Protective Effects of an Oligo-Fucoidan-Based Formula against Osteoarthritis Development via iNOS and COX-2 Suppression following Monosodium Iodoacetate Injection.

Osteoarthritis (OA) is a debilitating joint disorder characterized by cartilage degradation and chronic inflammation, accompanied by high oxidative stress. In this study, we utilized the monosodium iodoacetate (MIA)-induced OA model to investigate the efficacy of oligo-fucoidan-based formula (FF) intervention in mitigating OA progression. Through its capacity to alleviate joint bearing function and inflammation, improvements in cartilage integrity following oligo-fucoidan-based formula intervention were observed, highlighting its protective effects against cartilage degeneration and structural damage. Furthermore, the oligo-fucoidan-based formula modulated the p38 signaling pathway, along with downregulating cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, contributing to its beneficial effects. Our study provides valuable insights into targeted interventions for OA management and calls for further clinical investigations to validate these preclinical findings and to explore the translational potential of an oligo-fucoidan-based formula in human OA patients.

TPX2 upregulates MMP13 to promote the progression of lipopolysaccharide-induced osteoarthritis.

Purpose: This study seeks to identify potential clinical biomarkers for osteoarthritis (OA) using bioinformatics and investigate OA mechanisms through cellular assays. Methods: Differentially Expressed Genes (DEGs) from GSE52042 (four OA samples, four control samples) were screened and analyzed with protein-protein interaction (PPI) analysis. Overlapping genes in GSE52042 and GSE206848 (seven OA samples, and seven control samples) were identified and evaluated using Gene Set Enrichment Analysis (GSEA) and clinical diagnostic value analysis to determine the hub gene. Finally, whether and how the hub gene impacts LPS-induced OA progression was explored by in vitro experiments, including Western blotting (WB), co-immunoprecipitation (Co-IP), flow cytometry, etc. Result: Bioinformatics analysis of DEGs (142 up-regulated and 171 down-regulated) in GSE52042 identified two overlapping genes (U2AF2, TPX2) that exhibit significant clinical diagnostic value. These genes are up-regulated in OA samples from both GSE52042 and GSE206848 datasets. Notably, TPX2, which AUC = 0.873 was identified as the hub gene. In vitro experiments have demonstrated that silencing TPX2 can alleviate damage to chondrocytes induced by lipopolysaccharide (LPS). Furthermore, there is a protein interaction between TPX2 and MMP13 in OA. Excessive MMP13 can attenuate the effects of TPX2 knockdown on LPS-induced changes in OA protein expression, cell growth, and apoptosis. Conclusion: In conclusion, our findings shed light on the molecular mechanisms of OA and suggested TPX2 as a potential therapeutic target. TPX2 could promote the progression of LPS-induced OA by up-regulating the expression of MMP13, which provides some implications for clinical research.

The effect of low dose intra-articular S(+) ketamine on osteoarthritis in rats: an experimental study.

BACKGROUND: This study aimed to investigate the analgesic impact of S(+)-ketamine on pain behavior and synovial inflammation in an osteoarthritis (OA) model. METHODS: Animals were grouped as follows: OA-Saline (n = 24) and OA-Ketamine (n = 24), OA induced via intra-articular sodium monoiodoacetate (MIA); a Non-OA group (n = 24) served as the control. On the 7th day post OA induction, animals received either saline or S(+)-ketamine (0.5 mg.kg-1). Behavioral and histopathological assessments were conducted up to day 28. RESULTS: S(+)-ketamine reduced allodynia from day 7 to 28 and hyperalgesia from day 10 to 28. It notably alleviated weight distribution deficits from day 10 until the end of the study. Significant walking improvement was observed on day 14 in S(+)-ketamine-treated rats. Starting on day 14, OA groups showed grip force decline, which was countered by S(+)-ketamine on day 21. However, S(+)-ketamine did not diminish synovial inflammation. CONCLUSION: Low Intra-articular (IA) doses of S(+)-ketamine reduced MIA-induced OA pain but did not reverse synovial histopathological changes. IRB APPROVAL NUMBER: 23115 012030/2009-05.

Analgesic, Anti-Inflammatory, and Chondroprotective Activities of Siraitia grosvenorii Residual Extract.

Inflammation is crucial to osteoarthritis (OA) pathogenesis. The aim of this study was to evaluate Siraitia grosvenorii residue extract (NHGRE) obtained by extracting S. grosvenorii fruits with water as a potential food supplement for treating arthritis based on its analgesic, anti-inflammatory, and chondroprotective effects and the remaining residue with 70% ethanol. We observed the analgesic activity of NHGRE based on the acetic acid-induced writhing response in mice, examined its anti-inflammatory efficacy against carrageenan-induced paw oedema in mice, and investigated its effect on inflammatory cytokine expression in interleukin (IL)-1ß-induced SW1353 cells. Furthermore, we determined its effects on cartilage protection in interleukin-1ß (IL-1ß)-treated SW1353 cells. NHGRE at 200 mg/kg significantly reduced the acetic acid-induced writhing response and prevented oedema formation in the carrageenan-induced paw oedema model. In IL-1ß-induced SW1353 cells, NHGRE at 400 µg/mL reduced the expression of inflammation mediators such as tumour necrosis factor (TNF)-α (55.3%), IL-6 (35.4%), and prostaglandin E2 (PGE2) (36.9%) and down-regulated the expression of matrix metalloproteinase (MMP)-1 (38.6%), MMP-3 (29.3%), and MMP-13 (44.8%). Additionally, it restored degraded collagen II levels in chondrocytes. NHGRE plays a protective role in chondrocytes by regulating Nuclear factor kappa B (NF-κB) activation. Overall, NHGRE may be a useful therapeutic agent for OA by controlling pain, oedema formation, and inflammation-related mechanisms.

Anti-Inflammatory, Analgesic, Functional Improvement, and Chondroprotective Effects of Erigeron breviscapus (Vant.) Hand.-Mazz. Extract in Osteoarthritis: An In Vivo and In Vitro Study.

Osteoarthritis (OA) is a degenerative bone disease characterized by inflammation as a primary pathology and currently lacks therapeutic interventions to impede its progression. Erigeron breviscapus (Vant.) Hand.-Mazz. (EB) is an east Asian herbal medicine with a long history of use and a wide range of confirmed efficacy against cardiovascular and central nervous system diseases. The purpose of this study is to evaluate whether EB is worthy of further investigation as a treatment for OA based on anti-inflammatory activity. This study aims to assess the potential of EB as a treatment for OA, focusing on its anti-inflammatory properties. Analgesic effects, functional improvements, and inhibition of cartilage destruction induced by EB were evaluated in acetic acid-induced peripheral pain mice and monosodium iodoacetate-induced OA rat models. Additionally, the anti-inflammatory effect of EB was assessed in serum and cartilage tissue in vivo, as well as in lipopolysaccharide-induced RAW 264.7 cells. EB demonstrated a significant alleviation of pain, functional impairment, and cartilage degradation in OA along with a notable inhibition of pro-inflammatory cytokines, including interleukin-1ß, interleukin-6, matrix metalloproteinases 13, and nitric oxide synthase 2, both in vitro and in vivo, in a dose-dependent manner compared to the active control. Accordingly, EB merits further exploration as a potential disease-modifying drug for OA, capable of mitigating the multifaceted pathology of osteoarthritis through its anti-inflammatory properties. Nonetheless, additional validation through a broader experimental design is essential to substantiate the findings of this study.

Interference with SPARC inhibits Benzophenone-3 induced ferroptosis in osteoarthritis: Evidence from bioinformatics analyses and biological experimentation.

The aim of this study is to conduct a thorough evaluation of the association between Benzophenone-3 (BP-3) exposure and OA, offering critical insights into the underlying mechanisms involved. The National Health and Nutrition Examination Survey (NHANES) database was utilized to investigate the correlation between BP-3 and osteoarthritis. Proteomic sequencing from clinical sample and the PharmMapper online tool were employed to predict the biological target of BP-3. Cellular molecular assays and transfection studies were performed to verify the prediction from bioinformatics analyses. Through cross-sectional analysis of the NHANES database, we identified BP-3 as a risk factor for OA development. The results of proteomic sequencing showed that Secreted Protein Acidic and Rich in Cysteine (SPARC) was significantly elevated in the area of damage compared to the undamaged area. SPARC was also among the potential biological targets of BP-3 predicted by the online program. Through in vitro cell experiments, we further determined that the toxicological effects of BP-3 may be due to SPARC, which elevates intracellular GPX4 levels, activates the glutathione system, and promotes lipid peroxidation to mitigate ferroptosis. Inhibiting SPARC expression has been shown to reduce inflammation and ferroptosis in OA contexts. This research provides an expansive understanding of BP-3's influence on osteoarthritis development. We have identified SPARC as a potent target for combating chondrocyte ferroptosis in BP-3-associated osteoarthritis.

Ginkgolide C inhibits ROS-mediated activation of NLRP3 inflammasome in chondrocytes to ameliorate osteoarthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba, as the most widely available medicinal plant worldwide, has been frequently utilized for treat cardiovascular, cerebrovascular, diabetic and other diseases. Due to its distinct pharmacological effects, it has been broadly applications in pharmaceuticals, health products, dietary supplements, and so on. Ginkgolide C (GC), a prominent extract of Ginkgo biloba, possesses potential in anti-inflammatory and anti-oxidant efficacy. AIMS OF THE STUDY: To determine whether GC mitigated the progressive degeneration of articular cartilage in a Monosodium Iodoacetate (MIA)-induced osteoarthritis (OA) rat model by inhibiting the activation of the NLRP3 inflammasome, and the specific underlying mechanisms. MATERIALS AND METHODS: In vivo, an OA rat model was established by intra-articular injection of MIA. The protective effect of GC (10 mg/kg) on articular cartilage was evaluated. Application of ATDC5 cells to elucidate the mechanism of the protective effect of GC on articular cartilage. Specifically, the expression levels of molecules associated with cartilage ECM degrading enzymes, OS, ERS, and NLRP3 inflammasome activation were analyzed. RESULTS: In vivo, GC ameliorated MIA-induced OA rat joint pain, and exhibited remarkable anti-inflammatory and anti- ECM degradation effects via inhibition of the activation of NLRP3 inflammasome, the release of inflammatory factors, and the expression of matrix-degrading enzymes in cartilage. Mechanically, GC inhibited the activation of NLRP3 inflammasome by restraining ROS-mediated p-IRE1α and activating Nrf2/NQO1 signal path, thereby alleviating OA. The ROS scavenger NAC was as effective as GC in reducing ROS production and inhibiting the activation of NLRP3 inflammasome. CONCLUSIONS: GC have exerted chondroprotective effects by inhibiting the activation of NLRP3 inflammasome.

Risk of fall or fracture with concomitant use of prescription opioids and other medications in osteoarthritis patients.

BACKGROUND: Osteoarthritis (OA) patients taking prescription opioids for pain are at increased risk of fall or fracture, and the concomitant use of interacting drugs may further increase the risk of these events. AIMS: To identify prescription opioid-related medication combinations associated with fall or fracture. MATERIALS & METHODS: We conducted a case-crossover-based screening of two administrative claims databases spanning 2003 through 2021. OA patients were aged 40 years or older with at least 365 days of continuous enrollment and 90 days of continuous prescription opioid use before their first eligible fall or fracture event. The primary analysis quantified the odds ratio (OR) between fall and non-opioid medications dispensed in the 90 days before the fall date after adjustment for prescription opioid dosage and confounding using a case-time-control design. A secondary analogous analysis evaluated medications associated with fracture. The false discovery rate (FDR) was used to account for multiple testing. RESULTS: We identified 41 693 OA patients who experienced a fall and 24 891 OA patients who experienced a fracture after at least 90 days of continuous opioid therapy. Top non-opioid medications by ascending p-value with OR > 1 for fall were meloxicam (OR 1.22, FDR = 0.08), metoprolol (OR 1.06, FDR >0.99), and celecoxib (OR 1.13, FDR > 0.99). Top non-opioid medications for fracture were losartan (OR 1.20, FDR = 0.80), alprazolam (OR 1.14, FDR > 0.99), and duloxetine (OR 1.12, FDR = 0.97). CONCLUSION: Clinicians may seek to monitor patients who are co-prescribed drugs that act on the central nervous system, especially in individuals with OA.

Integrated Analysis of DNA Methylation and Gene Expression Profiles in a Rat Model of Osteoarthritis.

Osteoarthritis (OA) is common and affected by several factors, such as age, weight, sex, and genetics. The pathogenesis of OA remains unclear. Therefore, using a rat model of monosodium iodoacetate (MIA)-induced OA, we examined genomic-wide DNA methylation using methyl-seq and characterized the transcriptome using RNA-seq in the articular cartilage tissue from a negative control (NC) and MIA-induced rats. We identified 170 genes (100 hypomethylated and upregulated genes and 70 hypermethylated and downregulated genes) regulated by DNA methylation in OA. DNA methylation-regulated genes were enriched in functions related to focal adhesion, extracellular matrix (ECM)-receptor interaction and the PI3K-Akt and Hippo signaling pathways. Functions related to extracellular matrix organization, extracellular matrix proteoglycans, and collagen formation were involved in OA. A molecular and protein-protein network was constructed using methylated expression-correlated genes. Erk1/2 was a downstream target of OA-induced changes in DNA methylation and RNA expression. We found that the integrin subunit alpha 2 (ITGA2) gene is important in focal adhesion, alpha6-beta4 integrin signaling, and the inflammatory response pathway in OA. Overall, gene expression changes because DNA methylation influences OA pathogenesis. ITGA2, whose gene expression changes are regulated by DNA methylation during OA onset, is a candidate gene. Our findings provide insights into the epigenetic targets of OA processes in rats.

PPAR γ activation in chondrocytes alleviates glucocorticoid-induced oxidative stress, mitochondrial impairment, and pyroptosis via autophagic flow enhancement.

Osteoarthritis (OA) is a progressive age-related disease characterised by pathological changes in the synovium, articular cartilage, and subchondral bone, significantly reducing the patients' quality of life. This study investigated the role of glucocorticoids, specifically dexamethasone, in OA progression, with a particular focus on their effects on chondrocytes. Although glucocorticoids are commonly used for OA pain relief, our research demonstrated that high concentrations of dexamethasone may accelerate OA progression by enhancing the ability of reactive oxygen species to inhibit chondrocyte autophagy, resulting in cell death and accelerated cartilage degeneration. Despite reports on the acceleration of pathogenesis and cartilage damage in some patients of OA taking corticosteroids, the mechanism behind the same has not been investigated. This necessitates an investigation of the concentration-dependent changes in the cartilage cells upon dexamethasone administration. In addition, the protective effect of PPAR γ on chondrocytes can prevent the decrease in chondrocyte autophagy and delay cartilage degeneration. Therefore, our study suggests that the therapeutic use of glucocorticoids in OA treatment should be more nuanced considering their potential detrimental effects. Future investigations should focus on the mechanisms underlying the glucocorticoid-mediated modulation of cell death processes, which could provide insights into new therapeutic strategies for OA treatment.

Anti-osteoarthritis, Bone Protective and Antiinflammatory Effect of Lusianthridin against Monosodium Iodoacetate Induced Osteoarthritis via Suppression of Inflammatory Pathway.

Osteoarthritis (OA) is characterized by the gradual deterioration and worsening of the knee joint, leading to both pain and deformity. The current research exhibited the anti-osteoarthritis effect of lusianthridin against monosodium iodoacetate (MIA) induced OA in rats. RAW cells were used for the cell viability. The inflammatory cytokines and mediators were estimated in the cell lines after the lipopolysaccharide (LPS) treatment. For the in vivo study, the rats were received the intraperitoneal administration of MIA (3 mg/kg) for the induction of OA. The rats were received the oral administration of lusianthridin (5, 10 and 20 mg/kg) and the body and organ weight estimated. Antioxidant, cytokines, inflammatory and matrix metalloproteinases (MMP) level were also estimated. The mRNA expression of MMP were also estimated. The lusianthridin treatment remarkably suppressed the cell viability. LPS induced RAW cell suppressed the level of nitrate, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), prostaglandin (PGE2), MMP-2 and MMP-9 level. Lusianthridin remarkably altered the level of body weight and organ weight (liver, spleen, renal and heart weight). lusianthridin suppressed the oxidative stress via altered the level of antioxidant parameters. Lusianthridin significantly (p < 0.001) decreased the level of cartilage oligometrix matrix protein (COMP) and c-reactive protein (CRP); cytokines such as TNF-α, IL-1ß, IL-6, IL-10; inflammatory parameters include 5- Lipoxygenase (5-LOX), COX-2, leukotriene B4 (LTB4), PGE2; transforming growth factor beta (TGF-ß); MMP level like MMP-1, 3, 9, 13, respectively. Lusianthridin significantly suppressed the mRNA expression of MMP. Collectively, the result of the study showed that antiosteoarthritis effect of lusianthridin via suppression of inflammatory parameters.

Reversible SAHH inhibitor ameliorates MIA-induced osteoarthritis of rats through suppressing MEK/ERK pathway.

Osteoarthritis (OA) is characterized by gradual articular cartilage degradation, accompanied by persistent low-grade joint inflammation, correlating with radiographic and pain-related progression. The latent therapeutic potential of DZ2002, a reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH), holds promise for OA intervention. This study endeavored to examine the therapeutic efficacy of DZ2002 within the milieu of OA. The cytotoxicity of DZ2002 was evaluated using the MTT assay on bone marrow-derived macrophages. The inhibitory impact of DZ2002 during the process of osteoclastogenesis was assessed using TRAP staining, analysis of bone resorption pits, and F-actin ring formation. Mechanistic insights were derived from qPCR and Western blot analyses. Through the intra-articular injection of monosodium iodoacetate (MIA), an experimental rat model of OA was successfully instituted. This was subsequently accompanied by a series of assessments including Von Frey filament testing, analysis of weight-bearing behaviors, and micro-CT imaging, all aimed at assessing the effectiveness of DZ2002. The findings emphasized the effectiveness of DZ2002 in mitigating osteoclastogenesis induced by M-CSF/RANKL, evident through a reduction in TRAP-positive OCs and bone resorption. Moreover, DZ2002 modulated bone resorption-associated gene and protein expression (CTSK, CTR, Integrin ß3) via the MEK/ERK pathway. Encouragingly, DZ2002 also alleviates MIA-induced pain, cartilage degradation, and bone loss. In conclusion, DZ2002 emerges as a potential therapeutic contender for OA, as evidenced by its capacity to hinder in vitro M-CSF/RANKL-induced osteoclastogenesis and mitigate in vivo osteoarthritis progression. This newfound perspective provides substantial support for considering DZ2002 as a compelling agent for osteoarthritis intervention.

Effects of emulsified and non-emulsified palm tocotrienol on bone and joint health in ovariectomised rats with monosodium iodoacetate-induced osteoarthritis.

Postmenopausal women are susceptible to osteoporosis and osteoarthritis. Tocotrienol, a bone-protective nutraceutical, is reported to prevent osteoarthritis in male rats. However, its efficacy on joint health in oestrogen deficiency has not been validated. Besides, data on the use of emulsification systems in enhancing bioavailability and protective effects of tocotrienol are limited. Ovariectomised adult female Sprague-Dawley rats (3 months old) were treated with refined olive oil, emulsified (EPT, 100 mg/kg/day with 25% vitamin E content), non-emulsified palm tocotrienol (NEPT, 100 mg/kg/day with 50% vitamin E content) and calcium carbonate (1% w/v in drinking water) plus glucosamine sulphate (250 mg/kg/day) for 10 weeks. Osteoarthritis was induced with monosodium iodoacetate four weeks after ovariectomy. Baseline control was sacrificed upon receipt, while the sham group was not ovariectomised and treated with refined olive oil. EPT and NEPT prevented femoral metaphyseal and subchondral bone volume decline caused by ovariectomy. EPT decreased subchondral trabecular separation compared to the negative control. EPT preserved stiffness and Young's Modulus at the femoral mid-shaft of the rats. Circulating RANKL was reduced post-treatment in the EPT group. Joint width was reduced in all the treatment groups vs the negative control. The EPT group's grip strength was significantly improved over the negative control and NEPT group. EPT also preserved cartilage histology based on several Mankin's subscores. EPT performed as effectively as NEPT in preventing osteoporosis and osteoarthritis in ovariectomised rats despite containing less vitamin E content. This study justifies clinical trials for the use of EPT in postmenopausal women with both conditions.

Stimulation of nuclear receptor REV-ERBs alleviates monosodium iodoacetate-induced osteoarthritis pathology of mice and the induction of inflammatory molecules expression in primary cultured chondrocytes.

Because inflammation in chondrocytes contributes to the induction of osteoarthritis (OA), regulation of their activity is essential. A previous study showed that stimulation of the reverse erythroblastosis virus (REV-ERB) nuclear receptors in spinal glial cells elicits anti-inflammatory and antinociception effects in animal models of chronic pain. However, the involvement of REV-ERBs in chondrocyte functions and OA pathologies remains to be elucidated. In the current study, we found that pretreatment with the REV-ERB agonist SR9009 significantly blocked the increases in inflammatory molecules [(matrix metalloproteinase (MMP) 3, MMP9, and MMP13] and cytokines (interleukin-1ß and tumor necrosis factor) in primary cultured chondrocytes following treatment with lipopolysaccharide. Furthermore, repeated intra-articular treatment with SR9009 significantly prevented monosodium iodoacetate-induced mechanical hypersensitivity and tended to partially reduce knee joint damage in mice. In conclusion, our findings suggest that REV-ERBs have a critical role in alleviating nociceptive hypersensitivity in OA pathologies by negatively regulating inflammation in chondrocytes.

An alkaloid from Menispermum dauricum, dauricine mediates Ca2+ influx and inhibits NF-κB pathway to protect chondrocytes from IL-1ß-induced inflammation and catabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Dauricine (DA) is a natural plant-derived alkaloid extracted from Menispermum dauricum. Menispermum dauricum has been used in traditional Chinese medicine as a classic remedy for rheumatoid arthropathy and is believed to be effective in alleviating swelling and pain in the limbs. AIM OF THE STUDY: Osteoarthritis (OA) is a classic degenerative disease involving chondrocyte death, and there is still a lack of effective therapeutic agents that can reverse the progression of the disease. Here we explored the therapeutic effects of DA against OA and further explored the mechanism. MATERIALS AND METHODS: The effect of DA on cell viability was assessed by CCK-8. IL-1ß-treated mouse chondrocytes were used as an in vitro model of OA, and apoptosis was detected by flow cytometry. QRT-PCR, western blotting, cell staining, and immunofluorescence were used to detect relevant inflammatory factors and cartilage-specific expression. RNA sequencing was used to identify pertinent signaling pathways. The therapeutic effect of DA was verified by micro-CT, histological analysis and immunohistochemical analysis in a mouse OA model. RESULTS: DA demonstrated a high safety profile on chondrocytes, significantly reversing the inflammatory response induced by IL-1ß, and promoting factors associated with cartilage regeneration. Moreover, DA exhibited a significant protective effect on the knee joints of mice undergoing ACLT-DMM, effectively preventing cartilage degeneration and subchondral bone tissue destruction. These positive therapeutic effects were achieved through the modulation of the NF-κB pathway and the Ca2+ signaling pathway by DA. CONCLUSION: Being derived from a traditional herb, DA exhibits remarkable therapeutic potential and safety in OA treatment, presenting a promising option for patients dealing with osteoarthritis.

A Blend of Tamarindus Indica and Curcuma Longa Extracts Alleviates Monosodium Iodoacetate (MIA)-Induced Osteoarthritic Pain and Joint Inflammation in Rats.

BACKGROUND AND OBJECTIVE: NXT15906F6 (TamaFlexTM) is a proprietary herbal composition containing Tamarindus indica seeds and Curcuma longa rhizome extracts. NXT15906F6 supplementation has been shown clinically effective in reducing knee joint pain and improving musculoskeletal functions in healthy and knee osteoarthritis (OA) subjects. The objective of the present study was to assess the possible molecular basis of the anti-OA efficacy of NXT15906F6 in a monosodium iodoacetate (MIA)-induced model of OA in rats. METHODS: Healthy male Sprague Dawley rats (age: 8-9 wk body weight, B.W.: 225-308 g (n = 12) were randomly assigned to one of the six groups, (a) vehicle control, (b) MIA control, (c) Celecoxib (10 mg/kg B.W.), (d) TF-30 (30 mg/kg B.W.), (e) TF-60 (60 mg/kg B.W.), and (f) TF-100 (100 mg/kg B.W.). OA was induced by an intra-articular injection of 3 mg MIA into the right hind knee joint. The animals received either Celecoxib or TF through oral gavage over 28 days. The vehicle control animals received intra-articular sterile normal saline. RESULTS: Post-treatment, NXT15906F6 groups showed significant (p < 0.05) dose-dependent pain relief as evidenced by improved body weight-bearing capacity on the right hind limb. NXT15906F6 treatment also significantly reduced the serum tumor necrosis factor-α (TNF-α, p < 0.05) and nitrite (p < 0.05) levels in a dose-dependent manner. mRNA expression analyses revealed the up-regulation of collagen type-II (COL2A1) and down-regulation of matrix metalloproteinases (MMP-3, MMP-9 and MMP-13) in the cartilage tissues of NXT15906F6-supplemented rats. Cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) protein expressions were down-regulated. Decreased immunolocalization of NF-κß (p65) was observed in the joint tissues of NXT15906F6-supplemented rats. Furthermore, microscopic observations revealed that NXT15906F6 preserved MIA-induced rats' joint architecture and integrity. CONCLUSION: NXT15906F6 reduces MIA-induced joint pain, inflammation, and cartilage degradation in rats.

Low-Molecular-Weight Fish Collagen Peptide (Valine-Glycine-Proline-Hydroxyproline-Glycine-Proline-Alanine-Glycine) Prevents Osteoarthritis Symptoms in Chondrocytes and Monoiodoacetate-Injected Rats.

The objective of this study was to investigate the effect of low-molecular-weight fish collagen (valine-glycine-proline-hydroxyproline-glycine-proline-alanine-glycine; LMWCP) on H2O2- or LPS-treated primary chondrocytes and monoiodoacetate (MIA)-induced osteoarthritis rat models. Our findings indicated that LMWCP treatment exhibited protective effects by preventing chondrocyte death and reducing matrix degradation in both H2O2-treated primary chondrocytes and cartilage tissue from MIA-induced osteoarthritis rats. This was achieved by increasing the levels of aggrecan, collagen type I, collagen type II, TIMP-1, and TIMP-3, while simultaneously decreasing catabolic factors such as phosphorylation of Smad, MMP-3, and MMP-13. Additionally, LMWCP treatment effectively suppressed the activation of inflammation and apoptosis pathways in both LPS-treated primary chondrocytes and cartilage tissue from MIA-induced osteoarthritis rats. These results suggest that LMWCP supplementation ameliorates the progression of osteoarthritis through its direct impact on inflammation and apoptosis in chondrocytes.

Upregulation of cIAP1 induced by AZD8330 alleviates osteoarthritis progression by inhibiting the RIP1-associated necrosis signaling pathway.

BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative joint disease [1]. It has come to light that AZD8330 can suppress the generation of proinflammatory factors and deter the inflammatory response [2]. Given that inflammation is a primary causative factor in OA, it is posited that AZD8330 might exhibit superior efficacy in OA management. METHODS: In this study, we investigated the potential of intraperitoneal injection of AZD8330 to retard the progression of osteoarthritis in a murine model with surgically induced medial meniscus destruction (DMM). Concurrently, we employed ATDC5 cartilage cells to dissect the mechanism through which AZD8330 inhibits the TNF-α-induced NF-κB signaling pathway via modulation of RIP1. The findings revealed that AZD8330 mitigated cartilage degradation and the inflammatory response, leading to a substantial reduction in OARSI scores among DMM mice treated with AZD8330. Mechanistically, AZD8330 functioned as a suppressor of the TNF-α-induced NF-κB/p65 signaling pathway by facilitating the phosphorylation activation of cIAP1-mediated RIP1. The combination of data from both in vivo and in vitro experiments supports the conclusion that AZD8330 can attenuate chondrocyte degradation, thereby alleviating OA, by regulating the NF-κB/P65 signaling pathway through modulation of RIP1 activity. Consequently, the utilization of AZD8330 may hold potential in the prophylaxis of osteoarthritis. RESULTS: Our investigation delineates the role of AZD8330 in the regulation of inflammation in the context of OA treatment. Furthermore, we have unveiled that the inhibitory impact of AZD8330 on OA may hinge upon the activation of cIAP1, which in turn downregulates RIP1, thereby restraining the NF-κB/P65 signaling pathway. This study lends credence to the notion that AZD8330 may be a promising contender for osteoarthritis therapy. CONCLUSIONS: Our study provides compelling evidence attesting to the capacity of AZD8330 in managing inflammation within the realm of OA treatment. Likewise, our study has elucidated that the attenuation of OA by AZD8330 relies on the activation of cIAP1 to inhibit RIP1, consequently suppressing the NF-κB signaling pathway. On the strength of our present study, we may have identified a viable drug candidate for OA treatment.

Bixa orellana ethyl acetate fraction and its isolated compound ellagic acid attenuate the progression of MIA-induced osteoarthritis in rat knees.

Osteoarthritis (OA) is a pathology that is characterized by progressive erosion of articular cartilage. In this context, medicinal plants have become relevant tools regarding their potential role in the prevention and treatment of OA, being safe and effective. The aim of this work was investigate the therapeutic efficacy of the ethyl acetate fraction of Bixa orellana leaves (BoEA) and ellagic acid (ElAc) for the therapeutic treatment of OA induced by monosodium iodoacetate (MIA) in rats. The plant material was extracted via maceration with 70 % hydroalcoholic solvent (BoHE). The ethyl acetate (BoEA) fraction was by solvents in increasing order of polarity. The ElAc was identified and isolated in BoEA using high performance liquid chromatography (HPLC-DAD) and analytical curve. The OA was induced using MIA in the right knee at the knee joint. Doses of BoEA and ElAc were administered daily (every 24 h, orally) at concentrations of 50, 100 and 50 mg/kg, respectively, for 28 days after induced OA. We evaluated the animals through clinical and radiological examinations every 7 days and, on the 29th day, the animals were euthanized, the joints being removed for histopathological analysis and the serum for cytokine analysis. BoEA and ElAc compounds reduced inflammation and nociception in OA and were as effective as indomethacin in clinical parameters of joint discomfort and allodynia in rats, in addition to showing improvements in radiological and histopathological images, acting on the progress of cartilage deterioration, proving properties related to anti-inflammatory and analgesic processes, being important allies for new therapeutic interventions for the treatment of OA.

Achyranthes bidentate extracts protect the IL-1ß-induced osteoarthritis of SW1353 chondrocytes.

Osteoarthritis, the most common joint disease worldwide, is a degenerative disease characterized by cartilage degeneration and inflammation. The active ingredients in the traditional Chinese medicinal plant Achyranthes bidentate can be used to treat waist, leg, and joint pain caused by rheumatism arthralgia. In this study, we identified the optimal microwave extraction protocol for saponins from A. bidentate, evaluated their protective effects against IL-1ß-induced inflammation in SW1353 human chondrocytes, and explored their protective pathway. The microwave-extraction parameters required to obtain the maximum yield of A. bidentate saponins using 80% ethanol were identified using response surface methodology. The parameters were solid-liquid ratio, 1:10; extraction time, 20 min; power, 721 W; temperature, 65 °C. The actual yield of saponins extracted was to be 194.01 µg/mg extract. The SW1353 cells were pretreated with A. bidentate extract (ABE) at a concentration of 50 or 100 µg/mL for 3 h, after which an inflammatory response was stimulated using IL-1ß. The ABE significantly reduced the expression of proinflammatory factors IL-6, TNF-α, COX-2, iNOS, PGE2, and NO, and inhibited NF-κB activity, effectively attenuating the inflammatory response. ABE also inhibited MMP13 and ADAMTS-5 expression, reducing IL-1ß-induced degradation of the extrachondral matrix. This confirmed that ABE effectively inhibits NF-κB activity and reduces IL-1ß-induced inflammation, extracellular matrix degradation, and expression of apoptotic proteins Bax and caspase-3. Therefore, ABE has potential as a new botanical drug for preventing osteoarthritis.