Losartan protects against osteoarthritis by repressing the TGF-beta 1 signaling pathway via upregulation of PPAR gamma

Deng, Zhenhan1,2,3,4; Chen, Fei4; Liu, Yuwei1,4; Wang, Jinping4; Lu, Wei1,2,3,4; Jiang, Wei5,6; Zhu, Weimin1,2,3,4

2021-07-01

10.1016/j.jot.2021.03.005

Journal of Orthopaedic Translation   影响因子和分区

2214-031X

["Objective: Losartan and activation of the peroxisome proliferator-activated receptor-gamma (PPAR gamma) have been previously reported to alleviate the progression of osteoarthritis (OA). However, the nature of the interaction between losartan and PPAR gamma in OA remains elusive. Therefore, we aimed to investigate the mechanism of the regulation of PPAR gamma by losartan in the context of OA.","Methods: Clinical samples of OA patients were collected and the chondrocytes were further isolated, and used to construct OA chondrocyte model via induction with IL-1 beta. An OA mouse model was developed by the surgical destabilization of the medial meniscus (DMM). OA chondrocytes were treated with losartan, PPAR gamma siRNA and the PPAR-gamma agonist GW1929 alone or in combination. Furthermore, the OA mice were treated with varying doses of losartan to determine the best mode of administration and treatment dose. Subsequently, the DMM mice were treated with losartan and GW9662. Expression of PPAR gamma, key proteins of the transforming growth factor-beta1 (TGF-beta 1) signaling pathway and the markers of OA degeneration were evaluated by the Western blot analysis, while effects on OA inflammatory factors were determined by ELISA.","Results: The downregulation of PPAR gamma and the upregulation of TGF-beta 1 signaling pathway were detected in the OA cartilage tissues and chondrocytes. Losartan treatment or PPAR gamma activation contributes to reduced levels of IL-6, IL-1 beta, TNF-alpha, and COX-2, expression of TGF-beta 1, MMP-13, ADAMTS-4, ADAMTS-5, HtrA1, and iNOS, along with reduced Smad2 and Smad3 phosphorylation, but elevated PPAR gamma and Collagen II expression in vivo and in vitro. Additionally, the intraarticular injection of losartan into the knee joint proved to be the best mode of administration, and 10 mg/mL being the optimal treatment concentration.","Conclusion: Our results show that losartan could arrest the progression of OA by upregulating PPAR gamma expression and inactivating the TGF-beta 1 signaling pathway. The translational potential of this article: Our results provide a biological rationale for the use of losartan as a potential candidate for OA treatment."]

Osteoarthritis Losartan PPAR gamma TGF-beta 1 signaling pathway IL-1 beta

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英语

通讯

National Natural Science Foundation of China[81902303,81902233,81902558,81672234] ; Guangdong Basic and Applied Basic Research Foundation[2020A151501048] ; China Postdoctoral Science Foundation[2019M653080] ; Shenzhen Double Chain Project for Innovation and Development Industry by Bureau of Industry and Information Technology of Shenzhen[201806081524201510] ; Shenzhen Science and Technology Project["RCBS20200714114856299","JCYJ20190806164216661","GJHZ20180 416164801042","JCYJ20180305124912336"] ; Clinical Research Project of Shenzhen Second People's Hospital[20203357028,20203357007,20173357201814]

Orthopedics

Orthopedics

WOS:000684563000006

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Web of Science

1.Shenzhen Univ, Shenzhen Peoples Hosp 2, Dept Sports Med, Affiliated Hosp 1, Shenzhen 518035, Guangdong, Peoples R China
2.Shenzhen Univ, Clin Med Coll, Shenzhen 518000, Guangdong, Peoples R China
3.Guangzhou Med Univ, Guangzhou 510182, Guangdong, Peoples R China
4.Shenzhen Univ, Shenzhen Peoples Hosp Shenzhen 2, Shenzhen Key Lab Tissue Engn, Affiliated Hosp 1, Shenzhen 518035, Guangdong, Peoples R China
5.Shenzhen Peoples Hosp, Bone & Joint Dept, Dongmen North Rd, Shenzhen 518020, Guangdong, Peoples R China
6.Jinan Univ, Clin Med Coll 2, Affiliated Hosp 1, Southern Univ Sci & Technol, Shenzhen 518020, Guangdong, Peoples R China

Deng, Zhenhan,Chen, Fei,Liu, Yuwei,et al. Losartan protects against osteoarthritis by repressing the TGF-beta 1 signaling pathway via upregulation of PPAR gamma[J]. Journal of Orthopaedic Translation,2021,29.

Deng, Zhenhan.,Chen, Fei.,Liu, Yuwei.,Wang, Jinping.,Lu, Wei.,...&Zhu, Weimin.(2021).Losartan protects against osteoarthritis by repressing the TGF-beta 1 signaling pathway via upregulation of PPAR gamma.Journal of Orthopaedic Translation,29.

Deng, Zhenhan,et al."Losartan protects against osteoarthritis by repressing the TGF-beta 1 signaling pathway via upregulation of PPAR gamma".Journal of Orthopaedic Translation 29(2021).