Enhancement of the synthesis of n-3 PUFAs in<i>fat-1</i>transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice

Huang, Minjun; Wang, Liang; Jin, Dadi; Zhang, Zhongmin; Chen, Tianyu; Jia, Chunhong; Wang, Yan; Zhen, Xiaochen; Huang, Bin; Yan, Bo; Chen, Yuhui; Li, Shengfa; Yang, Jincheng; Dai, Yifan; Bai, Xia

doi:10.1136/annrheumdis-2013-203231

Cited by 72 publications

(57 citation statements)

References 30 publications

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“…While maintaining the same PUFA content, but altering ω-6 and ω-3 ratio in PUFA-rich high-fat diets, we found that the ω-6 mice developed severe OA and synovitis with elevated systemic inflammation. By contrast with ω-6 PUFAs, the beneficial effect of ω-3 PUFAs in OA and rheumatoid arthritis has been reported in animal models 8 18. However, most of these studies supplemented ω-3 PUFAs in regular chow (ie, low-fat diet) and, thus, the investigation of ω-3 PUFAs in the context of a high-fat diet is a novel aspect of this study.…”

Section: Discussionmentioning

confidence: 97%

Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury

et al. 2014

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Objective The mechanisms linking obesity and osteoarthritis (OA) are not fully understood and have been generally attributed to increased weight, rather than metabolic or inflammatory factors. Here, we examined the influence of dietary fatty acids, adipokines, and body weight following joint injury in mouse model of OA. Methods Mice were fed high-fat diets rich in various fatty acids (FAs) including saturated FAs (SFAs), ω-6 polyunsaturated FAs (PUFAs), and ω-3 PUFAs. OA was induced by destabilizing the medial meniscus. Wound healing was evaluated using an ear punch. OA, synovitis and wound healing were determined histologically, while bone changes were measured using microCT. Activity levels and serum cytokines were measured at various time-points. Multivariate models were performed to elucidate the associations of dietary, metabolic, and mechanical factors with OA and wound healing. Results Using weight-matched mice and multivariate models, we found that OA was significantly associated with dietary fatty acid content and serum adipokine levels, but not with body weight. Furthermore, spontaneous activity of the mice was independent of OA development. Small amounts of ω-3 PUFAs (8% by kcal) in a high-fat diet were sufficient to mitigate injury-induced OA, decreasing leptin and resistin levels. ω-3 PUFAs significantly enhanced wound repair, SFAs or ω-6 PUFAs independently increased OA severity, heterotopic ossification, and scar tissue formation. Conclusions Our results indicate that dietary FA content is a primary regulator of OA severity and wound regeneration with obesity, supporting the need for further studies of dietary FA supplements as a potential therapeutic approach for OA.

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Section: Discussionmentioning

confidence: 97%

Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury

et al. 2014

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“…25 5 weeks after surgery, articular cartilage was isolated, 26 and the expression of miR-483-5p was found to be significantly upregulated in DMM OA mice compared with that in sham-operated mice ( Figure 1D). These findings demonstrate that the upregulation of miR-483-5p in articular chondrocytes of patients and OA mice correlates with OA development.…”

Section: Mir-483-5p Expression Is Increased In the Cartilage Of Patiementioning

confidence: 99%

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

et al. 2017

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MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis (OA) pathogenesis. In our study, a real-time PCR assay revealed that miR-483-5p was upregulated in articular cartilage from OA patients and experimental OA mice induced by destabilization of the medial meniscus compared to their controls. Overexpression of miR-483-5p by intra-articular injection of lentivirus LV3-miR-483-5p significantly enhanced the severity of experimental OA. Consequently, we synthesized antago-miR-483-5p to silence the endogenous miR-483-5p and delivered it intra-articularly, which revealed that antagomiR-483-5p delayed the progression of experimental OA. To investigate the functional mechanism of miR-483-5p in OA development, we generated doxycycline-inducible miR-483 transgenic (TG483) mice. TG483 mice exhibited significant acceleration and increased severity of OA, and age-related OA occurred with higher incidence and greater severity in TG483 mice compared with their controls. Furthermore, our results revealed miR-483-5p directly targeted to the cartilage matrix protein matrilin 3 (Matn3) and tissue inhibitor of metalloproteinase 2 (Timp2) to stimulate chondrocyte hypertrophy, extracellular matrix degradation, and cartilage angiogenesis, and it consequently initiated and accelerated the development of OA. In conclusion, our findings reveal an miRNA functional pathway important for OA development. Targeting of miR-483-5p by intra-articular injection of antago-miR-483-5p represents an approach that could prevent the onset of OA and delay its progression.

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“…In contrast to feeding studies, studies using fat-1 mice could eliminate confounding factors of diet such as nutrient composition, total caloric intake, duration of feeding and contamination of trace elements. Furthermore, a recent study reported a delay of osteoarthritis development in fat-1 mice, suggesting favorable effects of endogenous n-3 PUFAs on the experimental arthritis model [20]. To our knowledge, however, there are no reports using fat-1 mice to study RA.…”

Section: Introductionmentioning

confidence: 94%

Endogenous conversion of n-6 to n-3 polyunsaturated fatty acids attenuates K/BxN serum-transfer arthritis in fat-1 mice

Woo

Lim

Park

et al. 2015

The Journal of Nutritional Biochemistry

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Enhancement of the synthesis of n-3 PUFAs infat-1transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice

Cited by 72 publications

References 30 publications

Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury

Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury

Intra-articular Delivery of Antago-miR-483-5p Inhibits Osteoarthritis by Modulating Matrilin 3 and Tissue Inhibitor of Metalloproteinase 2

Endogenous conversion of n-6 to n-3 polyunsaturated fatty acids attenuates K/BxN serum-transfer arthritis in fat-1 mice

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