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Local delivery of OSK factors enables partial cellular reprogramming to mitigate osteoarthritis and cartilage fibrosis.

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Τίτλος: Local delivery of OSK factors enables partial cellular reprogramming to mitigate osteoarthritis and cartilage fibrosis.
Συγγραφείς: Liu YW; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China., Zou JT; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China., Gong JS; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China., Jin L; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China., Cao J; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China.; Department of Neurology, Xiangya Hospital, Central South University, Changsha, China., He ZH; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China., Qian YX; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China., Wang X; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China., Wan MD; National Clinical Research Center for Geriatric Disease, Xiangya Hospital, Changsha, China., Hu XY; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China.; Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China., Hong CG; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China., Du W; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China.; National Clinical Research Center for Geriatric Disease, Xiangya Hospital, Changsha, China., Chen CY; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China.; Hunan Key Laboratory of Angmedicine, Changsha, China.; National Clinical Research Center for Geriatric Disease, Xiangya Hospital, Changsha, China., Liu HJ; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China. liuhongji@hnu.edu.cn.; Hunan Key Laboratory of Angmedicine, Changsha, China. liuhongji@hnu.edu.cn., Xie H; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China. huixie@csu.edu.cn.; Hunan Key Laboratory of Angmedicine, Changsha, China. huixie@csu.edu.cn.; National Clinical Research Center for Geriatric Disease, Xiangya Hospital, Changsha, China. huixie@csu.edu.cn., Wang ZX; Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China. wangzx@csu.edu.cn.; Hunan Key Laboratory of Angmedicine, Changsha, China. wangzx@csu.edu.cn.; National Clinical Research Center for Geriatric Disease, Xiangya Hospital, Changsha, China. wangzx@csu.edu.cn.
Πηγή: Experimental & molecular medicine [Exp Mol Med] 2026 Mar; Vol. 58 (3), pp. 782-797. Date of Electronic Publication: 2026 Mar 05.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 9607880 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2092-6413 (Electronic) Linking ISSN: 12263613 NLM ISO Abbreviation: Exp Mol Med Subsets: MEDLINE
Imprint Name(s): Publication: Jan. 2013- : New York : Nature Publishing Group
Original Publication: Seoul : Korean Society of Medical Biochemistry and Molecular Biology, 1996-
Ιατρικοί όροι (MeSH): Osteoarthritis*/therapy , Osteoarthritis*/pathology , Osteoarthritis*/metabolism , Osteoarthritis*/genetics , Osteoarthritis*/etiology , Cellular Reprogramming*/genetics , Kruppel-Like Transcription Factors*/genetics , Kruppel-Like Transcription Factors*/metabolism , SOXB1 Transcription Factors*/genetics , SOXB1 Transcription Factors*/metabolism , Cartilage*/pathology , Cartilage*/metabolism, Chondrocytes/metabolism ; Dependovirus/genetics ; Genetic Vectors/genetics ; Genetic Vectors/administration & dosage ; Animals ; Mice ; Kruppel-Like Factor 4 ; Fibrosis ; Humans ; Male ; Disease Models, Animal ; Cell Differentiation
Περίληψη: Osteoarthritis (OA) is a prevalent joint disease with a complex etiology, involving epigenetic alterations. Recent studies have suggested the potential of Oct4, Sox2 and Klf4 (OSK) in rejuvenating adult cells and facilitating tissue repair, but their specific role in OA pathophysiology and treatment remains unclear. Here we employed an adeno-associated virus (AAV) vector to achieve ectopic expression of OSK (AAV-OSK). Chondrocytes expressing OSK retained chondrocyte-specific markers with no increase in stemness-associated genes. AAV-OSK significantly preserved chondrocyte vitality in an inflammatory environment and counteracted the upregulation of osteogenic genes during OG differentiation. In OA murine models, AAV-OSK administration led to a notable improvement in cartilage integrity, a reduction in subchondral bone thickening and promoted the hyalinization of fibrocartilage. Furthermore, chondrocyte senescence and DNA methyltransferase expression were markedly diminished in the AAV-OSK group. Tet methylcytosine dioxygenase 2 was identified as a pivotal factor underlying the benefits of OSK-driven cartilage regeneration. Collectively, our study underscores that OSK expression within the knee joint modulates epigenetic alterations, mitigating OA progression and cartilage fibrosis through partial reprogramming, highlighting its therapeutic promise for comprehensive OA intervention.
(© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests.
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Grant Information: 82125023 National Natural Science Foundation of China (National Science Foundation of China); 82272562 National Natural Science Foundation of China (National Science Foundation of China)
Substance Nomenclature: 0 (Kruppel-Like Factor 4)
0 (Klf4 protein, mouse)
0 (Kruppel-Like Transcription Factors)
0 (SOXB1 Transcription Factors)
Entry Date(s): Date Created: 20260305 Date Completed: 20260710 Latest Revision: 20260813
Update Code: 20260813
PubMed Central ID: PMC13049178
DOI: 10.1038/s12276-026-01662-x
PMID: 41786976
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2092-6413
DOI:10.1038/s12276-026-01662-x