Kartogenin hydrolysis product 4-aminobiphenyl distributes to cartilage and mediates cartilage regeneration
| Autor: | Peilin Hu, Di Chen, Mo Cuiping, Jinqi Liao, Rana Hamid, Yong-Can Huang, Mauro Alini, Tao Liu, Shuai Zhang, Liru Wen, Sibylle Grad, Ting Wang, Zhen Li, Tianfu Wang, Guangqian Zhou |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male genetic structures Medicine (miscellaneous) Administration Oral 02 engineering and technology Osteoarthritis 4-aminobiphenyl Mice Phosphatidylinositol 3-Kinases RPS6KA2 Aminobiphenyl Compounds Anilides Tissue Distribution Pharmacology Toxicology and Pharmaceutics (miscellaneous) biology Chemistry Hydrolysis Cell Differentiation 021001 nanoscience & nanotechnology Cell biology medicine.anatomical_structure Stem cell 0210 nano-technology Chondrogenesis kartogenin Research Paper Signal Transduction Phthalic Acids 03 medical and health sciences stem cells Antigens CD medicine Animals Humans Regeneration Meniscus Cell Proliferation Cartilage CD44 Mesenchymal stem cell Mesenchymal Stem Cells Endoglin medicine.disease In vitro osteoarthritis 030104 developmental biology biology.protein Proto-Oncogene Proteins c-akt |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | Rationale The small molecule Kartogenin (KGN) promotes cartilage regeneration in osteoarthritis (OA) by activating stem cells differentiation, but its pharmacological mode-of-action remains unclear. KGN can be cleaved into 4-aminobiphenyl (4-ABP) and phthalic acid (PA) following enzymolysis of an amide bond. Therefore, this study investigated whether 4-ABP or PA exerted the same action as KGN. Methods KGN, 4-ABP and PA were analyzed in cartilage of mice after oral, intravenous or intra-articular administration of KGN by liquid chromatography-mass spectrometry method. Their effect on proliferation and chondrogenic differentiation of mesenchymal stem cells (MSC) was evaluated in vitro. Furthermore, their effect on cartilage preservation was tested in mice OA model induced by destabilization of medial meniscus. OA severity was quantified using OARSI histological scoring. Transcriptional analysis was used to find the possible targets of the chemicals, which were further validated. Results We demonstrated that while oral or intra-articular KGN delivery effectively ameliorated OA phenotypes in mice, only 4-ABP was detectable in cartilage. 4-ABP could induce chondrogenic differentiation and proliferation of MSC in vitro and promote cartilage repair in OA mouse models mainly by increasing the number of CD44+/CD105+ stem-cell and prevention of matrix loss. These effect of 4-ABP was stronger than that of KGN. Transcriptional profiling of 4-ABP-stimulated MSC suggested that RPS6KA2 and the PI3K-Akt pathway were 4-ABP targets; 4-ABP could activate the PI3K-Akt pathway to promote MSC proliferation and repair OA injury, which was blocked in RPS6KA2-knockdown MSC or RPS6KA2-deficient mice. Conclusion 4-ABP bio-distribution in cartilage promotes proliferation and chondrogenic differentiation of MSC, and repairs osteoarthritic lesions via PI3K-Akt pathway activation. |
| Databáze: | OpenAIRE |
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