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Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in
K Nishida1, T Matsushita1, K Takayama1
1Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho Chuo-ku, Kobe, Hyogo 6500017, Japan.
Objectives:
This study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model.
Methods:
Osteoarthritis was surgically induced by destabilization of the medial meniscus in eight-week-old C57BL/6 male mice. SRT1720 was administered intraperitoneally twice a week after surgery. Osteoarthritis progression was evaluated histologically using the Osteoarthritis Research Society International (OARSI) score at four, eight, 12 and 16 weeks. The expression of SIRT1, matrix metalloproteinase 13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), cleaved caspase-3, PARP p85, and acetylated nuclear factor (NF)-κB p65 in cartilage was examined by immunohistochemistry. Synovitis was also evaluated histologically. Primary mouse epiphyseal chondrocytes were treated with SRT1720 in the presence or absence of interleukin 1 beta (IL-1β), and gene expression changes were examined by real-time polymerase chain reaction (PCR).
Results:
The OARSI score was significantly lower in mice treated with SRT1720 than in control mice at eight and 12 weeks associated with the decreased size of osteophytes at four and eight weeks. The delayed OA progression in the mice treated with SRT1720 was also associated with increased SIRT1-positive chondrocytes and decreased MMP-13-, ADAMTS-5-, cleaved caspase-3-, PARP p85-, and acetylated NF-κB p65-positive chondrocytes and decreased synovitis at four and eight weeks. SRT1720 treatment partially rescued the decreases in collagen type II alpha 1 (COL2A1) and aggrecan caused by IL-1β, while also reducing the induction of MMP-13 by IL-1β in vitro.
Conclusion:
The intraperitoneal injection of SRT1720 attenuated experimental OA progression in mice, indicating that SRT1720 could be a new therapeutic approach for OA.Cite this article: K. Nishida, T. Matsushita, K. Takayama, T. Tanaka, N. Miyaji, K. Ibaraki, D. Araki, N. Kanzaki, T. Matsumoto, R. Kuroda. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. Bone Joint Res 2018;7:252-262. DOI: 10.1302/2046-3758.73.BJR-2017-0227.R1.
Insights
SRT1720, a SIRT1 activator, significantly slowed osteoarthritis progression in mice by reducing cartilage degradation and inflammation. This suggests SRT1720 holds promise as a novel therapeutic for osteoarthritis.
Area of Science:
- Biomedical research
- Pharmacology
- Orthopedics
Background:
- Osteoarthritis (OA) is a degenerative joint disease with limited treatment options.
- Sirtuin 1 (SIRT1) plays a role in cartilage homeostasis and inflammation.
- SRT1720 is a potent activator of SIRT1.
Purpose of the Study:
- To investigate the therapeutic potential of SRT1720 in an experimental model of osteoarthritis.
- To evaluate the effects of SRT1720 on OA progression and underlying molecular mechanisms.
Main Methods:
- Surgically induced osteoarthritis in C57BL/6 mice.
- Intraperitoneal administration of SRT1720.
- Histological evaluation of OA using OARSI scores and assessment of molecular markers (SIRT1, MMP-13, ADAMTS-5, cleaved caspase-3, PARP p85, acetylated NF-κB p65) and synovitis.
- In vitro study using primary chondrocytes treated with IL-1β and SRT1720.
Main Results:
- SRT1720 treatment significantly reduced OARSI scores and osteophyte size.
- SRT1720 increased SIRT1 expression and decreased markers of cartilage degradation, apoptosis, and inflammation.
- In vitro, SRT1720 partially restored collagen type II alpha 1 (COL2A1) and aggrecan expression and reduced MMP-13 induction.
Conclusions:
- Intraperitoneal administration of SRT1720 effectively attenuated experimental osteoarthritis progression in mice.
- SRT1720 demonstrates potential as a novel therapeutic agent for osteoarthritis treatment.
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