Lectin-like, oxidized low-density lipoprotein receptor-1-deficient mice show resistance to age-related knee osteoarthritis

Hashimoto, Kazuhiko; Oda, Yutaka; Nakamura, Fumihisa; Kakinoki, Ryosuke; Akagi, Masao

doi:10.4081/ejh.2017.2762

Cited by 19 publications

(18 citation statements)

References 49 publications

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“…In addition, it was also identified that the production of Runx2 was gradually increased as the rats aged. Therefore, we hypothesized that Runx2 may also be involved in age-associated OA ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

miR‑204‑5p inhibits the occurrence and development of osteoarthritis by targeting Runx2

Cao

Han

et al. 2018

Int J Mol Med

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One of the hallmarks of osteoarthritis (OA) development is endochondral ossification, in which Runt-related transcription factor-2 (Runx2) is aberrantly expressed. Runx2 was previously identified to be regulated by microRNA-204-5p (miR-204-5p). The aim of the present study was to investigate the potential function of miR-204-5p regulating Runx2 during the development of OA and the underlying molecular mechanism. The expression levels of miR-204-5p and Runx2 were determined in tissue specimens. Rat OA models were established by transecting the anterior and posterior cruciate ligaments and removing the meniscus. Rats were treated with miR-204-5p agomir and miR-204-5p negative control (NC). All in vitro experiments were performed using rat primary chondrocytes and the SW-1353 human bone chondrosarcoma cell line. It was identified that the expression of miR-204-5p was significantly decreased, whereas Runx2 was significantly increased, in human OA tissues compared with in non-OA tissues, and levels were inversely associated with each other in primary chondrocytes and chondrosarcoma cells. Overexpression of miR-204-5p decreased the proliferation of chondrocytes and SW-1353 cells. Using a luciferase reporter assay, Runx2 was identified to be a direct target of miR-204-5p in chondrocytes and overexpressed miR-204-5p altered the expression of collagens II, X and matrix metalloproteinase (MMP)-1 and MMP-13 in primary chondrocytes and SW-1353 cells. Histological analysis revealed that miR-204-5p treatment ameliorated the OA-like phenotype that is reflected by assessment of cartilage thickness and Mankin's score. Runx2 expression was gradually increased as the rats increased in age. At 10 weeks of miR-204-5p agomir treatment, altered expression levels of collagens II and X, cartilage oligomeric matrix protein fragment, aggrecan, MMP-1 and MMP-13 were observed in the treatment group compared with the NC group. In conclusion, the results of the present study indicated that miR-204-5p decreases chondrocyte proliferation and ameliorates the OA-like phenotype in rats with surgically induced OA by targeting Runx2.

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Section: Discussionmentioning

confidence: 99%

miR‑204‑5p inhibits the occurrence and development of osteoarthritis by targeting Runx2

Cao

Han

et al. 2018

Int J Mol Med

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“… 26 The positive cell rate of LOX-1, ox-LDL, and MMP-3 in chondrocytes was also measured as previously described. 15 , 16 The percentage of positive cells was measured as the number of stained cells relative to the number of total chondrocytes (mean [range]; 88.5 [78-102]) in the medial tibial plateau. The correlation between the cartilage degeneration score and the positive LOX-1 or ox-LDL cell rate in chondrocytes was also examined.…”

Section: Methodsmentioning

confidence: 99%

“… 14 We also demonstrated previously that the LOX- 1/ox-LDL system contributed to the pathogenesis of instability-induced and age-related knee osteoarthritis using LOX-1 KO mice. 15 , 16 A recent report showed that LOX-1 expression was detected in the chondrocytes of patients with rheumatoid arthritis (RA) and that matrix metalloproteinase-3 (MMP-3) expression was increased by stimulation of ox-LDL. 10 Ishikawa et al also reported that the LOX-1 signal has a possibility as a biomarker and therapeutic target in human RA.…”

Section: Introductionmentioning

confidence: 99%

LOX-1 deficient mice show resistance to zymosan-induced arthritis

et al. 2018

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Recent data suggest that the lectin-like oxidized low-density lipoprotein (ox-LDL) receptor-1 (LOX-1)/ox-LDL system may be involved in the pathogenesis of arthritis. We aimed to demonstrate the roles of the LOX- 1/ox-LDL system in arthritis development by using LOX-1 knockout (KO) mice. Arthritis was induced in the right knees of C57Bl/6 wild-type (WT) and LOX-1 KO mice via zymosan injection. Saline was injected in the left knees. Arthritis development was evaluated using inflammatory cell infiltration, synovial hyperplasia, and cartilage degeneration scores at 1, 3, and 7 days after administration. LOX-1, ox-LDL, and matrix metalloproteinase-3 (MMP-3) expression in the synovial cells and chondrocytes was evaluated by immunohistochemistry. The LOX-1, ox-LDL, and MMP-3 expression levels in synovial cells were scored on a grading scale. The positive cell rate of LOX-1, ox-LDL, and MMP-3 in chondrocytes was measured. The correlation between the positive cell rate of LOX-1 or ox-LDL and the cartilage degeneration score was also examined. Inflammatory cell infiltration, synovial hyperplasia, and cartilage degeneration were significantly reduced in the LOX-1 KOmice with zymosan-induced arthritis (ZIA) compared to WT mice with ZIA. In the saline-injected knees, no apparent arthritic changes were observed. LOX-1 and ox-LDL expression in synovial cells and chondrocytes were detected in the knees of WT mice with ZIA. No LOX-1 and ox-LDL expression was detected in the knees of LOX-1 KO mice with ZIA or the salineinjected knees of both mice. MMP-3 expression in the synovial cells and chondrocytes was also detected in knees of both mice with ZIA, and was significantly less in the LOX-1 KO mice than in WT mice. The positive cell rate of LOX-1 or ox-LDL and the cartilage degeneration score showed a positive correlation. Our data show the involvement of the LOX-1/ox-LDL system in murine ZIA development. LOX-1-positive synovial cells and chondrocytes are potential therapeutic targets for arthritis prevention.

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“…Thus, LOX-1 plays a pivotal role in the development of atherosclerosis, by inducing oxLDL uptake, lipidosis, foam cell generation and ultimately atheroma plaque formation (62,63). This OxLDL/LOX-1 axis was also shown to play a role in cartilage degeneration during age-related osteoarthritis progression in the murine knee (64). Similarly, the triggering of LOX-1 by AGEs, contributes to diabetic complications such as atherosclerosis (65,66).…”

Section: Clec8a (Lox-1 Olr-1)mentioning

confidence: 99%