Academic Journal
Local delivery of OSK factors enables partial cellular reprogramming to mitigate osteoarthritis and cartilage fibrosis.
| Title: | Local delivery of OSK factors enables partial cellular reprogramming to mitigate osteoarthritis and cartilage fibrosis. |
|---|---|
| Authors: | 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. |
| Source: | Experimental & molecular medicine [Exp Mol Med] 2026 Mar; Vol. 58 (3), pp. 782-797. Date of Electronic Publication: 2026 Mar 05. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | 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- |
| MeSH Terms: | 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 |
| Abstract: | 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. |
| References: | Mahmoudian, A., Lohmander, L. S., Mobasheri, A., Englund, M. & Luyten, F. P. Early-stage symptomatic osteoarthritis of the knee—time for action. Nat. Rev. Rheumatol. 17, 621–632 (2021). (PMID: 3446590210.1038/s41584-021-00673-4) Katz, J. N., Arant, K. R. & Loeser, R. F. Diagnosis and treatment of hip and knee osteoarthritis: a review. JAMA 325, 568–578 (2021). (PMID: 33560326822529510.1001/jama.2020.22171) Li, J. et al. Articular fibrocartilage-targeted therapy by microtubule stabilization. Sci. Adv. https://doi.org/10.1126/sciadv.abn8420 (2022). (PMID: 10.1126/sciadv.abn84203656316411809618) Coryell, P. R., Diekman, B. O. & Loeser, R. F. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat. Rev. Rheumatol. 17, 47–57 (2021). (PMID: 3320891710.1038/s41584-020-00533-7) Makris, E. A., Gomoll, A. H., Malizos, K. N., Hu, J. C. & Athanasiou, K. A. Repair and tissue engineering techniques for articular cartilage. Nat. Rev. Rheumatol. 11, 21–34 (2015). (PMID: 2524741210.1038/nrrheum.2014.157) Armiento, A. R., Alini, M. & Stoddart, M. J. Articular fibrocartilage—why does hyaline cartilage fail to repair? Adv. Drug Deliv. Rev. 146, 289–305 (2019). (PMID: 3060573610.1016/j.addr.2018.12.015) Liu, Q. et al. DDX5 inhibits hyaline cartilage fibrosis and degradation in osteoarthritis via alternative splicing and G-quadruplex unwinding. Nat. Aging 4, 664–680 (2024). (PMID: 387605761110878610.1038/s43587-024-00624-0) Jones, I. A., Togashi, R., Wilson, M. L., Heckmann, N. & Vangsness, C. T. Jr Intra-articular treatment options for knee osteoarthritis. Nat. Rev. Rheumatol. 15, 77–90 (2019). (PMID: 30498258639084310.1038/s41584-018-0123-4) Tuesta, L. M. & Zhang, Y. Mechanisms of epigenetic memory and addiction. EMBO J. 33, 1091–1103 (2014). (PMID: 24778453419391710.1002/embj.201488106) Grandi, F. C. & Bhutani, N. Epigenetic therapies for osteoarthritis. Trends Pharmacol. Sci. 41, 557–569 (2020). (PMID: 325866531062199710.1016/j.tips.2020.05.008) Núñez-Carro, C., Blanco-Blanco, M., Villagrán-Andrade, K. M., Blanco, F. J. & de Andrés, M. C. Epigenetics as a therapeutic target in osteoarthritis. Pharmaceuticals https://doi.org/10.3390/ph16020156 (2023). Kiełbowski, K. et al. The role of genetics and epigenetic regulation in the pathogenesis of osteoarthritis. Int. J. Mol. Sci. https://doi.org/10.3390/ijms241411655 (2023). Rice, S. J., Beier, F., Young, D. A. & Loughlin, J. Interplay between genetics and epigenetics in osteoarthritis. Nat. Rev. Rheumatol. 16, 268–281 (2020). Fathollahi, A., Aslani, S., Jamshidi, A. & Mahmoudi, M. Epigenetics in osteoarthritis: novel spotlight. J. Cell Physiol. 234, 12309–12324 (2019). (PMID: 3065962310.1002/jcp.28020) Miranda-Duarte, A. DNA methylation in osteoarthritis: current status and therapeutic implications. Open Rheumatol. J. 12, 37–49 (2018). (PMID: 29682093588546910.2174/1874312901812010037) Zhu, X. et al. PPARgamma preservation via promoter demethylation alleviates osteoarthritis in mice. Ann. Rheum. Dis. 78, 1420–1429 (2019). (PMID: 3123924410.1136/annrheumdis-2018-214940) Thampi, P. et al. Gene therapy approaches for equine osteoarthritis. Front. Vet. Sci. https://doi.org/10.3389/fvets.2022.962898 (2022). (PMID: 10.3389/fvets.2022.962898366861739558289) Wang, H., Yang, Y., Liu, J. & Qian, L. Direct cell reprogramming: approaches, mechanisms and progress. Nat. Rev. Mol. Cell Biol. 22, 410–424 (2021). (PMID: 33619373816151010.1038/s41580-021-00335-z) Shi, Y. et al. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3, 568–574 (2008). (PMID: 1898397010.1016/j.stem.2008.10.004) Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). (PMID: 1690417410.1016/j.cell.2006.07.024) Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, 1719–1733.e1712 (2016). (PMID: 27984723567927910.1016/j.cell.2016.11.052) Abad, M. et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature 502, 340–345 (2013). (PMID: 2402577310.1038/nature12586) Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020). (PMID: 33268865775213410.1038/s41586-020-2975-4) Yang, J. H. et al. Loss of epigenetic information as a cause of mammalian aging. Cell 186, 305–326.e327 (2023). (PMID: 366387921016613310.1016/j.cell.2022.12.027) Cheng, F. et al. Partial reprogramming strategy for intervertebral disc rejuvenation by activating energy switch. Aging Cell https://doi.org/10.1111/acel.13577 (2022). (PMID: 10.1111/acel.13577362545839741512) Hollander, J. M. et al. Single injection AAV2–FGF18 gene therapy reduces cartilage loss and subchondral bone damage in a mechanically induced model of osteoarthritis. Curr. Gene Ther. 24, 331–345 (2024). (PMID: 3878353110.2174/0115665232275532231213063634) Gosset, M., Berenbaum, F., Thirion, S. & Jacques, C. Primary culture and phenotyping of murine chondrocytes. Nat. Protoc. 3, 1253–1260 (2008). (PMID: 1871429310.1038/nprot.2008.95) Jin, Y. et al. A novel prostaglandin E receptor 4 (EP4) small molecule antagonist induces articular cartilage regeneration. Cell Discov. 8, 24 (2022). (PMID: 35256606890174810.1038/s41421-022-00382-6) Glasson, S. S., Blanchet, T. J. & Morris, E. A. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 15, 1061–1069 (2007). (PMID: 1747040010.1016/j.joca.2007.03.006) Akagi, R. et al. Effective knock down of matrix metalloproteinase-13 by an intra-articular injection of small interfering RNA (siRNA) in a murine surgically-induced osteoarthritis model. J. Orthop. Res. 32, 1175–1180 (2014). (PMID: 2484843910.1002/jor.22654) Liu, Z. et al. ALS-associated E478G mutation in human OPTN (Optineurin) promotes inflammation and induces neuronal cell death. Front. Immunol. https://doi.org/10.3389/fimmu.2018.02647 (2018). Glasson, S. S., Chambers, M. G., Van Den Berg, W. B. & Little, C. B. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis Cartilage 18, S17–S23 (2010). (PMID: 2086401910.1016/j.joca.2010.05.025) Kanehisa, M. et al. KEGG for linking genomes to life and the environment. Nucleic Acids Res. 36, D480–D484 (2008). (PMID: 1807747110.1093/nar/gkm882) Petkovich, D. A. et al. Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab. 25, 954–960.e956 (2017). (PMID: 28380383557845910.1016/j.cmet.2017.03.016) Ye, X. et al. α-Ketoglutarate ameliorates age-related and surgery induced temporomandibular joint osteoarthritis via regulating IKK/NF-κB signaling. Aging Cell https://doi.org/10.1111/acel.14269 (2024). (PMID: 10.1111/acel.142693955254011896485) Allègre, N. et al. NANOG initiates epiblast fate through the coordination of pluripotency genes expression. Nat. Commun. 13, 3550 (2022). (PMID: 35729116921355210.1038/s41467-022-30858-8) Bradley, P. X. et al. The interplay of biomechanical and biological changes following meniscus injury. Curr. Rheumatol. Rep. 25, 35–46 (2023). (PMID: 3647966910.1007/s11926-022-01093-3) Robinson, W. H. et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 580–592 (2016). (PMID: 27539668550021510.1038/nrrheum.2016.136) Chow, Y. Y. & Chin, K. Y. The role of inflammation in the pathogenesis of osteoarthritis. Mediators Inflamm. https://doi.org/10.1155/2020/8293921 (2020). (PMID: 10.1155/2020/8293921321899977072120) Charlier, E. et al. Chondrocyte dedifferentiation and osteoarthritis (OA). Biochem. Pharmacol. 165, 49–65 (2019). (PMID: 3085339710.1016/j.bcp.2019.02.036) Coaccioli, S., Sarzi-Puttini, P., Zis, P., Rinonapoli, G. & Varrassi, G. Osteoarthritis: new insight on its pathophysiology. J. Clin. Med. https://doi.org/10.3390/jcm11206013 (2022). Lin, C. et al. Activation of mTORC1 in subchondral bone preosteoblasts promotes osteoarthritis by stimulating bone sclerosis and secretion of CXCL12. Bone Res. 7, 5 (2019). (PMID: 30792936638118710.1038/s41413-018-0041-8) Catheline, S. E. et al. Chondrocyte-specific RUNX2 overexpression accelerates post-traumatic osteoarthritis progression in adult mice. J. Bone Miner. Res. 34, 1676–1689 (2019). (PMID: 31189030704761110.1002/jbmr.3737) Ansari, M. M., Ghosh, M., Lee, D. S. & Son, Y. O. Senolytic therapeutics: an emerging treatment modality for osteoarthritis. Ageing Res. Rev. https://doi.org/10.1016/j.arr.2024.102275 (2024). (PMID: 10.1016/j.arr.2024.10227538762102) Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018). (PMID: 2964344310.1038/s41576-018-0004-3) Stubbs, T. M. et al. Multi-tissue DNA methylation age predictor in mouse. Genome Biol. 18, 68 (2017). (PMID: 28399939538917810.1186/s13059-017-1203-5) Parras, A. et al. In vivo reprogramming leads to premature death linked to hepatic and intestinal failure. Nat. Aging 3, 1509–1520 (2023). (PMID: 3801228710.1038/s43587-023-00528-5) Rand, T. A. et al. MYC releases early reprogrammed human cells from proliferation pause via retinoblastoma protein inhibition. Cell Rep. 23, 361–375 (2018). (PMID: 29641997824122310.1016/j.celrep.2018.03.057) Wolpaw, A. J. & Dang, C. V. MYC-induced metabolic stress and tumorigenesis. Biochim. Biophys. Acta Rev. Cancer 1870, 43–50 (2018). (PMID: 2979187010.1016/j.bbcan.2018.05.003) Gao, H. et al. Identification of chondrocyte subpopulations in osteoarthritis using single-cell sequencing analysis. Gene https://doi.org/10.1016/j.gene.2022.147063 (2023). (PMID: 10.1016/j.gene.2022.1470633807078910370284) Skalny, A. V. et al. Molecular mechanisms of environmental pollutant-induced cartilage damage: from developmental disorders to osteoarthritis. Arch. Toxicol. 98, 2763–2796 (2024). (PMID: 3875840710.1007/s00204-024-03772-9) Jouan, Y. et al. Lin28a induces SOX9 and chondrocyte reprogramming via HMGA2 and blunts cartilage loss in mice. Sci. Adv. https://doi.org/10.1126/sciadv.abn3106 (2022). (PMID: 10.1126/sciadv.abn3106360264439417174) Hall, A. C. The role of chondrocyte morphology and volume in controlling phenotype-implications for osteoarthritis, cartilage repair, and cartilage engineering. Curr. Rheumatol. Rep. 21, 38 (2019). (PMID: 31203465657108210.1007/s11926-019-0837-6) Cai, Z., Long, T., Zhao, Y., Lin, R. & Wang, Y. Epigenetic regulation in knee osteoarthritis. Front. Genet. https://doi.org/10.3389/fgene.2022.942982 (2022). Shen, J. et al. DNA methyltransferase 3b regulates articular cartilage homeostasis by altering metabolism. JCI Insight https://doi.org/10.1172/jci.insight.93612 (2017). Smeriglio, P. et al. Inhibition of TET1 prevents the development of osteoarthritis and reveals the 5hmC landscape that orchestrates pathogenesis. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aax2332 (2020). Ohnishi, K. et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell 156, 663–677 (2014). (PMID: 2452937210.1016/j.cell.2014.01.005) Barbier, A. J., Jiang, A. Y., Zhang, P., Wooster, R. & Anderson, D. G. The clinical progress of mRNA vaccines and immunotherapies. Nat. Biotechnol. 40, 840–854 (2022). (PMID: 3553455410.1038/s41587-022-01294-2) Pupo, A. et al. AAV vectors: the Rubik’s cube of human gene therapy. Mol. Ther. 30, 3515–3541 (2022). (PMID: 36203359973403110.1016/j.ymthe.2022.09.015) |
| 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: 20260710 |
| Update Code: | 20260711 |
| PubMed Central ID: | PMC13049178 |
| DOI: | 10.1038/s12276-026-01662-x |
| PMID: | 41786976 |
| Database: | MEDLINE |
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