Induction of osteoarthritis by injecting monosodium iodoacetate into the patellofemoral joint of an experimental rat model

Takahashi, I.; Matsuzaki, Taro; Kuroki, Hiroshi; Hoso, Masahiro

doi:10.1371/journal.pone.0196625

Cited by 69 publications

(56 citation statements)

References 45 publications

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“…HIPK2 knockdown showed small decreases in IL-6 and IL-1b expression with no effects on TNF-a and IL-8 expression in LPSstimulated BEAS-2B cells [ Supplementary Fig. 20(d) Anti-inflammation and cartilage protection in vivo: lorecivivint inhibited inflammation, protected cartilage, and improved pain and function in the monosodium iodoacetate (MIA)-induced rat knee OA model IA MIA causes local inflammation, cartilage degeneration, and increased pain in the joint 36,37 . Lorecivivint [0.3 mg, single IA injection; Supplementary Fig.…”

Section: Anti-inflammation: Inhibition Of Dyrk1a and Clk2 Together Rementioning

confidence: 99%

Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment

Deshmukh

O'Green

Bossard

et al. 2019

Osteoarthritis and Cartilage

122

145

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Objectives: Wnt pathway upregulation contributes to knee osteoarthritis (OA) through osteoblast differentiation, increased catabolic enzymes, and inflammation. The small-molecule Wnt pathway inhibitor, lorecivivint (SM04690), which previously demonstrated chondrogenesis and cartilage protection in an animal OA model, was evaluated to elucidate its mechanism of action. Design: Biochemical assays measured kinase activity. Western blots measured protein phosphorylation in human mesenchymal stem cells (hMSCs), chondrocytes, and synovial fibroblasts. siRNA knockdown effects in hMSCs and BEAS-2B cells on Wnt pathway, chondrogenic genes, and LPS-induced inflammatory cytokines was measured by qPCR. In vivo anti-inflammation, pain, and function were evaluated following single intra-articular (IA) lorecivivint or vehicle injection in the monosodium iodoacetate (MIA)-induced rat OA model. Results: Lorecivivint inhibited intranuclear kinases CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Lorecivivint inhibited CLK2-mediated phosphorylation of serine/arginine-rich (SR) splicing factors and DYRK1A-mediated phosphorylation of SIRT1 and FOXO1. siRNA knockdowns identified a role for CLK2 and DYRK1A in Wnt pathway modulation without affecting b-catenin with CLK2 inhibition inducing early chondrogenesis and DYRK1A inhibition enhancing mature chondrocyte function. NF-kB and STAT3 inhibition by lorecivivint reduced inflammation. DYRK1A knockdown was sufficient for anti-inflammatory effects, while combined DYRK1A/CLK2 knockdown enhanced this effect. In the MIA model, lorecivivint inhibited production of inflammatory cytokines and cartilage degradative enzymes, resulting in increased joint cartilage, decreased pain, and improved weight-bearing function. Conclusions: Lorecivivint inhibition of CLK2 and DYRK1A suggested a novel mechanism for Wnt pathway inhibition, enhancing chondrogenesis, chondrocyte function, and anti-inflammation. Lorecivivint shows potential to modify structure and improve symptoms of knee OA.

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Section: Anti-inflammation: Inhibition Of Dyrk1a and Clk2 Together Rementioning

confidence: 99%

Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment

Deshmukh

O'Green

Bossard

et al. 2019

Osteoarthritis and Cartilage

122

145

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“…This was a study concomitant to our previous study 24 . A portion of the data was derived from our previous study.…”

Section: Experimental Animals and Animal Carementioning

confidence: 72%

“…To clarify the histopathological changes that occur in OA, we quantitatively evaluated these changes using the OA cartilage histopathology assessment system (OARSI score) 24,26 and modified Mankin score 27e29 . The OARSI score was established by Pritzker et al; the total score ranges from 0 to 24, with higher values indicating more advanced cartilage degeneration 26 .…”

Section: Histological Analysismentioning

confidence: 99%

Joint unloading inhibits articular cartilage degeneration in knee joints of a monosodium iodoacetate-induced rat model of osteoarthritis

Takahashi

Matsuzaki

Kuroki

et al. 2019

Osteoarthritis and Cartilage

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s u m m a r yObjective: The aim of the study was to examine how mechanical unloading affects articular cartilage degeneration in the patellofemoral (PF) and tibiofemoral (TF) joints of a monosodium iodoacetate (MIA)induced rat model of osteoarthritis (OA). Design: The study involved 60 male rats. OA was induced by intra-articular injecting MIA into both knee joints. All animals were equally divided into two groups: sedentary (SE) and hindlimb unloading (HU) groups. Histopathological changes in the articular cartilage of the PF and TF joints were evaluated using the Osteoarthritis Research Society International (OARSI) score and modified Mankin score at 2 and 4 weeks after MIA injection. Results: In the SE and HU groups, representative histopathological changes in OA were detected in the PF and TF joints. The OARSI and modified Mankin scores for the PF and TF joints tended to increase over time after the injection of 0.2 mg or 1.0 mg of MIA in the SE and HU groups. Both the scores for the HU group were significantly lower than those for the SE group [OARSI score: P < 0.0001 (1.0-mg injection at 4 weeks); modified Mankin score: P ¼ 0.0116 (0.2-mg injection at 4 weeks); P ¼ 0.0004 and < 0.0001 (1.0-mg injection at 2 and 4 weeks, respectively)]. Conclusion: This study revealed new histological evidence that indicates that unloading condition suppresses articular cartilage degeneration and is beneficial in many areas of basal and clinical research involving OA.

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“…Osteoarthritis is a degenerative joint disease that can ultimately lead to joint damage. 1 Articular cartilage degeneration, subchondral sclerosis and synovial inflammation are the characteristics of osteoarthritis. 2 The etiology of osteoarthritis is multifactorial, including aging, strain, trauma, infection, obesity, joint congenital anomalies, metabolic disease, and so on.…”

Section: Introductionmentioning

confidence: 99%

<p>Downregulation of miR-34a Promotes Proliferation and Inhibits Apoptosis of Rat Osteoarthritic Cartilage Cells by Activating PI3K/Akt Pathway</p>

Tao¹,

Cheng²,

Yang³

2020

CIA

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Objective: To elucidate the expression and function of miR-34a in rat osteoarthritic cartilage cells, and further to explore its mechanism. Material and Methods: Rat model of osteoarthritis was constructed and knee joint cartilage cells were isolated in vitro. Immunocytochemical staining was used for identification. qRT-PCR was used to detect the expression of miR-34a in cartilaginous tissues and cartilage cells. Cartilage cells were divided into blank control (BC), negative control (NC), miR-34a inhibitor (34aI), osteoarthritis model (OA), osteoarthritis model + negative control (OA + NC) and osteoarthritis model + miR-34a inhibitor (OA + 34aI) groups. Cell proliferation was detected by CCK-8 and colony formation assays. Cell apoptosis was studied by flow cytometry and Western blot. PI3K/AKT-pathway-related proteins were also analyzed by Western blot. To further validate the effect of miR-34a on the PI3K/Akt pathway, the cartilage cells were divided into blank control (BC), osteoarthritis model (OA), osteoarthritis model + miR-34a inhibitor (OA + 34aI), osteoarthritis model + PI3K activator (OA + IGF-1) and osteoarthritis model + miR-34a inhibitor + PI3K inhibitor (OA + 34aI + LY) groups, the experiments above were repeated. Results: The expression of miR-34a in cartilaginous tissues and cells of osteoarthritis model was significantly higher than that in normal (p < 0.05). After silencing miR-34a gene, the cell proliferation and proteins expression of PI3K/Akt pathway were increased, while the apoptosis rate and expression of apoptosis-related proteins were decreased. Addition of PI3K activator also evidently promoted proliferation and inhibited apoptosis. The protein expression of Bax, Cleaved caspase-3 and Cleaved caspase-9 were dramatically decreased, while the ratios of p-PI3K/PI3K and p-Akt/Akt were increased in OA + IGF-1 group. Conclusion: Downregulation of miR-34a regulated proliferation and apoptosis of cartilage cells by activating PI3K/Akt pathway, providing a potential therapeutic approach for the treatment of osteoarthritis.

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Induction of osteoarthritis by injecting monosodium iodoacetate into the patellofemoral joint of an experimental rat model

Cited by 69 publications

References 45 publications

Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment

Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment

Joint unloading inhibits articular cartilage degeneration in knee joints of a monosodium iodoacetate-induced rat model of osteoarthritis

<p>Downregulation of miR-34a Promotes Proliferation and Inhibits Apoptosis of Rat Osteoarthritic Cartilage Cells by Activating PI3K/Akt Pathway</p>

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