Intra-articular injection of kartogenin-conjugated polyurethane nanoparticles attenuates the progression of osteoarthritis

Wei, Fan Yan; Li, Jinghuan; Liu, Yuan; Chen, Jifei; Wang, Zhe; Wang, Yiming; Guo, Changan; Mo, Xiumei; Yan, Zuoqin

doi:10.1080/10717544.2018.1461279

Cited by 66 publications

(51 citation statements)

References 34 publications

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“…In addition, when cultured in KGN thermogel, OA chondrocytes produced higher amount of GAG and COL-2 than those in thermogel without addition of KGN. These data are consistent with others which showed that KGN promoted cartilage regeneration and induced chondrogenic differentiation of mesenchymal stem cells (Kang et al, 2014, 2016; Wang et al, 2016b; Fan et al, 2018; Han et al, 2019). In addition, the level of MMP-13 produced by OA chondrocytes in KGN thermogel was much less compared to that in thermogel.…”

Section: Discussionsupporting

confidence: 92%

“…Recently a small molecule, kartogenin (KGN), has been reported to promote collagen synthesis (Johnson, 2012). Intra-articular injection of KGN has been reported to enhance cartilage regeneration (Kang et al, 2014; Mohan et al, 2016; Fan et al, 2018). However, KGN cannot provide long-term therapeutic effects due to fast clearance and short retention of KGN in joints, posing a disadvantage in its clinical application.…”

Section: Introductionmentioning

confidence: 99%

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Intra-articular Injection of Kartogenin-Incorporated Thermogel Enhancing Osteoarthritis Treatment

et al. 2019

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To provide a vehicle for sustained release of cartilage-protective agent for the potential application of osteoarthritis (OA) treatment, we developed a kartogenin (KGN)-incorporated thermogel for intra-articular injection. We fabricated a poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA–PEG–PLGA) thermogel as a KGN carrier for IA injection. OA chondrocytes were cultured in thermogel with or with no KGN to investigate the effect of KGN thermogel on cartilage matrix. The in vivo effect of KGN thermogel on OA was examined in a rabbit OA model. The KGN thermogel showed a sustained in vitro release of KGN for 3 weeks. OA chondrocytes proliferated well both in thermogel and KGN thermogel. In addition, OA chondrocytes produced higher amount of [type 2 collagen (COL-2) and glycosaminoglycan (GAG)], as well as lower level of matrix metalloproteinase 13 (MMP-13) in KGN thermogel that those in thermogel with no addition of KGN. The gene analysis supported that KGN thermogel enhanced expression of hyaline-cartilage specific genes Col 2 and AGC, and inhibited the expression of MMP-13. Compared with intra-articular injection of saline or thermogel containing no KGN, KGN thermogel can enhance cartilage regeneration and inhibit joint inflammation of arthritic knees in a rabbit ACLT-induced OA model at 3 weeks after the injection. Therefore, the KGN-incorporated PLGA–PEG–PLGA thermogel may provide a novel treatment modality for OA treatment with IA injection.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Intra-articular Injection of Kartogenin-Incorporated Thermogel Enhancing Osteoarthritis Treatment

et al. 2019

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“…Among the most attractive polymer candidates, poly(lactic-co-glycolic acid) (PLGA)—a typical compound used in fabrication of biodegradable microspheres or nanoparticles, which has been approved for use by the Food and Drug Administration—is widely used as a vehicle for delivery of pharmaceutically relevant payloads ( Danhier et al, 2012 ; Fernando et al, 2018 ). Furthermore, the amino groups of PLGA can bind covalently to the carboxyl groups of KGN, thus enhancing the permeability and retention of KGN and promoting its therapeutic effects ( Kang et al, 2014 ; Fan et al, 2018 ; Chen et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Cartilage Extracellular Matrix Scaffold With Kartogenin-Encapsulated PLGA Microspheres for Cartilage Regeneration

Zhao

Zhang

et al. 2020

Front. Bioeng. Biotechnol.

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Repair of articular cartilage defects is a challenging aspect of clinical treatment. Kartogenin (KGN), a small molecular compound, can induce the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into chondrocytes. Here, we constructed a scaffold based on chondrocyte extracellular matrix (CECM) and poly(lactic-co-glycolic acid) (PLGA) microspheres (MP), which can slowly release KGN, thus enhancing its efficiency. Cell adhesion, live/dead staining, and CCK-8 results indicated that the PLGA(KGN)/CECM scaffold exhibited good biocompatibility. Histological staining and quantitative analysis demonstrated the ability of the PLGA(KGN)/CECM composite scaffold to promote the differentiation of BMSCs. Macroscopic observations, histological tests, and specific marker analysis showed that the regenerated tissues possessed characteristics similar to those of normal hyaline cartilage in a rabbit model. Use of the PLGA(KGN)/CECM scaffold may mimic the regenerative microenvironment, thereby promoting chondrogenic differentiation of BMSCs in vitro and in vivo. Therefore, this innovative composite scaffold may represent a promising approach for acellular cartilage tissue engineering.

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“…Kartogenin (KGN), a heterocyclic‐structured small‐molecule compound, can promote the chondrogenic differentiation of MSCs and protect chondrocytes from ossification (12). The applications of KGN in tissue engineering and regenerative medicine have been widely expanded since its discovery, including musculoskeletal, meniscal, and articular cartilaginous regeneration strategies (13–15). However, the efficiency of chondrogenesis induced by KGN alone has been far from satisfactory, impeding its further clinical application (16, 17).…”

mentioning

confidence: 99%

Kartogenin preconditioning commits mesenchymal stem cells to a precartilaginous stage with enhanced chondrogenic potential by modulating JNK and β‐catenin–related pathways

et al. 2019

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Cartilage engineering strategies using mesenchymal stem cells (MSCs) could provide preferable solutions to resolve long‐segment tracheal defects. However, the drawbacks of widely used chondrogenic protocols containing TGF‐β3, such as inefficiency and unstable cellular phenotype, are problematic. In our research, to optimize the chondrogenic differentiation of human umbilical cord MSCs (hUCMSCs), kartogenin (KGN) preconditioning was performed prior to TGF‐β3 induction. hUCMSCs were preconditioned with 1 µM of KGN for 3 d, sequentially pelleted, and incubated with TGF‐β3 for 28 d. Then, the expression of chondrogenesis‐ and ossification‐related genes was evaluated by immunohistochemistry and RT‐PCR. The underlying mechanism governing the beneficial effects of KGN preconditioning was explored by phosphorylated kinase screening and validated in vitro and in vivo using JNK inhibitor (SP600125) and β‐catenin activator (SKL2001). After KGN preconditioning, expression of fibroblast growth factor receptor 3, a marker of precartilaginous stem cells, was up‐regulated in hUCMSCs. Furthermore, the KGN‐preconditioned hUCMSCs efficiently differentiated into chondrocytes with elevated chondrogenic gene (SOX9, aggrecan, and collagen II) expression and reduced expression of ossifie genes (collagen X and MMP13) compared with hUCMSCs treated with TGF‐β3 only. Phosphokinase screening indicated that the beneficial effects of KGN preconditioning are directly related to an up‐regulation of JNK phosphorylation and a suppression of β‐catenin levels. Blocking and activating tests revealed that the prochondrogenic effects of KGN preconditioning was achieved mainly by activating the JNK/Runt‐related transcription factor (RUNX)1 pathway, and antiossific effects were imparted by suppressing the β‐catenin/RUNX2 pathway. Eventually, tracheal patches, based on KGN‐preconditioned hUCMSCs and TGF‐β3 encapsulated electrospun poly (l‐lactic acid‐co‐ε‐caprolactone)/collagen nanofilms, were successfully used for restoring tracheal defects in rabbit models. In summary, KGN preconditioning likely improves the chondrogenic differentiation of hUCMSCs by committing them to a precartilaginous stage with enhanced JNK phosphorylation and suppressed β‐catenin. This novel protocol consisting of KGN preconditioning and subsequent TGF‐β3 induction might be preferable for cartilage engineering strategies using MSCs.—Jing, H., Zhang, X., Gao, M., Luo, K., Fu, W., Yin, M., Wang, W., Zhu, Z., Zheng, J., He, X. Kartogenin preconditioning commits mesenchymal stem cells to a precartilaginous stage with enhanced chondrogenic potential by modulating JNK and β‐catenin—related pathways. FASEB J. 33, 5641–5653 (2019). http://www.fasebj.org

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Intra-articular injection of kartogenin-conjugated polyurethane nanoparticles attenuates the progression of osteoarthritis

Cited by 66 publications

References 34 publications

Intra-articular Injection of Kartogenin-Incorporated Thermogel Enhancing Osteoarthritis Treatment

Intra-articular Injection of Kartogenin-Incorporated Thermogel Enhancing Osteoarthritis Treatment

Cartilage Extracellular Matrix Scaffold With Kartogenin-Encapsulated PLGA Microspheres for Cartilage Regeneration

Kartogenin preconditioning commits mesenchymal stem cells to a precartilaginous stage with enhanced chondrogenic potential by modulating JNK and β‐catenin–related pathways

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