Effect of the small compound
            <scp>TD</scp>
            ‐198946 on glycosaminoglycan synthesis and transforming growth factor β3‐associated chondrogenesis of human synovium‐derived stem cells in vitro

Chijimatsu, Ryota; Yano, Fumiko; Saito, Taku; Kobayashi, Masato; Hamamoto, Shuichi; Kaito, Takashi; Kushioka, Junichi; Hart, David A.; Chung, Ung‐il; Tanaka, Sakae; Yoshikawa, Hideki; Nakamura, Norimasa

doi:10.1002/term.2795

Cited by 12 publications

(24 citation statements)

References 43 publications

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“…Another explanation is that the increase in the expression of Col2a1 by TD-198946 was milder than that of Acan or Has2 even in mNPCs. Moreover, our previous study using hSSCs also revealed that TD-198946 enhances GAG production but does not affect the expression of COL2A1 in hSSCs 17 . Thus, we considered that the expression of COL2A1 is not a direct target of TD-198946.…”

Section: Discussionmentioning

confidence: 84%

“…Our previous studies revealed that TD-198946 enhances GAG synthesis in mouse chondrocytes, human bone marrow stromal cells, and human synovium-derived stem cells (hSSCs) 10 , 17 , 18 . Moreover, our previous study identified a unique effect of TD-198946 on hyaluronan secretion by hSSCs 17 . Consistent with previous studies, TD-198946 was found to enhance the gene expression of aggrecan and hyaluronan synthase 2, resulting in increased GAG synthesis in both mNPCs and hNPCs of all donors.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we considered that the expression of COL2A1 is not a direct target of TD-198946. TD-198946 synergistically increases the expression of COL2A1 when combined with transforming growth factor-β3 or bone morphogenetic protein-2 17 , 19 . Further research is needed to explore the optimal combinations of TD-198946 and growth factors that enhance the expression of COL2A1 in hNPCs.…”

Section: Discussionmentioning

confidence: 99%

“…Herein, the same lot of TD-198946 employed in our previous study 17 was utilized for all experiments. TD-198946 was dissolved in dimethyl sulfoxide (DMSO, Sigma-Aldrich, St. Louis, MO) and diluted in phosphate-buffered saline (PBS) (1:1,000) for the in vivo analysis, and culture medium (1:1,000) for the in vitro analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Two-dimensional micromass culture was performed as described previously 17 , 25 . Briefly, a high concentration of mNPCs or hNPCs was cultured in micromass (1 × 10 5 cells/10 μL) in chondrogenic basal medium (DMEM with 1% ITS [insulin, transferrin, selenium, Corning Inc., Corning, NY], 50 μg/mL ascorbic acid [Sigma-Aldrich], 40 μg/mL L-proline [Fujifilm Wako], 1% FBS, and 1% A/A) supplemented with vehicle or TD-198946 (1 nM to 1 μM) for 7 days.…”

Section: Methodsmentioning

confidence: 99%

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The small compound, TD-198946, protects against intervertebral degeneration by enhancing glycosaminoglycan synthesis in nucleus pulposus cells

Kushioka

Kaito

Chijimatsu

et al. 2020

Sci Rep

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Degeneration of the nucleus pulposus (NP) might serve as a trigger for intervertebral disc degeneration (IDD). A recent drug screening study revealed that the thienoindazole derivative, TD-198946, is a novel drug for the treatment of osteoarthritis. Because of the environmental and functional similarities between articular cartilage and intervertebral disc, TD-198946 is expected to prevent IDD. Herein, we sought to evaluate the effects of TD-198946 on IDD. TD-198946 enhanced glycosaminoglycan (GAG) production and the related genes in mouse NP cells and human NP cells (hNPCs). Further, Kyoto Encyclopedia of Genes and Genomes pathway analysis using the mRNA sequence of hNPCs suggested that the mechanism of action of TD-198946 primarily occurred via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. The Akt inhibitor suppressed the enhancement of GAG production induced by TD-198946. The effects of TD-198946 on IDD at two different time points (immediate treatment model, immediately after the puncture; latent treatment model, 2 weeks after the puncture) were investigated using a mouse tail-disc puncture model. At both time points, TD-198946 prevented a loss in disc height. Histological analysis also demonstrated the preservation of the NP structures. TD-198946 exhibited therapeutic effects on IDD by enhancing GAG production via PI3K/Akt signaling.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

The small compound, TD-198946, protects against intervertebral degeneration by enhancing glycosaminoglycan synthesis in nucleus pulposus cells

Kushioka

Kaito

Chijimatsu

et al. 2020

Sci Rep

Self Cite

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Evidence that TD‐198946 enhances the chondrogenic potential of human synovium‐derived stem cells through the NOTCH3 signaling pathway

Kobayashi

Chijimatsu

Hart

et al. 2020

J Tissue Eng Regen Med

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Human synovium‐derived stem cells (hSSCs) are an attractive source of cells for cartilage repair. At present, the quality of tissue and techniques used for cartilage regeneration have scope for improvement. A small compound, TD‐198946, was reported to enhance chondrogenic induction from hSSCs; however, other applications of TD‐198946, such as priming the cell potential of hSSCs, remain unknown. Our study aimed to examine the effect of TD‐198946 pretreatment on hSSCs. HSSCs were cultured with or without TD‐198946 for 7 days during expansion culture and then converted into a three‐dimensional pellet culture supplemented with bone morphogenetic protein‐2 (BMP2) and/or transforming growth factor beta‐3 (TGFβ3). Chondrogenesis in cultures was assessed based on the GAG content, histology, and expression levels of chondrogenic marker genes. Cell pellets derived from TD‐198946‐pretreated hSSCs showed enhanced chondrogenic potential when chondrogenesis was induced by both BMP2 and TGFβ3. Moreover, cartilaginous tissue was efficiently generated from TD‐198946‐pretreated hSSCs using a combination of BMP2 and TGFβ3. Microarray analysis revealed that NOTCH pathway‐related genes and their target genes were significantly upregulated in TD‐198946‐treated hSSCs, although TD‐198946 alone did not upregulate chondrogenesis related markers. The administration of the NOTCH signal inhibitor diminished the effect of TD‐198946. Thus, TD‐198946 enhances the chondrogenic potential of hSSCs via the NOTCH3 signaling pathway. This study is the first to demonstrate the gradual activation of NOTCH3 signaling during chondrogenesis in hSSCs. The priming of NOTCH3 using TD‐198946 provides a novel insight regarding the regulation of the differentiation of hSSCs into chondrocytes.

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Pharmaceutical therapeutics for articular regeneration and restoration: state-of-the-art technology for screening small molecular drugs

Chen

Yao

et al. 2021

Cell. Mol. Life Sci.

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Effect of the small compound TD ‐198946 on glycosaminoglycan synthesis and transforming growth factor β3‐associated chondrogenesis of human synovium‐derived stem cells in vitro

Cited by 12 publications

References 43 publications

The small compound, TD-198946, protects against intervertebral degeneration by enhancing glycosaminoglycan synthesis in nucleus pulposus cells

The small compound, TD-198946, protects against intervertebral degeneration by enhancing glycosaminoglycan synthesis in nucleus pulposus cells

Evidence that TD‐198946 enhances the chondrogenic potential of human synovium‐derived stem cells through the NOTCH3 signaling pathway

Pharmaceutical therapeutics for articular regeneration and restoration: state-of-the-art technology for screening small molecular drugs

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