Academic Journal
HMGCR-Driven Cholesterol Metabolism Promotes Osteoarthritis Progression by Accelerating Synovial Fibroblast Senescence.
| Τίτλος: | HMGCR-Driven Cholesterol Metabolism Promotes Osteoarthritis Progression by Accelerating Synovial Fibroblast Senescence. |
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| Συγγραφείς: | Zhang X; Department of Rehabilitation Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Zhou S; War Trauma Medical Center, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical Center, Daping Hospital, Army Medical University, Chongqing, China., Liu X; Department of Otorhinolaryngology and Maxillofacial Surgery, The 988th Hospital of the Joint Logistics Support Force, Zhengzhou, China., Xiang W; Department of Rehabilitation Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Peng X; Metabolism and Repair, Laboratory For Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma and Chemical Poisoning, Trauma Center, Research Institute of Surgery, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Tian Y; Metabolism and Repair, Laboratory For Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma and Chemical Poisoning, Trauma Center, Research Institute of Surgery, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Li S; Metabolism and Repair, Laboratory For Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma and Chemical Poisoning, Trauma Center, Research Institute of Surgery, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Wang H; Metabolism and Repair, Laboratory For Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma and Chemical Poisoning, Trauma Center, Research Institute of Surgery, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Liao B; Department of Rehabilitation Medicine, Key Laboratory of Physical Medicine and Precision Rehabilitation of Chongqing Municipal Health Commission, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China., Fang S; Department of Emergency Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Jin R; Department of Rehabilitation Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Wu J; Department of Rehabilitation Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Bai C; Department of Rehabilitation Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Zhang W; Department of Rehabilitation Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Huang B; Department of Rehabilitation Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Li B; Department of Rehabilitation Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Chen L; Department of Rehabilitation Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Chen L; Metabolism and Repair, Laboratory For Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma and Chemical Poisoning, Trauma Center, Research Institute of Surgery, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China., Zhang B; Metabolism and Repair, Laboratory For Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma and Chemical Poisoning, Trauma Center, Research Institute of Surgery, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China.; Rehabilitation Center, Key Specialty of Neck and Low Back Pain Rehabilitation, Xingcheng Special Duty Sanatorium, Xingcheng, China., Ni Z; Department of Rehabilitation Medicine, Army Medical Center, Daping Hospital, Army Medical University of PLA, Chongqing, China. |
| Πηγή: | Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2026 Oct; Vol. 13 (55), pp. e76498. Date of Electronic Publication: 2026 Jul 13. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Weinheim : WILEY-VCH, [2014]- |
| Ιατρικοί όροι (MeSH): | Cellular Senescence*/genetics , Cellular Senescence*/physiology , Fibroblasts*/metabolism , Fibroblasts*/pathology , Synovial Membrane*/metabolism , Synovial Membrane*/pathology , Cholesterol*/metabolism , Hydroxymethylglutaryl CoA Reductases*/metabolism , Hydroxymethylglutaryl CoA Reductases*/genetics , Osteoarthritis*/metabolism , Osteoarthritis*/pathology , Osteoarthritis*/genetics, Animals ; Humans ; Mice ; Disease Progression ; Male ; Disease Models, Animal |
| Περίληψη: | Dysregulated cholesterol metabolism has been implicated in several aging-associated disorders, including osteoarthritis (OA). 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the key enzyme in cholesterol biosynthesis, but the role of HMGCR in OA and the underlying mechanism remain unclear. In this study, we found that HMGCR+ fibroblasts (FLSs) were significantly increased in the knee synovium of OA patients and OA mice. Elevated expression of HMGCR in synovial FLSs was positively correlated with cellular senescence and OA progression. The inhibition of HMGCR reversed cellular senescence of FLSs induced by TNF-α in vitro. Additionally, the HMGCR-mediated cholesterol biosynthetic pathway contributed to cellular senescence. Targeted inhibition of HMGCR in synovial FLSs via intra-articular adeno-associated virus delivery effectively reversed cellular senescence of FLSs and mitigated synovitis, cartilage degradation, and pain behaviors in OA mice. Mechanistically, the phosphorylation of AKT1 at Ser473 enhanced its binding to Lys140 of Insig1, facilitating AKT1-Insig1 complex formation. The activation of AKT1 induced the phosphorylation of Insig1 at Ser189 and the dissociation of Insig1 from sterol regulatory element‑binding protein cleavage‑activating protein (SCAP), which contributed to HMGCR transcription and cellular senescence of FLSs. Collectively, our study reveals a novel mechanism of HMGCR-driven cellular senescence of FLSs in OA, which highlights HMGCR as a promising therapeutic target for OA. (© 2026 The Author(s). Advanced Science published by Wiley‐VCH GmbH.) |
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| Grant Information: | 82394444 82572843 82372495 National Natural Science Foundation of China; CSTB2024NSCQ-JQX0019 Natural Science Foundation of Chongqing; 2024DBXM008 Chongqing Medical Scientific Research Project (Joint project of Chongqing Municipal Health Commission and Chongqing Science and Technology Commission) |
| Contributed Indexing: | Keywords: HMGCR; cellular senescence; osteoarthritis; synovial fibroblast |
| Substance Nomenclature: | 97C5T2UQ7J (Cholesterol) EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases) EC 1.1.1.- (HMGCR protein, human) |
| Entry Date(s): | Date Created: 20260713 Date Completed: 20261005 Latest Revision: 20261005 |
| Update Code: | 20261005 |
| PubMed Central ID: | PMC13360124 |
| DOI: | 10.1002/advs.76498 |
| PMID: | 42439400 |
| Βάση Δεδομένων: | MEDLINE |
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