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. 2022 May 18;24(1):113.
doi: 10.1186/s13075-022-02802-0.

Ketogenic diet ameliorates inflammation by inhibiting the NLRP3 inflammasome in osteoarthritis

Ganggang Kong #  1   2 , Jinyang Wang #  3 , Rong Li  4 , Zhiping Huang  4 , Le Wang  5
Affiliations

Ketogenic diet ameliorates inflammation by inhibiting the NLRP3 inflammasome in osteoarthritis

Ganggang Kong et al. Arthritis Res Ther. .

Abstract

Background: The nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been reported to be involved in the pathological process of osteoarthritis (OA) inflammation. Here, we investigated the ketogenic diet (KD), which has been previously demonstrated to inhibit NLRP3 inflammasome activation, to elucidate its protective mechanism against OA in rats.

Methods: Anterior cruciate ligament transaction (ACLT) together with partial medial meniscectomy was used to create a rat knee joint OA model. After treatment with KD or standard diet (SD) for 8 weeks, the knee specimens were obtained for testing.

Results: The KD significantly increased the content of β-hydroxybutyrate (βOHB) in rats. Compared to the SD group, the KD significantly reduced the damage caused by OA in the articular cartilage and subchondral bone. The NLRP3 inflammasome and inflammatory cytokines interleukin-1 β (IL-1β) and IL-18 were significantly increased in the SD group compared with the sham group, while their expression was significantly decreased in rats treated with the KD. In addition, MMP13 was significantly decreased in the KD group compared to that in the SD group, while COL2 was significantly increased.

Conclusions: KD can protect the articular cartilage and subchondral bone in a rat OA model by inhibiting NLRP3 inflammasome activation and reducing the OA inflammatory response.

Keywords: Ketogenic diet; NLRP3 inflammasome; Osteoarthritis.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The body weight and blood βOHB levels at different times. A There was no significant difference in body weight between the KD and SD groups at all time points. B The blood βOHB levels in the KD group were significantly higher than those in the SD group. n = 6 per group, with a total of 12 animals used. *P < 0.05 versus the SD group
Fig. 2
Fig. 2
Bone micro-architecture in the subchondral bone. A Micro-CT images of the tibial subchondral bone at 8 weeks after surgery. Scale bar, 5 mm. B–E Quantitative analysis of the structural parameters of the subchondral bone. BV/TV, bone volume fraction; Tb. N, trabecular number; Tb. Sp, trabecular separation; Tb. Th, trabecular thickness. n = 6 per group, with a total of 18 animals used. #P < 0.05 versus the sham group, *P < 0.05 versus the SD group
Fig. 3
Fig. 3
The macroscopic and histopathological appearance of the knee joints. A Gross observation, Safranin O-fast green, H&E, and Alcian blue staining of the knee joint at 8 weeks after surgery treatment (from top to bottom). Scale bar of histopathological images, 1 mm. B, C Macroscopic score and OARSI score of the knee joint. n = 3 per group, with a total of 9 animals used. #P < 0.05 versus the sham group, *P < 0.05 versus the SD group. Ulcers are indicated using arrows
Fig. 4
Fig. 4
NLRP3 inflammasome activation in the knee joint. A The influence of KD on the activation of NLRP3 inflammasome was detected by immunohistochemistry. Scale bar, 20 μm. B–D Quantitative analysis of the expression of NLRP3 inflammasome in immunohistochemical results. E The expression of NLRP3 inflammasome was measured by western blot. F Quantitative analysis of the expression of NLRP3 inflammasome in western blot results. n = 3 per group, with a total of 18 animals used. #P < 0.05 versus the sham group, *P < 0.05 versus the SD group
Fig. 5
Fig. 5
Expression of pro-inflammatory cytokines in the knee joint. A IL-1β and IL-18 expression levels in the articular cartilage of the knee joints, as detected by immunohistochemistry. Scale bar, 20 μm. B, C Quantitative analysis of the expression of IL-1β and IL-18 by immunohistochemistry. D, E Quantitative analysis of IL-1β and IL-18 by ELISA. n = 3 per group, with a total of 9 animals used. #P < 0.05 versus the sham group, *P < 0.05 versus the SD group
Fig. 6
Fig. 6
Evaluation of cartilage degeneration in the knee joint. A Expression of MMP13 and COL2 was detected using immunohistochemistry. Scale bar, 20 μm. B, C Quantitative analysis of the expression of MMP13 and COL2 in immunohistochemical results. n = 3 per group, with a total of 9 animals used. #P < 0.05 versus the sham group, *P < 0.05 versus the SD group
Fig. 7
Fig. 7
βOHB inhibited inflammatory cytokine and MMP13 expression in chondrocytes through NLRP3. A NLRP3, IL-1β, and MM13 were detected in the cell lysates by western blot. B Quantification of NLRP3, IL-1β, and MM13 in western blot results. #P < 0.05 versus the control group, *P < 0.05 versus the LPS+ATP group
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