scholarly journals Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yasutaka Murahashi ◽  
Fumiko Yano ◽  
Ryota Chijimatsu ◽  
Hideki Nakamoto ◽  
Yuji Maenohara ◽  
...  
Keyword(s):  
Oral Administration ◽  
Cartilage Degeneration ◽  
Necrosis Factor Alpha ◽  
Chondrocyte Hypertrophy ◽  
Knee Oa ◽  
Selective Agonist ◽  
Histone Deacetylase 4 ◽  
Factor Alpha ◽  
Disease Modifying Treatment ◽  
Tnf Secretion

AbstractOsteoarthritis (OA) is one of the world’s most common degenerative diseases, but there is no disease-modifying treatment available. Previous studies have shown that prostaglandin E2 (PGE2) and PGE2 receptor 4 (EP4) are involved in OA pathogenesis; however, their roles are not fully understood. Here, we examined the efficacy of oral administration of KAG-308, an EP4-selective agonist, in surgically induced mouse knee OA. Cartilage degeneration and synovitis were significantly inhibited by the KAG-308 treatment. Chondrocyte hypertrophy and expression of tumor necrosis factor alpha (TNF) and matrix metalloproteinase 13 (Mmp13) in the synovium were suppressed in the KAG-308-treated mice. In cultured chondrocytes, hypertrophic differentiation was inhibited by KAG-308 and intranuclear translocation of histone deacetylase 4 (Hdac4) was enhanced. In cultured synoviocytes, lipopolysaccharide (LPS)-induced expression of TNF and Mmp13 was also suppressed by KAG-308. KAG-308 was detected in the synovium and cartilage of orally treated mice. TNF secretion from the synovia of KAG-308-treated mice was significantly lower than control mice. Thus, we conclude that oral administration of KAG-308 suppresses OA development through suppression of chondrocyte hypertrophy and synovitis. KAG-308 may be a potent candidate for OA drug development.

Dose-Dependent Effects of Interleukin-1Alpha on Functional Degradation of Lateral and Medial Menisci

2010 ◽  
Author(s):  
Carrie H. Ling ◽  
Janice H. Lai ◽  
James F. Nishimuta ◽  
Marc E. Levenston
Keyword(s):  
Interleukin 1 ◽  
Cartilage Degeneration ◽  
Meniscal Extrusion ◽  
Knee Oa ◽  
Degenerative Lesion ◽  
Disease Modifying Treatment ◽  
Dose Dependent ◽  
Meniscal Degeneration ◽  
Pro Inflammatory Cytokines

Despite a growing recognition that meniscal degeneration often precedes cartilage degeneration in the development of knee osteoarthritis (OA), little is known about the role of meniscal degeneration in the onset and progression of knee OA. Even a mild degenerative lesion increases meniscal extrusion, implying changes in biomechanical function. Understanding the mechanisms of meniscal degeneration may enable the diagnosis and disease-modifying treatment of early knee OA, potentially preventing or slowing the progression of the disease. The roles of pro-inflammatory cytokines such as interleukin-1 (IL-1) in promoting cartilage matrix degradation and mediating inflammation in the progression of OA have been widely demonstrated [1,2]. Recent results from our group indicated that 20ng/ml hrIL-1α produced similar cell-mediated degradation and loss of mechanical properties in immature cartilage and meniscus, but progresses more rapidly in meniscus explants [3]. This study further explored the effects of IL-1α dosage and medial-lateral differences on the functional degradation of meniscal explants.

Dynamic Compression in the Presence of TNF-Alpha Differentially Effects Gene Expression in Tibial Plateau Cartilage Covered and Uncovered by the Meniscus

2008 ◽  
Author(s):  
Scott L. Bevill ◽  
Thomas P. Andriacchi
Keyword(s):  
Tibial Plateau ◽  
Dynamic Compression ◽  
Cruciate Ligament ◽  
Cartilage Degeneration ◽  
Joint Loading ◽  
Necrosis Factor Alpha ◽  
Joint Injury ◽  
Factor Alpha ◽  
Anterior Cruciate ◽  
Necrosis Factor

It has been suggested that altered joint loading may be a cause of the cartilage degeneration commonly observed following joint destabilizing events such as anterior cruciate ligament (ACL) injury [1]. Changes in the biochemical environment of the joint accompany these changes in joint loading, though, with acute and chronic increases in synovial concentrations of proinflammatory cytokines such as tumor necrosis factor-alpha (TNFα) [2, 3]. TNFα is a potent catabolic factor associated with increased expression [4] and synthesis [5] of matrix proteases in articular cartilage, and therefore may play in important role in the degenerative events following joint injury.

scholarly journals HDAC4 mutant represses chondrocyte hypertrophy by locating in the nucleus and attenuates disease progression of posttraumatic osteoarthritis

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Xiaodong Gu ◽  
Fei Li ◽  
Yangyang Gao ◽  
Xianda Che ◽  
Pengcui Li
Keyword(s):  
Articular Cartilage ◽  
Histone Deacetylase ◽  
Cartilage Damage ◽  
Adenovirus Vector ◽  
Cartilage Degeneration ◽  
Sprague Dawley ◽  
Chondrocyte Hypertrophy ◽  
Sprague Dawley Rats ◽  
Histone Deacetylase 4 ◽  
Safranin O

Abstract Background The aim of this study was to evaluate whether histone deacetylase 4 S246/467/632A mutant (m-HDAC4) has enhanced function at histone deacetylase 4 (HDAC4) to attenuate cartilage degeneration in a rat model of osteoarthritis (OA). Methods Chondrocytes were infected with Ad-m-HDAC4-GFP or Ad-HDAC4-GFP for 24 h, incubated with interleukin-1β (IL-1β 10 ng/mL) for 24 h, and then measured by RT-qPCR. Male Sprague-Dawley rats (n = 48) were randomly divided into four groups and transduced with different vectors: ACLT/Ad-GFP, ACLT/Ad-HDAC4-GFP, ACLT/Ad-m-HDAC4-GFP, and sham/Ad-GFP. All rats received intra-articular injections 48 h after the operation and every 3 weeks thereafter. Cartilage damage was assessed using radiography and Safranin O staining and quantified using the OARSI score. The hypertrophic and anabolic molecules were detected by immunohistochemistry and RT-qPCR. Results M-HDAC4 decreased the expression levels of Runx-2, Mmp-13, and Col 10a1, but increased the levels of Col 2a1 and ACAN more effectively than HDAC4 in the IL-1β-induced chondrocyte OA model; upregulation of HDAC4 and m-HDAC4 in the rat OA model suppressed Runx-2 and MMP-13 production, and enhanced Col 2a1 and ACAN synthesis. Stronger Safranin O staining was detected in rats treated with m-HDAC4 than in those treated with HDAC4. The resulting OARSI scores were lower in the Ad-m-HDAC4 group (5.80 ± 0.45) than in the Ad-HDAC4 group (9.67 ± 1.83, P = 0.045). The OARSI scores were highest in rat knees that underwent ACLT treated with Ad-GFP control adenovirus vector (14.93 ± 2.14, P = 0.019 compared with Ad-HDAC4 group; P = 0.003 compared with Ad-m-HDAC4 group). Lower Runx-2 and MMP-13 production, and stronger Col 2a1 and ACAN synthesis were detected in rats treated with m-HDAC4 than in those treated with HDAC4. Conclusions M-HDAC4 repressed chondrocyte hypertrophy and induced chondrocyte anabolism in the nucleus. M-HDAC4 was more effective in attenuating articular cartilage damage than HDAC4.

In Vivo and In Vitro Anti-inflammatory Activities of Neoandrographolide

2007 ◽  
Vol 35 (02) ◽  
pp. 317-328 ◽  
Author(s):  
Jun Liu ◽  
Zheng-Tao Wang ◽  
Li-Li Ji
Keyword(s):  
Oral Administration ◽  
Potential Candidate ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor ◽  
Dimethyl Benzene

Neoandrographolide, one of the principal diterpene lactones, isolated from a medicinal herb Andrographis paniculata Nees, was tested in vivo and in vitro for its anti-inflammatory activities and mechanism. Oral administration of neoandrographolide (150 mg/kg) significantly suppressed ear edema induced by dimethyl benzene in mice. Oral administration of neoandrographolide (100–150 mg/kg) also reduced the increase in vascular permeability induced by acetic acid in mice. In vitro studies were performed using the macrophage cell line RAW264.7 to study the effect of neoandrographolide on suppressing phorbol-12-myristate-13-acetate (PMA)-stimulated respiratory bursts and lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α). Respiratory bursts were quantified by chemiluminescence (CL) measurements.Results showed that neoandrographolide suppressed PMA-stimulated respiratory bursts dose-dependently from 30 μM to 150 μM. Neoandrographolide also inhibited NO and TNF-α production in LPS-induced macrophages, contributing to the anti-inflammatory activity of A. paniculata. These results indicate that neoandrographolide possesses significant anti-inflammatory effects, which implies that it would be one of the major contributing components to participate in the anti-inflammatory effect of A. paniculata. and a potential candidate for further clinical trial.

scholarly journals Alleviation of Osteoarthritis-Induced Pain and Motor Deficits in Rats by a Novel Device for the Intramuscular Insertion of Cog Polydioxanone Filament

2021 ◽  
Vol 11 (22) ◽  
pp. 10534
Author(s):  
Kilyong Lee ◽  
Geung Gyu Gang ◽  
Yun Gyu Kang ◽  
Sung Sam Jung ◽  
Hee-Gon Park ◽  
...  
Keyword(s):  
Motor Impairment ◽  
Rectus Femoris ◽  
Motor Deficits ◽  
Mobility Limitations ◽  
Necrosis Factor Alpha ◽  
Cross Sectional ◽  
Knee Oa ◽  
Novel Device ◽  
Structural Improvement ◽  
Factor Alpha

The importance of skeletal muscles in the development of osteoarthritis (OA) is known. However, in OA, strengthening the muscle is arduous process. This study investigated the effects of muscle enhancement and support therapy (MEST), a novel device for the intramuscular insertion of cog polydioxanone filament intended to hold and stimulate surrounding muscles, on OA-induced symptoms. In our results, the MEST attenuated OA-induced pain and mobility limitations, as evidenced by increases in withdrawal thresholds, rearing duration and travelled distance in an open cage, and fall latency from rotarod. It further restored atrophic rectus femoris muscle (RFM) in OA animals by increasing mass, decreasing nucleus density, and increasing the cross-sectional area of muscle fibers. Decreased collagen and insulin-like growth factor 1 levels in OA animals were restored without affecting the interleukin-6 and tumor necrosis factor-alpha levels in RFM. No evidence of structural improvement in the knee was observed via computed tomography after MEST. These results suggest that MEST in the quadriceps is effective for relieving pain and motor impairment in knee OA animals by restoring atrophic muscles, providing a novel therapeutic strategy for OA symptom management.

scholarly journals Anti-inflammatory activity of synthetic and natural glucoraphanin

2019 ◽  
Vol 84 (5) ◽  
pp. 445-453
Author(s):  
Quan Vo ◽  
Pham Nam ◽  
Thuc Dinh ◽  
Adam Mechler ◽  
Thi Tran
Keyword(s):  
Tumor Necrosis Factor ◽  
Total Synthesis ◽  
Potassium Salt ◽  
Tumor Necrosis ◽  
Inflammatory Activity ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor ◽  
Tnf Secretion

Glucoraphanin is one of the best known glucosinolates because of its health benefits. The compound is known to eliminate carcinogens in tissue and hence is frequently studied for its cancer preventative properties. In this work, the total synthesis of ?- and ?-glucoraphanin epimers was attempted. ?-Glucoraphanin potassium salt was successfully synthesized in high overall yield, whereas the ?-epimer was found to be unstable as it decomposed in the final step of the total synthesis. The anti-inflammatory activity of the synthetic glucoraphanin was determined by inhibition of the release of tumor necrosis factor alpha (TNF-?) secretion in lipopolysaccharide-stimulated THP-1 cells. It was shown that in the presence of either the synthetic or natural glucoraphanin, TNF-? secretion was significantly reduced (?52 % inhibition) at a concentration of 15 ?M.

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