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Molecular Mechanisms and Therapeutic Approaches to Osteoarthritis

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

Deadline for manuscript submissions: 20 June 2025 | Viewed by 4418

Special Issue Editor


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Guest Editor
Department of Orthopedic Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan
Interests: osteoarthritis; cartilage repair; regeneration; platelet rich plasma; MSCs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Osteoarthritis is a common disease that affects 10% of the world’s population. Despite the fact that Osteoarthritis shortens the healthy life expectancy of many elderly people, its molecular mechanisms remain largely unknown and, therefore, preventive and therapeutic measures are still limited to symptomatic treatment. On the other hand, the development of disease-modifying drugs has been long-awaited. In recent years, attention has been focused on the development of point-of-care cells and drugs that are administered intra-articularly. Local rather than systemic administration is attractive from the standpoint of reduced side effects and drug delivery; so, the delivery of macromolecular agents, genes, nucleic acids, cells, and regenerative medicine are being developed.

This Special Issue, "Molecular Mechanisms and Therapeutic Approaches to Osteoarthritis", focuses on the molecular mechanisms of pathogenesis and therapeutic approaches to Osteoarthritis, which is a heterogeneous disease. We welcome papers on basic and translational research of Osteoarthritis.

Dr. Masato Sato
Guest Editor

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Keywords

  • mode of action
  • molecular mechanisms
  • pathogenesis
  • drug delivery
  • disease-modifying drug
  • translational research
  • cell therapy
  • regenerative medicine

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Published Papers (4 papers)

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Research

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23 pages, 2236 KiB  
Article
Development and Characterization of Magnetic Nanoemulsion-Based Senolytic Peptides for Osteoarthritis Treatment
by Camelia-Mihaela Zara-Danceanu, Jenifer García-Fernández, Dumitru-Daniel Herea, Daniel Gherca, Irene de Francisco Carrera, Luminita Labusca and Maria de la Fuente
Int. J. Mol. Sci. 2025, 26(3), 1292; https://doi.org/10.3390/ijms26031292 - 3 Feb 2025
Viewed by 92
Abstract
The formulation and characterization of a novel nanoemulsion (NE) delivery system for senomodulator peptides aimed at enhancing the treatment of osteoarthritis (OA) are reported, in combination with magnetic nanoparticles (MNPs), for improving targeted delivery and traceability. Osteoarthritis, a prevalent degenerative joint disease associated [...] Read more.
The formulation and characterization of a novel nanoemulsion (NE) delivery system for senomodulator peptides aimed at enhancing the treatment of osteoarthritis (OA) are reported, in combination with magnetic nanoparticles (MNPs), for improving targeted delivery and traceability. Osteoarthritis, a prevalent degenerative joint disease associated with aging, is currently not effectively treated by disease-modifying therapies, posing a consistent health burden on individuals and healthcare systems worldwide. Existing treatments, such as nonsteroidal anti-inflammatory drugs and intra-articular injections, are limited by inadequate local drug concentrations and rapid clearance, often necessitating costly joint replacement. Lipid-based NE composed of biocompatible and biodegradable vitamin E and sphingomyelin, associated with the senolytic peptide NE:TUB1, is able to target senescent cells implicated in OA progression. Improved cellular retention and therapeutic effects of the associated TUB1 peptide, compared to its free form, have been demonstrated, suggesting a significant enhancement in therapeutic potential. The incorporation of MNPs to obtain NE:TUB1-MNP formulations offers the advantage of being traceable in vivo through clinically available imaging technologies, with the potential to enhance targeting capabilities through magnetic guidance. The characterization of NE:TUB1-MNPs involved the assessment of their physical and chemical properties, interaction with cells, cytotoxicity profile, and nanoparticle uptake in vitro using human primary adipose-derived stem cells. NE and NE:TUB1-MNP are shown to be stable, non-toxic, and capable of efficient intracellular uptake. The inclusion of MNPs not only supports cell viability and proliferation but also facilitates medium and long-term product traceability within joints, offering a promising approach for localized treatment. The enhanced anti-senescent role of NE:TUB1-MNP formulations are highlighted, suggesting their potential utility in mitigating OA progression and possibly other degenerative diseases. In conclusion, the study presents a novel therapeutic approach for OA, NE:TUB1-MNPs, leveraging the synergistic effects of peptide-functionalized nanoemulsions and magnetic nanoparticles to improve targeted delivery and therapeutic outcomes. This innovative formulation could pave the way for new treatments for OA and other joint-related conditions, offering significant advancements in regenerative medicine. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Approaches to Osteoarthritis)
16 pages, 8288 KiB  
Article
Disease-Modifying Effects of Lenvatinib, a Multiple Receptor Tyrosine Kinase Inhibitor, on Posttraumatic Osteoarthritis of the Knee
by Yasuyuki Sogo, Eriko Toyoda, Toshihiro Nagai, Takumi Takahashi, Daichi Takizawa, Masahiko Watanabe and Masato Sato
Int. J. Mol. Sci. 2024, 25(12), 6514; https://doi.org/10.3390/ijms25126514 - 13 Jun 2024
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Abstract
Angiogenesis and vascular endothelial growth factor (VEGF) are involved in osteoarthritis (OA). We previously reported the inhibitory effect of bevacizumab in a rabbit model of OA. In the current study, we investigated the effects of lenvatinib, an angiogenesis inhibitor targeting the VEGF and [...] Read more.
Angiogenesis and vascular endothelial growth factor (VEGF) are involved in osteoarthritis (OA). We previously reported the inhibitory effect of bevacizumab in a rabbit model of OA. In the current study, we investigated the effects of lenvatinib, an angiogenesis inhibitor targeting the VEGF and fibroblast growth factor receptors, on synovitis, osteophyte formation, and cartilage degeneration in a rabbit OA model. Posttraumatic OA was induced by anterior cruciate ligament transection (ACLT) on one knee of each rabbit. Rabbits were placed into four groups according to the following lenvatinib doses: untreated control (n = 12), L0.3: 0.3 mg/kg/day (n = 15), L1.0: 1.0 mg/kg/day (n = 14), and L3.0: 3.0 mg/kg/day (n = 13) groups. We evaluated limb pain using the weight distribution ratio measured with an incapacitance tester, macroscopic osteophyte formation, and femoral condyle synovium and cartilage histology. For cartilage evaluation, the following distal sites of the femur were evaluated separately: femoral–tibial (FT), femoral–patellar (FP), and femoral corner (between FP and FT). The weight distribution ratio at 12 weeks after surgery was higher in the L0.3 and L1.0 groups than in the control group. Osteophyte formation and synovitis scores were significantly lower in the L0.3, L1.0, and L3.0 groups than in the control group. The Osteoarthritis Research Society International scores of the FT, corner, and FP sites in the L0.3 group were lower than in the control group. The cartilage thickness ratio at the FT and corner sites was significantly lower in the L0.3 group than in the control group. Krenn’s grading system of cartilage synovitis showed that all lenvatinib-administered groups had significantly lower scores than the control group. MMP3 expression level in cartilage tissue was significantly lower in the L3.0 group compared with the other three groups. ADAMTS5 expression was lower in the L3.0 group compared with the control and L0.3 groups. Oral administration of lenvatinib inhibited synovitis, osteophyte formation, and cartilage degeneration and reduced pain in a rabbit ACLT model. Lenvatinib is an oral VEGF inhibitor that is easier to administer than other VEGF inhibitors and may have potential as a treatment of posttraumatic OA. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Approaches to Osteoarthritis)
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14 pages, 2653 KiB  
Article
Osteophyte Cartilage as a Potential Source for Minced Cartilage Implantation: A Novel Approach for Articular Cartilage Repair in Osteoarthritis
by Shingo Kawabata, Tomoyuki Nakasa, Akinori Nekomoto, Dilimulati Yimiti, Shigeru Miyaki and Nobuo Adachi
Int. J. Mol. Sci. 2024, 25(10), 5563; https://doi.org/10.3390/ijms25105563 - 20 May 2024
Viewed by 1476
Abstract
Osteoarthritis (OA) is a common joint disorder characterized by cartilage degeneration, often leading to pain and functional impairment. Minced cartilage implantation (MCI) has emerged as a promising one-step alternative for large cartilage defects. However, the source of chondrocytes for MCI remains a challenge, [...] Read more.
Osteoarthritis (OA) is a common joint disorder characterized by cartilage degeneration, often leading to pain and functional impairment. Minced cartilage implantation (MCI) has emerged as a promising one-step alternative for large cartilage defects. However, the source of chondrocytes for MCI remains a challenge, particularly in advanced OA, as normal cartilage is scarce. We performed in vitro studies to evaluate the feasibility of MCI using osteophyte cartilage, which is present in patients with advanced OA. Osteophyte and articular cartilage samples were obtained from 22 patients who underwent total knee arthroplasty. Chondrocyte migration and proliferation were assessed using cartilage fragment/atelocollagen composites to compare the characteristics and regenerative potential of osteophytes and articular cartilage. Histological analysis revealed differences in cartilage composition between osteophytes and articular cartilage, with higher expression of type X collagen and increased chondrocyte proliferation in the osteophyte cartilage. Gene expression analysis identified distinct gene expression profiles between osteophytes and articular cartilage; the expression levels of COL2A1, ACAN, and SOX9 were not significantly different. Chondrocytes derived from osteophyte cartilage exhibit enhanced proliferation, and glycosaminoglycan production is increased in both osteophytes and articular cartilage. Osteophyte cartilage may serve as a viable alternative source of MCI for treating large cartilage defects in OA. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Approaches to Osteoarthritis)
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Review

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18 pages, 973 KiB  
Review
Glycosphingolipids in Osteoarthritis and Cartilage-Regeneration Therapy: Mechanisms and Therapeutic Prospects Based on a Narrative Review of the Literature
by Kentaro Homan, Tomohiro Onodera, Masatake Matsuoka and Norimasa Iwasaki
Int. J. Mol. Sci. 2024, 25(9), 4890; https://doi.org/10.3390/ijms25094890 - 30 Apr 2024
Viewed by 1503
Abstract
Glycosphingolipids (GSLs), a subtype of glycolipids containing sphingosine, are critical components of vertebrate plasma membranes, playing a pivotal role in cellular signaling and interactions. In human articular cartilage in osteoarthritis (OA), GSL expression is known notably to decrease. This review focuses on the [...] Read more.
Glycosphingolipids (GSLs), a subtype of glycolipids containing sphingosine, are critical components of vertebrate plasma membranes, playing a pivotal role in cellular signaling and interactions. In human articular cartilage in osteoarthritis (OA), GSL expression is known notably to decrease. This review focuses on the roles of gangliosides, a specific type of GSL, in cartilage degeneration and regeneration, emphasizing their regulatory function in signal transduction. The expression of gangliosides, whether endogenous or augmented exogenously, is regulated at the enzymatic level, targeting specific glycosyltransferases. This regulation has significant implications for the composition of cell-surface gangliosides and their impact on signal transduction in chondrocytes and progenitor cells. Different levels of ganglioside expression can influence signaling pathways in various ways, potentially affecting cell properties, including malignancy. Moreover, gene manipulations against gangliosides have been shown to regulate cartilage metabolisms and chondrocyte differentiation in vivo and in vitro. This review highlights the potential of targeting gangliosides in the development of therapeutic strategies for osteoarthritis and cartilage injury and addresses promising directions for future research and treatment. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Approaches to Osteoarthritis)
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