels of MPC markers—CD105, CD166, Notch 1, Sox9; mature chondrocyte markers—Aggrecan (Acan), Col II A1, hypertrophic chondrocyte and osteoarthritis-related markers—Col I A1, MMP-13 and ALPL were measured at the tissue level (day 0), after 2 weeks of in vitro expansion (day 14) and following chondrogenic in vitro re-differentiation (day 35). Pellet matrix composition after in vitro chondrogenesis of different OA-derived cells was tested for proteoglycans, collagen II and I by safranin O and immunofluorescence staining. Multiple MPC markers were found in OA cartilage resident tissue within a single OA joint with no significant difference between grades except for Notch1, which was higher in severe OA tissues. Expression levels of CD105 and Notch 1 were comparable between OA cartilage-derived cells of different disease grades and bone marrow mesenchymal stem cell (BM-MSC) line (healthy control). However, the MPC marker Sox 9 was conserved after in vitro expansion and significantly higher in OA cartilage-derived cells compared to its levels in the BM-MSC. The in vitro expansion of cartilage-derived cells resulted in enrichment while re–differentiation in reduction of MPC markers for all three analyzed grades. However, only moderate OA-derived cells after the in vitro chondrogenesis resulted in the formation of hyaline cartilage-like tissue. The latter tissue samples were also highly positive for collagen II and proteoglycans with no expression of osteoarthritis-related markers (collagen I, ALPL and MMP13). MPC marker expression did not differ between OA grades at the tissue level. Interestingly after in vitro re-differentiation, only moderate OA-derived cells showed the capacity to form hyaline cartilage-like tissue. These findings may have implications for clinical practice to understand the intrinsic repair capacity of articular cartilage in OA tissues and raises the possibility of these progenitor cells as a candidate for articular cartilage repair. Full article

(This article belongs to the Special Issue Musculoskeletal Disorders (MSDs) and Osteoimmunology)

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16 pages, 3966 KiB

Open AccessArticle

TNF-α Activating Osteoclasts in Patients with Psoriatic Arthritis Enhances the Recruitment of Osteoclast Precursors: A Plausible Role of WNT5A-MCP-1 in Osteoclast Engagement in Psoriatic Arthritis

by Shang-Hung Lin, Ji-Chen Ho, Sung-Chou Li, Yu-Wen Cheng, Chung-Yuan Hsu, Wen-Yi Chou, Chang-Chun Hsiao and Chih-Hung Lee

Int. J. Mol. Sci. 2022, 23(2), 921; https://doi.org/10.3390/ijms23020921 - 15 Jan 2022

Cited by 6 | Viewed by 2415

Abstract

Psoriatic arthritis (PsA) results from joint destruction by osteoclasts. The promising efficacy of TNF-α blockage indicates its important role in osteoclastogenesis of PsA. WNT ligands actively regulate osteoclastogenesis. We investigated how WNT ligands activate osteoclasts amid the TNF-α milieu in PsA. We first profiled the expression of WNT ligands in CD14⁺ monocyte-derived osteoclasts (MDOC) from five PsA patients and five healthy controls (HC) and then validated the candidate WNT ligands in 32 PsA patients and 16 HC. Through RNA interference against WNT ligands in MDOC, we determined the mechanisms by which TNF-α exerts its effects on osteclastogenesis or chemotaxis. WNT5A was selectively upregulated by TNF-α in MDOC from PsA patients. The number of CD68⁺WNT5A⁺ osteoclasts increased in PsA joints. CXCL1, CXCL16, and MCP-1 was selectively increased in supernatants of MDOC from PsA patients. RNA interference against WNT5A abolished the increased MCP-1 from MDOC and THP-1-cell-derived osteoclasts. The increased migration of osteoclast precursors (OCP) induced by supernatant from PsA MDOC was abolished by the MCP-1 neutralizing antibody. WNT5A and MCP-1 expressions were decreased in MDOC from PsA patients treated by biologics against TNF-α but not IL-17. We conclude that TNF-α recruits OCP by increased MCP-1 production but does not directly activate osteoclastogenesis in PsA. Full article

(This article belongs to the Special Issue Musculoskeletal Disorders (MSDs) and Osteoimmunology)

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Review

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26 pages, 1046 KiB

Open AccessReview

Application of Single-Cell and Spatial Omics in Musculoskeletal Disorder Research

by Site Feng, Jiahao Li, Jingjing Tian, Sheng Lu and Yu Zhao

Int. J. Mol. Sci. 2023, 24(3), 2271; https://doi.org/10.3390/ijms24032271 - 23 Jan 2023

Cited by 4 | Viewed by 4945

Abstract

Musculoskeletal disorders, including fractures, scoliosis, heterotopic ossification, osteoporosis, osteoarthritis, disc degeneration, and muscular injury, etc., can occur at any stage of human life. Understanding the occurrence and development mechanism of musculoskeletal disorders, as well as the changes in tissues and cells during therapy, might help us find targeted treatment methods. Single-cell techniques provide excellent tools for studying alterations at the cellular level of disorders. However, the application of these techniques in research on musculoskeletal disorders is still limited. This review summarizes the current single-cell and spatial omics used in musculoskeletal disorders. Cell isolation, experimental methods, and feasible experimental designs for single-cell studies of musculoskeletal system diseases have been reviewed based on tissue characteristics. Then, the paper summarizes the latest findings of single-cell studies in musculoskeletal disorders from three aspects: bone and ossification, joint, and muscle and tendon disorders. Recent discoveries about the cell populations involved in these diseases are highlighted. Furthermore, the therapeutic responses of musculoskeletal disorders, especially single-cell changes after the treatments of implants, stem cell therapies, and drugs are described. Finally, the application potential and future development directions of single-cell and spatial omics in research on musculoskeletal diseases are discussed. Full article

(This article belongs to the Special Issue Musculoskeletal Disorders (MSDs) and Osteoimmunology)

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31 pages, 2068 KiB

Open AccessReview

Role of Mesenchymal Stem Cells and Their Paracrine Mediators in Macrophage Polarization: An Approach to Reduce Inflammation in Osteoarthritis

by Sree Samanvitha Kuppa, Hyung Keun Kim, Ju Yeon Kang, Seok Cheol Lee and Jong Keun Seon

Int. J. Mol. Sci. 2022, 23(21), 13016; https://doi.org/10.3390/ijms232113016 - 27 Oct 2022

Cited by 17 | Viewed by 4252

Abstract

Osteoarthritis (OA) is a low-grade inflammatory disorder of the joints that causes deterioration of the cartilage, bone remodeling, formation of osteophytes, meniscal damage, and synovial inflammation (synovitis). The synovium is the primary site of inflammation in OA and is frequently characterized by hyperplasia of the synovial lining and infiltration of inflammatory cells, primarily macrophages. Macrophages play a crucial role in the early inflammatory response through the production of several inflammatory cytokines, chemokines, growth factors, and proteinases. These pro-inflammatory mediators are activators of numerous signaling pathways that trigger other cytokines to further recruit more macrophages to the joint, ultimately leading to pain and disease progression. Very few therapeutic alternatives are available for treating inflammation in OA due to the condition’s low self-healing capacity and the lack of clear diagnostic biomarkers. In this review, we opted to explore the immunomodulatory properties of mesenchymal stem cells (MSCs) and their paracrine mediators-dependent as a therapeutic intervention for OA, with a primary focus on the practicality of polarizing macrophages as suppression of M1 macrophages and enhancement of M2 macrophages can significantly reduce OA symptoms. Full article

(This article belongs to the Special Issue Musculoskeletal Disorders (MSDs) and Osteoimmunology)

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10 pages, 291 KiB

Open AccessReview

Proton Pump Inhibitors and Bone Health: An Update Narrative Review

by Eric Lespessailles and Hechmi Toumi

Int. J. Mol. Sci. 2022, 23(18), 10733; https://doi.org/10.3390/ijms231810733 - 14 Sep 2022

Cited by 33 | Viewed by 13588

Abstract

Proton pump inhibitors (PPIs) are an antacid drug often used in acid-related disorders. They decrease acid secretion in the stomach by blocking an enzyme called H+/K+ ATPase which controls acid production. Introduced to the market in 1989, their use has increased rapidly worldwide and they are now among the top 10 most prescribed drugs in the United States. As of 2015, the FDA has already approved six drugs of this class (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole). Recently, the risks and benefits of long-term PPI use were questioned and many studies indicated that their use should be carefully considered, especially in young patients, whose treatment with these drugs could last many years. Even greater concerns have been raised about a potential positive association between PPIs and osteoporotic fracture risk including the hip, spine and wrist. Although based on observational studies, there is substantial evidence associating the long-term use of PPIs and fracture. This relationship is only partially admitted due to the lack of consistent effects of PPIs on bone mineral density loss. Therefore, this narrative review aimed to discuss the recent findings pertaining to the risk of osteoporotic fracture associated with PPIs, in particular prolonged use, and to call for further research to elucidate the mechanisms associated with this bone fragility. Full article

(This article belongs to the Special Issue Musculoskeletal Disorders (MSDs) and Osteoimmunology)

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