title: Intra-articular transplantation of atsttrin-transduced mesenchymal stem cells ameliorate osteoarthritis development.
abstract: Osteoarthritis (OA) remains an intractable clinical challenge. Few drugs are available for reversing this degenerative disease, although some promising candidates have performed well in preclinical studies. Tumor necrosis factor α (TNFα) has been identified as a crucial effector modulating OA pathogenesis. This study aimed to investigate the therapeutic effects of Atsttrin, a novel TNFα blocker, on OA treatment. We developed genetically modified mesenchymal stem cells (MSCs) that expressed recombinant Atsttrin (named as MSC-Atsttrin). Expression levels of ADAMTS-5, MMP13, and iNOS of human chondrocytes were analyzed when cocultured with MSC-GFP/Atsttrin. OA animal models were induced by anterior cruciate ligament transection, and MSC-GFP/Atsttrin were injected into the articular cavity 1 week postsurgery. The results showed that MSC-Atsttrin significantly suppressed TNFα-driven up-regulation of matrix proteases and inflammatory factors. Intra-articular injection of MSC-Atsttrin prevented the progression of degenerative changes in the surgically induced OA mouse model. Additionally, levels of detrimental matrix hydrolases were significantly diminished. Compared with nontreated OA samples at 8 weeks postsurgery, the percentages of MMP13- and ADAMTS-5-positive cells were significantly reduced from 91.33% ± 9.87% to 24.33% ± 5.7% (p < .001) and from 91.33% ± 7.1% to 16.67% ± 3.1% (p < .001), respectively. Our results thus indicated that suppression of TNFα activity is an effective strategy for OA treatment and that intra-articular injection of MSCs-Atsttrin could be a promising therapeutic modality.
authors.affiliation: Center for Stem Cells and Tissue Engineering, School of Medicine, Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Department of Orthopedics, the First Affiliated Hospital, College of Medicine, and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Biosystems Science & Engineering, ETH-Zurich, Basel, Switzerland.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Center for Stem Cells and Tissue Engineering, School of Medicine, Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Department of Orthopedics, the First Affiliated Hospital, College of Medicine, and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Biosystems Science & Engineering, ETH-Zurich, Basel, Switzerland.
authors.forename: Shouan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Center for Stem Cells and Tissue Engineering, School of Medicine, Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Department of Orthopedics, the First Affiliated Hospital, College of Medicine, and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Biosystems Science & Engineering, ETH-Zurich, Basel, Switzerland.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Center for Stem Cells and Tissue Engineering, School of Medicine, Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Department of Orthopedics, the First Affiliated Hospital, College of Medicine, and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Biosystems Science & Engineering, ETH-Zurich, Basel, Switzerland.
authors.forename: Jiaqiu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Stem Cells and Tissue Engineering, School of Medicine, Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Department of Orthopedics, the First Affiliated Hospital, College of Medicine, and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Biosystems Science & Engineering, ETH-Zurich, Basel, Switzerland.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Center for Stem Cells and Tissue Engineering, School of Medicine, Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Department of Orthopedics, the First Affiliated Hospital, College of Medicine, and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Biosystems Science & Engineering, ETH-Zurich, Basel, Switzerland.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Chen
authors.affiliation: Center for Stem Cells and Tissue Engineering, School of Medicine, Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Department of Orthopedics, the First Affiliated Hospital, College of Medicine, and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Biosystems Science & Engineering, ETH-Zurich, Basel, Switzerland.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Stem Cells and Tissue Engineering, School of Medicine, Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Department of Orthopedics, the First Affiliated Hospital, College of Medicine, and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Biosystems Science & Engineering, ETH-Zurich, Basel, Switzerland.
authors.forename: Boon Chin
authors.initials: BC
authors.lastname: Heng
authors.affiliation: Center for Stem Cells and Tissue Engineering, School of Medicine, Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Department of Orthopedics, the First Affiliated Hospital, College of Medicine, and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Biosystems Science & Engineering, ETH-Zurich, Basel, Switzerland hwoy@zju.edu.cn lupingzju@zju.edu.cn.
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Ouyang
authors.affiliation: Center for Stem Cells and Tissue Engineering, School of Medicine, Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Department of Orthopedics, the First Affiliated Hospital, College of Medicine, and College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China; Department of Biosystems Science & Engineering, ETH-Zurich, Basel, Switzerland hwoy@zju.edu.cn lupingzju@zju.edu.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
mesh_terms: D000818:Animals; D064987:Cell- and Tissue-Based Therapy; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007270:Injections, Intra-Articular; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D010003:Osteoarthritis / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C557987:Atsttrin fusion protein; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha
keywords: Atsttrin; Coculture; Mesenchymal stem cells; Osteoarthritis; TNFα
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