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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 (31 January 2022) | Viewed by 22380

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Dr. Masaharu Takigawa

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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
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Special Issue Information

Dear Colleagues,

Cartilage is a unique tissue in that it is avascular and composed of only chondrocytes. Vascular invasion into 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, regeneration or repair of damaged cartilages such as those in osteoarthritis is difficult to be achieved. The old-yet-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” focuses on recent progress in the molecular aspect of cartilage metabolism and its regulation in normal as well as in 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 (6 papers)

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Research

Jump to: Review

15 pages, 2947 KiB

Open AccessArticle

Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study

by Junko Inagaki, Airi Nakano, Omer Faruk Hatipoglu, Yuka Ooka, Yurina Tani, Akane Miki, Kentaro Ikemura, Gabriel Opoku, Ryosuke Ando, Shintaro Kodama, Takashi Ohtsuki, Hirosuke Yamaji, Shusei Yamamoto, Eri Katsuyama, Shogo Watanabe and Satoshi Hirohata

Int. J. Mol. Sci. 2022, 23(5), 2681; https://doi.org/10.3390/ijms23052681 - 28 Feb 2022

Cited by 5 | Viewed by 2135

Abstract

Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1β-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1β-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints. Full article

(This article belongs to the Special Issue Molecular Metabolisms in Cartilage Health and Diseases)

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11 pages, 1402 KiB

Open AccessArticle

Identification of Surface Antigens That Define Human Pluripotent Stem Cell-Derived PRRX1+Limb-Bud-like Mesenchymal Cells

by Daisuke Yamada, Tomoka Takao, Masahiro Nakamura, Toki Kitano, Eiji Nakata and Takeshi Takarada

Int. J. Mol. Sci. 2022, 23(5), 2661; https://doi.org/10.3390/ijms23052661 - 28 Feb 2022

Cited by 2 | Viewed by 2473

Abstract

Stem cell-based therapies and experimental methods rely on efficient induction of human pluripotent stem cells (hPSCs). During limb development, the lateral plate mesoderm (LPM) produces limb-bud mesenchymal (LBM) cells that differentiate into osteochondroprogenitor cells and form cartilage tissues in the appendicular skeleton. Previously, we generated PRRX1-tdTomato reporter hPSCs to establish the protocol for inducing the hPSC-derived PRRX1⁺ LBM-like cells. However, surface antigens that assess the induction efficiency of hPSC-derived PRRX1⁺ LBM-like cells from LPM have not been identified. Here, we used PRRX1-tdTomato reporter hPSCs and found that high pluripotent cell density suppressed the expression of PRRX1 mRNA and tdTomato after LBM-like induction. RNA sequencing and flow cytometry suggested that PRRX1-tdTomato⁺ LBM-like cells are defined as CD44^high CD140B^high CD49f⁻. Importantly, other hPSC lines, including four human induced pluripotent stem cell lines (414C2, 1383D2, HPS1042, HPS1043) and two human embryonic stem cell lines (SEES4, SEES7), showed the same results. Thus, an appropriate cell density of hPSCs before differentiation is a prerequisite for inducing the CD44^high CD140B^high CD49f⁻ PRRX1⁺ LBM-like cells. Full article

(This article belongs to the Special Issue Molecular Metabolisms in Cartilage Health and Diseases)

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16 pages, 2839 KiB

Open AccessArticle

Adipose-Derived Extract Suppresses IL-1β-Induced Inflammatory Signaling Pathways in Human Chondrocytes and Ameliorates the Cartilage Destruction of Experimental Osteoarthritis in Rats

by Hideki Ohashi, Keiichiro Nishida, Aki Yoshida, Yoshihisa Nasu, Ryuichi Nakahara, Yoshinori Matsumoto, Ayumu Takeshita, Daisuke Kaneda, Masanori Saeki and Toshifumi Ozaki

Int. J. Mol. Sci. 2021, 22(18), 9781; https://doi.org/10.3390/ijms22189781 - 10 Sep 2021

Cited by 9 | Viewed by 2899

Abstract

We investigated the effects of adipose-derived extract (AE) on cultured chondrocytes and in vivo cartilage destruction. AE was prepared from human adipose tissues using a nonenzymatic approach. Cultured human chondrocytes were stimulated with interleukin-1 beta (IL-1β) with or without different concentrations of AE. The effects of co-treatment with AE on intracellular signaling pathways and their downstream gene and protein expressions were examined using real-time PCR, Western blotting, and immunofluorescence staining. Rat AE prepared from inguinal adipose tissues was intra-articularly delivered to the knee joints of rats with experimental osteoarthritis (OA), and the effect of AE on cartilage destruction was evaluated histologically. In vitro, co-treatment with IL-1β combined with AE reduced activation of the p38 and ERK mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of the p65 subunit of nuclear factor-kappa B (NF-κB), and subsequently downregulated the expressions of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, IL-6, and IL-8, whereas it markedly upregulated the expression of IL-1 receptor type 2 (IL-1R2) in chondrocytes. Intra-articular injection of homologous AE significantly ameliorated cartilage destruction six weeks postoperatively in the rat OA model. These results suggested that AE may exert a chondroprotective effect, at least in part, through modulation of the IL-1β-induced inflammatory signaling pathway by upregulation of IL-1R2 expression. Full article

(This article belongs to the Special Issue Molecular Metabolisms in Cartilage Health and Diseases)

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16 pages, 2934 KiB

Open AccessArticle

Effect of Angiotensin II on Chondrocyte Degeneration and Protection via Differential Usage of Angiotensin II Receptors

by Takashi Nishida, Sho Akashi, Masaharu Takigawa and Satoshi Kubota

Int. J. Mol. Sci. 2021, 22(17), 9204; https://doi.org/10.3390/ijms22179204 - 25 Aug 2021

Cited by 2 | Viewed by 2521

Abstract

The renin–angiotensin system (RAS) controls not only systemic functions, such as blood pressure, but also local tissue-specific events. Previous studies have shown that angiotensin II receptor type 1 (AT₁R) and type 2 (AT₂R), two RAS components, are expressed in chondrocytes. However, the angiotensin II (ANG II) effects exerted through these receptors on chondrocyte metabolism are not fully understood. In this study, we investigated the effects of ANG II and AT₁R blockade on chondrocyte proliferation and differentiation. Firstly, we observed that ANG II significantly suppressed cell proliferation and glycosaminoglycan content in rat chondrocytic RCS cells. Additionally, ANG II decreased CCN2, which is an anabolic factor for chondrocytes, via increased MMP9. In Agtr1a-deficient RCS cells generated by the CRISPR-Cas9 system, Ccn2 and Aggrecan (Acan) expression increased. Losartan, an AT₁R antagonist, blocked the ANG II-induced decrease in CCN2 production and Acan expression in RCS cells. These findings suggest that AT₁R blockade reduces ANG II-induced chondrocyte degeneration. Interestingly, AT₁R-positive cells, which were localized on the surface of the articular cartilage of 7-month-old mice expanded throughout the articular cartilage with aging. These findings suggest that ANG II regulates age-related cartilage degeneration through the ANG II–AT₁R axis. Full article

(This article belongs to the Special Issue Molecular Metabolisms in Cartilage Health and Diseases)

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17 pages, 1945 KiB

Open AccessArticle

Curcumin Attenuates Environment-Derived Osteoarthritis by Sox9/NF-kB Signaling Axis

by Constanze Buhrmann, Aranka Brockmueller, Anna-Lena Mueller, Parviz Shayan and Mehdi Shakibaei

Int. J. Mol. Sci. 2021, 22(14), 7645; https://doi.org/10.3390/ijms22147645 - 16 Jul 2021

Cited by 61 | Viewed by 5589

Abstract

Inflammation has a fundamental impact on the pathophysiology of osteoarthritis (OA), a common form of degenerative arthritis. It has previously been established that curcumin, a component of turmeric (Curcuma longa), has anti-inflammatory properties. This research evaluates the potentials of curcumin on the pathophysiology of OA in vitro. To explore the anti-inflammatory efficacy of curcumin in an inflamed joint, an osteoarthritic environment (OA-EN) model consisting of fibroblasts, T-lymphocytes, 3D-chondrocytes is constructed and co-incubated with TNF-α, antisense oligonucleotides targeting NF-kB (ASO-NF-kB), or an IkB-kinase (IKK) inhibitor (BMS-345541). Our results show that OA-EN, similar to TNF-α, suppresses chondrocyte viability, which is accompanied by a significant decrease in cartilage-specific proteins (collagen II, CSPG, Sox9) and an increase in NF-kB-driven gene proteins participating in inflammation, apoptosis, and breakdown (NF-kB, MMP-9, Cox-2, Caspase-3). Conversely, similar to knockdown of NF-kB at the mRNA level or at the IKK level, curcumin suppresses NF-kB activation, NF-kB-promotes gene proteins derived from the OA-EN, and stimulates collagen II, CSPG, and Sox9 expression. Furthermore, co-immunoprecipitation assay shows that curcumin reduces OA-EN-mediated inflammation and chondrocyte apoptosis, with concomitant chondroprotective effects, due to modulation of Sox-9/NF-kB signaling axis. Finally, curcumin selectively hinders the interaction of p-NF-kB-p65 directly with DNA—this association is disrupted through DTT. These results suggest that curcumin suppresses inflammation in OA-EN via modulating NF-kB-Sox9 coupling and is essential for maintaining homeostasis in OA by balancing chondrocyte survival and inflammatory responses. This may contribute to the alternative treatment of OA with respect to the efficacy of curcumin. Full article

(This article belongs to the Special Issue Molecular Metabolisms in Cartilage Health and Diseases)

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Review

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15 pages, 1723 KiB

Open AccessReview

Regulatory Mechanisms of Prg4 and Gdf5 Expression in Articular Cartilage and Functions in Osteoarthritis

by Yoshifumi Takahata, Hiromasa Hagino, Ayaka Kimura, Mitsuki Urushizaki, Shiori Yamamoto, Kanta Wakamori, Tomohiko Murakami, Kenji Hata and Riko Nishimura

Int. J. Mol. Sci. 2022, 23(9), 4672; https://doi.org/10.3390/ijms23094672 - 23 Apr 2022

Cited by 24 | Viewed by 5874

Abstract

Owing to the rapid aging of society, the numbers of patients with joint disease continue to increase. Accordingly, a large number of patients require appropriate treatment for osteoarthritis (OA), the most frequent bone and joint disease. Thought to be caused by the degeneration and destruction of articular cartilage following persistent and excessive mechanical stimulation of the joints, OA can significantly impair patient quality of life with symptoms such as knee pain, lower limb muscle weakness, or difficulty walking. Because articular cartilage has a low self-repair ability and an extremely low proliferative capacity, healing of damaged articular cartilage has not been achieved to date. The current pharmaceutical treatment of OA is limited to the slight alleviation of symptoms (e.g., local injection of hyaluronic acid or non-steroidal anti-inflammatory drugs); hence, the development of effective drugs and regenerative therapies for OA is highly desirable. This review article summarizes findings indicating that proteoglycan 4 (Prg4)/lubricin, which is specifically expressed in the superficial zone of articular cartilage and synovium, functions in a protective manner against OA, and covers the transcriptional regulation of Prg4 in articular chondrocytes. We also focused on growth differentiation factor 5 (Gdf5), which is specifically expressed on the surface layer of articular cartilage, particularly in the developmental stage, describing its regulatory mechanisms and functions in joint formation and OA pathogenesis. Because several genetic studies in humans and mice indicate the involvement of these genes in the maintenance of articular cartilage homeostasis and the presentation of OA, molecular targeting of Prg4 and Gdf5 is expected to provide new insights into the aetiology, pathogenesis, and potential treatment of OA. Full article

(This article belongs to the Special Issue Molecular Metabolisms in Cartilage Health and Diseases)

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