Deletion of 12/15-lipoxygenase accelerates the development of aging-associated and instability-induced osteoarthritis

Habouri, L; Mansouri, Fatima Ezzahra El; Ouhaddi, Yassine; Lussier, Bertrand; Pelletier, Jean‐Pierre; Martel‐Pelletier, Johanne; Benderdour, Mohamed; Fahmi, Hassan

doi:10.1016/j.joca.2017.07.001

Cited by 27 publications

(12 citation statements)

References 36 publications

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“…For example, EPI-743 has recently been shown to have beneficial effects in some neurodegenerative disorders, such as Huntington’s disease, Friedreich’s ataxia, Leigh’s syndrome and Leber’s hereditary optic neuropathy, by complex and concerted mechanisms [ 55 , 56 ]. EPI-743 also prevented ferroptosis in vitro by specifically inhibiting the activity of 15-lipoxygenase [ 35 , 57 ], which is responsible for inflammatory mediator biosynthesis [ 58 ]. In addition, EPI-743 increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of cellular resistance to ROS damage [ 59 , 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Antioxidant Amelioration of Riboflavin Transporter Deficiency in Motoneurons Derived from Patient-Specific Induced Pluripotent Stem Cells

Marioli

Magliocca

Petrini

et al. 2020

IJMS

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Mitochondrial dysfunction is a key element in the pathogenesis of neurodegenerative disorders, such as riboflavin transporter deficiency (RTD). This is a rare, childhood-onset disease characterized by motoneuron degeneration and caused by mutations in SLC52A2 and SLC52A3, encoding riboflavin (RF) transporters (RFVT2 and RFVT3, respectively), resulting in muscle weakness, ponto-bulbar paralysis and sensorineural deafness. Based on previous findings, which document the contribution of oxidative stress in RTD pathogenesis, we tested possible beneficial effects of several antioxidants (Vitamin C, Idebenone, Coenzyme Q10 and EPI-743, either alone or in combination with RF) on the morphology and function of neurons derived from induced pluripotent stem cells (iPSCs) from two RTD patients. To identify possible improvement of the neuronal morphotype, neurite length was measured by confocal microscopy after β-III tubulin immunofluorescent staining. Neuronal function was evaluated by determining superoxide anion generation by MitoSOX assay and intracellular calcium (Ca2+) levels, using the Fluo-4 probe. Among the antioxidants tested, EPI-743 restored the redox status, improved neurite length and ameliorated intracellular calcium influx into RTD motoneurons. In conclusion, we suggest that antioxidant supplementation may have a role in RTD treatment.

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Section: Discussionmentioning

confidence: 99%

Antioxidant Amelioration of Riboflavin Transporter Deficiency in Motoneurons Derived from Patient-Specific Induced Pluripotent Stem Cells

Marioli

Magliocca

Petrini

et al. 2020

IJMS

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“…Immunohistochemical analysis was performed 2 weeks postsurgery (n = 6 per group) as previously described (32,33). We selected this time point because it is suitable to detect and quantify MMP-13 and ADAMTS-5 in the cartilage of DMM-operated mice (32,33 Isolation of primary chondrocytes and measurement of PGD 2 levels. Primary epiphyseal chondrocytes were isolated from 5-6-day-old mice as previously reported (32).…”

Section: Histologic Evaluation Of Osteoarthritic Changesmentioning

confidence: 99%

“…Statistical analysis. Sample size calculations were based on our primary outcome measure "OA histopathology" and our previous studies (32,33). Our sample size would provide >80% power to detect a 50% change in mean OARSI scores with a significance level of P = 0.05.…”

Section: Micro-ct Analysis Of Bonementioning

confidence: 99%

Role of Lipocalin‐Type Prostaglandin D Synthase in Experimental Osteoarthritis

Najar

Ouhaddi

Paré

et al. 2020

Arthritis & Rheumatology

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Objective Lipocalin‐type prostaglandin D synthase (L‐PGDS) catalyzes the formation of prostaglandin D2 (PGD2), which has important roles in inflammation and cartilage metabolism. We undertook this study to investigate the role of L‐PGDS in the pathogenesis of osteoarthritis (OA) using an experimental mouse model. Methods Experimental OA was induced in wild‐type (WT) and L‐PGDS–deficient (L‐PGDS−/−) mice (n = 10 per genotype) by destabilization of the medial meniscus (DMM). Cartilage degradation was evaluated by histology. The expression of matrix metalloproteinase 13 (MMP‐13) and ADAMTS‐5 was assessed by immunohistochemistry. Bone changes were determined by micro–computed tomography. Cartilage explants from L‐PGDS−/− and WT mice (n = 6 per genotype) were treated with interleukin‐1α (IL‐1α) ex vivo in order to evaluate proteoglycan degradation. Moreover, the effect of intraarticular injection of a recombinant adeno‐associated virus type 2/5 (rAAV2/5) encoding L‐PGDS on OA progression was evaluated in WT mice (n = 9 per group). Results Compared to WT mice, L‐PGDS−/− mice had exacerbated cartilage degradation and enhanced expression of MMP‐13 and ADAMTS‐5 (P < 0.05). Furthermore, L‐PGDS−/− mice displayed increased synovitis and subchondral bone changes (P < 0.05). Cartilage explants from L‐PGDS−/− mice showed enhanced proteoglycan degradation following treatment with IL‐1α (P < 0.05). Intraarticular injection of rAAV2/5 encoding L‐PGDS attenuated the severity of DMM‐induced OA‐like changes in WT mice (P < 0.05). The L‐PGDS level was increased in OA tissues of WT mice (P < 0.05). Conclusion Collectively, these findings suggest a protective role of L‐PGDS in OA, and therefore enhancing levels of L‐PGDS may constitute a promising therapeutic strategy.

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“…[4][5][6][7] Chondrocytes account for the only cell type constituting articular cartilage, and hence, play an important role in maintaining the synthesis of normal tissues and renewal of aged extracellular matrix (ECM). 8,9 The IL-1β-enhanced catabolic response serves to suppress the expression of cartilage-related genes and promote that of matrix-degrading related genes, including collagenases and matrix metalloproteinases (MMPs), which were previously reported to increase the anabolic activities of chondrocytes via promoting ECM degradation. 5,10,11 Moreover, IL-1β promotes chondrocytes to express inflammatory-related genes and proteins, such as INOS and COX-2, which reduce aggrecan and collagen II production, the primary components of cartilage ECM.…”

Section: Introductionmentioning

confidence: 99%

<p>Morusin Ameliorates IL-1β-Induced Chondrocyte Inflammation and Osteoarthritis via NF-κB Signal Pathway</p>

Jia

Zhang

et al. 2020

DDDT

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Osteoarthritis (OA) is one of the most common degenerative joint diseases in the world, characterized primarily by the progressive degradation of articular cartilage. Accumulating evidence has shown that Morusin, a flavonoid derived from the root bark of Morus alba (mulberry) plants, exerts unique protective properties in several diseases. However, its effects on OA, specifically, have not yet been characterized. Methods: In this study, we evaluated the anti-inflammatory effect of Morusin on mouse chondrocytes and its underlying mechanism in vitro. In addition, the protective effect of Morusin on destabilization of the medial meniscus (DMM) model was also explored in vivo. Results: In vitro, IL-1β-induced activation of inflammatory factors (TNF-α, IL-6, INOS and COX2) was dramatically suppressed by Morusin. Further, Morusin treatment inhibited the expression of ADAMTS5 and metalloproteinase (MMPs), both of which regulate extracellular matrix degradation. Morusin also decreased IL-1β-induced p65 phosphorylation and IκBα degradation. In vivo, degradation of the articular cartilage following surgical DMM, which mimicked OA pathology, was abrogated following treatment with Morusin, thus demonstrating a protective effect in the DMM model. Conclusion: Herein, we demonstrate that Morusin reduces the OA inflammatory response in vitro and protects against articular cartilage degradation in vivo potentially via regulation of the NF-κB pathway. Hence, Morusin may prove to be an effective candidate for novel OA therapeutic strategies.

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Deletion of 12/15-lipoxygenase accelerates the development of aging-associated and instability-induced osteoarthritis

Abstract: These data suggest an important role of 12/15-LOX in the pathogenesis of OA. They also suggest that activation of this pathway may provide a novel strategy for prevention and treatment of OA.

Cited by 27 publications

References 36 publications

Antioxidant Amelioration of Riboflavin Transporter Deficiency in Motoneurons Derived from Patient-Specific Induced Pluripotent Stem Cells

Antioxidant Amelioration of Riboflavin Transporter Deficiency in Motoneurons Derived from Patient-Specific Induced Pluripotent Stem Cells

Role of Lipocalin‐Type Prostaglandin D Synthase in Experimental Osteoarthritis

<p>Morusin Ameliorates IL-1β-Induced Chondrocyte Inflammation and Osteoarthritis via NF-κB Signal Pathway</p>

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