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通过微管稳定作用进行的关节纤维软骨靶向治疗。

Articular fibrocartilage-targeted therapy by microtubule stabilization.

作者信息

Li Jiawei, Jiang Huiming, Lv Zhongyang, Sun Ziying, Cheng Chaoqun, Tan Guihua, Wang Maochun, Liu Anlong, Sun Heng, Guo Hu, Chen Fufei, Liu Zizheng, Fei Yuxiang, Liu Yuan, Wu Rui, Xu Xingquan, Yan Wenjin, Jiang Qing, Shi Dongquan

机构信息

State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical School Nanjing, Nanjing, 210008 Jiangsu, P.R. China.

Department of Sports Medicine and Adult Reconstructive Surgery, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, 210000 Jiangsu, P.R. China.

出版信息

Sci Adv. 2022 Nov 16;8(46):eabn8420. doi: 10.1126/sciadv.abn8420. Epub 2022 Nov 18.


DOI:10.1126/sciadv.abn8420
PMID:36399569
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9674280/
Abstract

The fibrocartilage presented on the joint surface was caused by cartilage injury or degeneration. There is still a lack of effective strategies for fibrocartilage. Here, we hypothesized that the fibrocartilage could be viewed as a raw material for the renewal of hyaline cartilage and proposed a previously unidentified strategy of cartilage regeneration, namely, "fibrocartilage hyalinization." Cytoskeleton remodeling plays a vital role in modifying the cellular phenotype. We identified that microtubule stabilization by docetaxel repressed cartilage fibrosis and increased the hyaline cartilage extracellular matrix. We further designed a fibrocartilage-targeted negatively charged thermosensitive hydrogel for the sustained delivery of docetaxel, which promoted fibrocartilage hyalinization in the cartilage defect model. Moreover, the mechanism of fibrocartilage hyalinization by microtubule stabilization was verified as the inhibition of Sparc (secreted protein acidic and rich in cysteine). Together, our study suggested that articular fibrocartilage-targeted therapy in situ was a promising strategy for hyaline cartilage repair.

摘要

关节表面出现的纤维软骨是由软骨损伤或退变引起的。目前针对纤维软骨仍缺乏有效的治疗策略。在此,我们假设纤维软骨可被视为透明软骨更新的原材料,并提出了一种此前未被发现的软骨再生策略,即“纤维软骨透明化”。细胞骨架重塑在改变细胞表型中起着至关重要的作用。我们发现多西他赛对微管的稳定作用可抑制软骨纤维化并增加透明软骨细胞外基质。我们进一步设计了一种靶向纤维软骨的带负电荷的热敏水凝胶,用于持续递送多西他赛,该水凝胶在软骨缺损模型中促进了纤维软骨透明化。此外,通过微管稳定实现纤维软骨透明化的机制被证实是抑制Sparc(富含半胱氨酸的酸性分泌蛋白)。总之,我们的研究表明,针对关节纤维软骨的原位治疗是一种有前景的透明软骨修复策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/2f1b865158a7/sciadv.abn8420-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/3b4a521ceb38/sciadv.abn8420-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/9f40a40add18/sciadv.abn8420-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/8e7c3751b5be/sciadv.abn8420-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/a26b2aae94d1/sciadv.abn8420-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/f2c19ac342d4/sciadv.abn8420-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/624c8f95e812/sciadv.abn8420-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/f303651f5931/sciadv.abn8420-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/2f1b865158a7/sciadv.abn8420-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/3b4a521ceb38/sciadv.abn8420-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/9f40a40add18/sciadv.abn8420-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/8e7c3751b5be/sciadv.abn8420-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/a26b2aae94d1/sciadv.abn8420-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/f2c19ac342d4/sciadv.abn8420-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/624c8f95e812/sciadv.abn8420-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/f303651f5931/sciadv.abn8420-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0aeb/9674280/2f1b865158a7/sciadv.abn8420-f8.jpg

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本文引用的文献

[1]
Microtubule Stabilization Enhances the Chondrogenesis of Synovial Mesenchymal Stem Cells.

Front Cell Dev Biol. 2021-10-20

[2]
Microtubule acetylation: A reading key to neural physiology and degeneration.

Neurosci Lett. 2021-6-11

[3]
Load-induced regulation of tendon homeostasis by SPARC, a genetic predisposition factor for tendon and ligament injuries.

Sci Transl Med. 2021-2-24

[4]
The Role of Fibrosis in Osteoarthritis Progression.

Life (Basel). 2020-12-23

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Fibroblast growth factor signalling in osteoarthritis and cartilage repair.

Nat Rev Rheumatol. 2020-10

[6]
Efficacy and Safety of Pembrolizumab Plus Docetaxel vs Docetaxel Alone in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer: The PROLUNG Phase 2 Randomized Clinical Trial.

JAMA Oncol. 2020-6-1

[7]
Rethinking articular cartilage regeneration based on a 250-year-old statement.

Nat Rev Rheumatol. 2019-10

[8]
The Role of Chondrocyte Morphology and Volume in Controlling Phenotype-Implications for Osteoarthritis, Cartilage Repair, and Cartilage Engineering.

Curr Rheumatol Rep. 2019-6-15

[9]
Advances of injectable hydrogel-based scaffolds for cartilage regeneration.

Regen Biomater. 2019-6

[10]
Articular fibrocartilage - Why does hyaline cartilage fail to repair?

Adv Drug Deliv Rev. 2018-12-31

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