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Molecular Metabolisms in Cartilage Health and Diseases: 3rd Edition
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Molecular Metabolisms in Cartilage Health and Diseases: 3rd Edition

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: 20 December 2024 | Viewed by 4044

Special Issue Editor

Dr. Masaharu Takigawa

E-Mail Website
Guest Editor
Advanced Research Center for Oral and Craniofacial Sciences, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
Interests: cartilage; chondrocytes; CCN proteins; bone; osteoblasts
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Molecular Metabolisms in Cartilage Health and Diseases 2.0”.

Cartilage is a unique tissue as it is avascular and composed of only chondrocytes. Vascular invasion into the cartilage is a key step towards endochondral bone formation, as well as being involved in the pathogenesis of osteoarthritis. Because of the lack of blood flow, the regeneration or repair of damaged cartilage, such as those in osteoarthritis, is difficult to be achieved. The old and new problems in cartilage medicine are how to maintain cartilage homeostasis and how to regenerate or repair damaged cartilage. Many factors, such as growth factors, transcription factors, nutrition and its metabolites, extracellular matrix, and physical forces, are involved in cartilage growth, homeostasis, and regeneration. This Special Issue titled “Molecular Metabolisms in Cartilage Health and Diseases 3.0” focuses on the recent progress in the molecular aspects of cartilage metabolism and its regulation in normal and diseased cartilage.

Dr. Masaharu Takigawa
Guest Editor

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Keywords

  • cartilage
  • chondrocytes
  • growth
  • regeneration
  • endochondral ossification
  • arthritis
  • joint
  • growth factors
  • mechanical stress
  • nutrition

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Published Papers (4 papers)

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Research

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9 pages, 1976 KiB  
Communication
Efficient Production of Chondrocyte Particles from Human iPSC-Derived Chondroprogenitors Using a Plate-Based Cell Self-Aggregation Technique
by Shojiro Hanaki, Daisuke Yamada, Tomoka Takao, Ryosuke Iwai and Takeshi Takarada
Int. J. Mol. Sci. 2024, 25(22), 12063; https://doi.org/10.3390/ijms252212063 - 10 Nov 2024
Viewed by 558
Abstract
The limited capacity of articular cartilage for self-repair is a critical challenge in orthopedic medicine. Here, we aimed to develop a simplified method of generating chondrocyte particles from human-induced pluripotent stem cell-derived expandable limb-bud mesenchymal cells (ExpLBM) using a cell self-aggregation technique (CAT). [...] Read more.
The limited capacity of articular cartilage for self-repair is a critical challenge in orthopedic medicine. Here, we aimed to develop a simplified method of generating chondrocyte particles from human-induced pluripotent stem cell-derived expandable limb-bud mesenchymal cells (ExpLBM) using a cell self-aggregation technique (CAT). ExpLBM cells were induced to form chondrocyte particles through a stepwise differentiation protocol performed on a CAT plate (prevelex-CAT®), which enables efficient and consistent production of an arbitrary number of uniformly sized particles. Histological and immunohistochemical analyses confirmed that the generated chondrocyte particles expressed key cartilage markers, such as type II collagen and aggrecan, but not hypertrophic markers, such as type X collagen. Additionally, when these particles were transplanted into osteochondral defects in rats with X-linked severe combined immunodeficiency, they demonstrated successful engraftment and extracellular matrix production, as evidenced by Safranin O and Toluidine Blue staining. These data suggest that the plate-based CAT system offers a robust and scalable approach to produce a large number of chondrocyte particles in a simplified and efficient manner, with potential application to cartilage regeneration. Future studies will focus on refining the system and exploring its clinical applications to the treatment of cartilage defects. Full article
(This article belongs to the Special Issue Molecular Metabolisms in Cartilage Health and Diseases: 3rd Edition)
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13 pages, 2439 KiB  
Article
Distribution and Incorporation of Extracellular Vesicles into Chondrocytes and Synoviocytes
by Takashi Ohtsuki, Ikumi Sato, Ren Takashita, Shintaro Kodama, Kentaro Ikemura, Gabriel Opoku, Shogo Watanabe, Takayuki Furumatsu, Hiroshi Yamada, Mitsuru Ando, Kazunari Akiyoshi, Keiichiro Nishida and Satoshi Hirohata
Int. J. Mol. Sci. 2024, 25(22), 11942; https://doi.org/10.3390/ijms252211942 - 6 Nov 2024
Viewed by 801
Abstract
Osteoarthritis (OA) is a chronic disease affecting over 500 million people worldwide. As the population ages and obesity rates rise, the societal burden of OA is increasing. Pro-inflammatory cytokines, particularly interleukin-1β, are implicated in the pathogenesis of OA. Recent studies suggest that crosstalk [...] Read more.
Osteoarthritis (OA) is a chronic disease affecting over 500 million people worldwide. As the population ages and obesity rates rise, the societal burden of OA is increasing. Pro-inflammatory cytokines, particularly interleukin-1β, are implicated in the pathogenesis of OA. Recent studies suggest that crosstalk between cartilage and synovium contributes to OA development, but the mechanisms remain unclear. Extracellular vesicles (EVs) were purified from cell culture-conditioned medium via ultracentrifugation and confirmed using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. We demonstrated that EVs were taken up by human synoviocytes and chondrocytes in vitro, while in vivo experiments revealed that fluorescent-labelled EVs injected into mouse joints were incorporated into chondrocytes and synoviocytes. EV uptake was significantly inhibited by dynamin-mediated endocytosis inhibitors, indicating that endocytosis plays a major role in this process. Additionally, co-culture experiments with HEK-293 cells expressing red fluorescent protein (RFP)-tagged CD9 and the chondrocytic cell line OUMS-27 confirmed the transfer of RFP-positive EVs across a 600-nm but not a 30-nm filter. These findings suggest that EVs from chondrocytes are released into joint fluid and taken up by cells within the cartilage, potentially facilitating communication between cartilage and synovium. The results underscore the importance of EVs in OA pathophysiology. Full article
(This article belongs to the Special Issue Molecular Metabolisms in Cartilage Health and Diseases: 3rd Edition)
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19 pages, 4077 KiB  
Article
Analysis of the Actions of RARγ Agonists on Growing Osteochondromas in a Mouse Model
by Sonia A. Garcia, Kimberly Wilson, Ningfeng Tang, Hongying Tian, Takeshi Oichi, Aruni T. Gunawardena, Michael Chorny, Ivan S. Alferiev, John E. Herzenberg, Vincent Y. Ng, Masahiro Iwamoto and Motomi Enomoto-Iwamoto
Int. J. Mol. Sci. 2024, 25(14), 7610; https://doi.org/10.3390/ijms25147610 - 11 Jul 2024
Viewed by 1257
Abstract
The actions of the retinoic acid nuclear receptor gamma (RARγ) agonist, palovarotene, on pre-existing osteochondromas were investigated using a mouse multiple osteochondroma model. This approach was based on the knowledge that patients often present to the clinic after realizing the existence of osteochondroma [...] Read more.
The actions of the retinoic acid nuclear receptor gamma (RARγ) agonist, palovarotene, on pre-existing osteochondromas were investigated using a mouse multiple osteochondroma model. This approach was based on the knowledge that patients often present to the clinic after realizing the existence of osteochondroma masses, and the findings from preclinical investigations are the effects of drugs on the initial formation of osteochondromas. Systemic administration of palovarotene, with increased doses (from 1.76 to 4.0 mg/kg) over time, fully inhibited tumor growth, keeping the tumor size (0.31 ± 0.049 mm3) similar to the initial size (0.27 ± 0.031 mm3, p = 0.66) while the control group tumor grew (1.03 ± 0.23 mm3, p = 0.023 to the drug-treated group). Nanoparticle (NP)-based local delivery of the RARγ agonist also inhibited the growth of osteochondromas at an early stage (Control: 0.52 ± 0.11 mm3; NP: 0.26 ± 0.10, p = 0.008). Transcriptome analysis revealed that the osteoarthritis pathway was activated in cultured chondrocytes treated with palovarotene (Z-score = 2.29), with the upregulation of matrix catabolic genes and the downregulation of matrix anabolic genes, consistent with the histology of palovarotene-treated osteochondromas. A reporter assay performed in cultured chondrocytes demonstrated that the Stat3 pathway, but not the Stat1/2 pathway, was stimulated by RARγ agonists. The activation of Stat3 by palovarotene was confirmed using immunoblotting and immunohistochemistry. These findings suggest that palovarotene treatment is effective against pre-existing osteochondromas and that the Stat3 pathway is involved in the antitumor actions of palovarotene. Full article
(This article belongs to the Special Issue Molecular Metabolisms in Cartilage Health and Diseases: 3rd Edition)
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Review

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16 pages, 1727 KiB  
Review
Cartilage Homeostasis under Physioxia
by Yuji Arai, Ryota Cha, Shuji Nakagawa, Atsuo Inoue, Kei Nakamura and Kenji Takahashi
Int. J. Mol. Sci. 2024, 25(17), 9398; https://doi.org/10.3390/ijms25179398 - 29 Aug 2024
Viewed by 862
Abstract
Articular cartilage receives nutrients and oxygen from the synovial fluid to maintain homeostasis. However, compared to tissues with abundant blood flow, articular cartilage is exposed to a hypoxic environment (i.e., physioxia) and has an enhanced hypoxic stress response. Hypoxia-inducible factors (HIFs) play a [...] Read more.
Articular cartilage receives nutrients and oxygen from the synovial fluid to maintain homeostasis. However, compared to tissues with abundant blood flow, articular cartilage is exposed to a hypoxic environment (i.e., physioxia) and has an enhanced hypoxic stress response. Hypoxia-inducible factors (HIFs) play a pivotal role in this physioxic environment. In normoxic conditions, HIFs are downregulated, whereas in physioxic conditions, they are upregulated. The HIF-α family comprises three members: HIF-1α, HIF-2α, and HIF-3α. Each member has a distinct function in articular cartilage. In osteoarthritis, which is primarily caused by degeneration of articular cartilage, HIF-1α is upregulated in chondrocytes and is believed to protect articular cartilage by acting anabolically on it. Conversely, in contrast to HIF-1α, HIF-2α exerts a catabolic influence on articular cartilage. It may therefore be possible to develop a new treatment for OA by controlling the expression of HIF-1α and HIF-2α with drugs or by altering the oxygen environment in the joints. Full article
(This article belongs to the Special Issue Molecular Metabolisms in Cartilage Health and Diseases: 3rd Edition)
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