MIA-induced Osteoarthritis Research Articles

Targeted non-invasive Metformin-Curcumin co-loaded nanohyaluosomes halt osteoarthritis progression and improve articular cartilage structure: A preclinical study

Osteoarthritis (OA) is a degenerative disease that affects the quality of life in elderly and young populations. Current therapies using corticosteroids and non-steroidal anti-inflammatory drugs via parenteral or oral routes show limited ability to retard progression of the disease and achieve long term effectiveness and safety. Herein, the potential of MT-Cur combinatorial nano-formulations in OA management was explored for the first time. MT-Cur loaded nanohyaluosomes (MT-Cur-HL1) were designed for topical administration of the combined therapy in OA. The optimized MT-Cur-HL1 showed particle size 247.7 ± 3.7 nm, zeta potential −37.3 ± 0.4 mV; and entrapment efficiency (%EE) 70.22 %±0.303 and 76.7 %±0.077 for MT and Cur, respectively. MT-Cur-HL1 exhibited sustained drug release over 24 h and were stable over 3 months at 4 °C in terms of P.S., ZP and %EE. A detailed preclinical study, using MIA-induced osteoarthritis rat model, revealed the most significant anti-arthritic effect and halted OA progression of MT-Cur-HL1. This was proved to be mainly through the potentiation of p-AMPK signaling that ultimately led to suppression of its downstream TLR4/ NF-κB signaling pathway with subsequent reduction in MMP13 and ADAMTS5 induced chondrocytes degeneration. This study proved that this trajectory effectively promotes a significant improvement in the articular cartilage structure and reinforcement of joint mobility with an efficient antinociceptive effect. In conclusion, the novel MT-Cur coloaded nanohyaluosomes offer a promising non-invasive approach for the local management of OA.

Osteoarthritis induced by monosodium iodoacetate model

Objectives: this study aimed to highlight the evolution of the osteoarthritis (OA) model induced by monosodium iodoacetate (MIA) and its collaboration with the knowledge of the pathophysiology of inflammation, hypernociception and cartilage degeneration. Methods: PubMed and Science Direct were used with the descriptors: knee osteoarthritis or osteoarthritis of ankle) and (rat or osteoarthritis induced by monoiodoacetate) and (animal model of osteoarthritis or joint nociception). Studies containing rats, mice, and monoiodoacetate-induced osteoathritis were included. Exclusion criteria were: Animal models of osteoarthritis induced by destabilization; meniscectomy-induced osteoarthritis; non-invasive animal models of osteoarthritis induced by fracture, compression and tibial overload; animal models of osteoarthritis with large animals and models of osteoarthritis by papain or bacterial collagenase. We summarized studies that used MIA to induce knee or ankle OA in rats or mice and the evolution of the inflammatory markers. Results: a total of 38 original manuscripts met the inclusion criteria and were considered in the study. The model of OA induced by MIA is well-established and explored with several methodologies and has been widely used in different species. MIA induces cell death, progressive loss of chondrocytes and histological changes that mimics human OA. Studies with this model demonstrated inflammation, neurogenic hyperalgesia, release of cytokines and matrix metalloproteinases. More recently, molecular biology data confirm the activation of nuclear transcription factors, which modulates the expression of citokines in apoptotic chondrocytes. Conclusion: the MIA-induced OA has been useful in predicting several characteristics for the elucidation of osteoarthritis pathophysiology.

The Oral Administration of Lactobacillus delbrueckii subsp. lactis 557 (LDL557) Ameliorates the Progression of Monosodium Iodoacetate-Induced Osteoarthritis.

Low-grade body inflammation is a major cause of osteoarthritis (OA), a common joint disease. Gut dysbiosis may lead to systemic inflammation which can be prevented by probiotic administration. The Lactobacillus delbrueckii subsp. lactis 557 (LDL557) has been demonstrated to have beneficial effects for anti-inflammation. This study investigated the effects of LDL557 on OA progress using monosodium iodoacetate (MIA)-induced OA of rats. Live or heat-killed (HK)-LDL557 of a low or high dose was administrated for two weeks before MIA-induced OA, and then continuously administrated for another six weeks. After taking supplements for eight weeks, OA progress was analyzed. Results showed that MIA induced knee joint swelling, chondrocyte damage, and cartilage degradation, and supplementation with a high dose of LDL557 reduced MIA-induced knee joint swelling, chondrocyte damage, and cartilage degradation. Additionally, MIA increased serum levels of the matrix-degrading enzyme MMP-13, while a high dose of HK-LDL557 decreased it for the controls. Simultaneously, bone turnover markers and inflammatory cytokines of serum were assayed, but no significant differences were found except for a TNF-α decrease from a low dose of live LDL557. These results demonstrated that supplementation with high doses of live LDL557 or HK-LDL557 can reduce the progression of MIA-induced OA in rats.

Evaluation of Pain-Associated Behavioral Changes in Monoiodoacetate-Induced Osteoarthritic Rats Using Dynamic Weight Bearing Analysis.

Pain is the primary clinical indication of osteoarthritis (OA), and behavioral assessments in rodent pain models are widely used to understand pain patterns. These preclinical pain assessments can also help us to understand the effectiveness of emerging therapeutics for prolonged OA pain management. Along with evoked methods like mechanical allodynia and thermal hyperalgesia, non-evoked methods such as dynamic weight bearing (DWB) analysis are valuable tools for behavioral assessments of pain. Both these methods were utilized to study pain-induced behavioral changes in a monoiodoacetate (MIA)-induced osteoarthritic pain model, which is a well-established preclinical OA pain model. However, the utility of DWB analysis as an indicator of long-term pain sensitivity (more than 4 weeks) remains largely unexplored. Understanding the long-term sensitivity of DWB is valuable to study the effectiveness of novel prolonged pain-relieving therapeutics. Here, we studied the dynamic behavioral changes in MIA-induced OA rats over a period of 16 weeks using DWB measurements. Female Sprague Dawley rats were injected in the right knee joint with MIA (3 mg) using X-ray guidance. Multiple dynamic postural evaluations such as ipsilateral weight percentage, paw area, contralateral/ipsilateral weight ratio and area ratio were assessed to understand the behavioral changes. The data showed that the ipsilateral weight bearing percentage alone is not sufficient to assess pain-related behavior beyond 6 weeks. This study shows the advantages and limitations of dynamic weight bearing as an assessment tool for the long-term progression of pain behavior in MIA-induced OA rats.

Disease-modifying rdHSV-CA8* non-opioid analgesic gene therapy treats chronic osteoarthritis pain by activating Kv7 voltage-gated potassium channels.

Chronic pain is common in our population, and most of these patients are inadequately treated, making the development of safer analgesics a high priority. Knee osteoarthritis (OA) is a primary cause of chronic pain and disability worldwide, and lower extremity OA is a major contributor to loss of quality-adjusted life-years. In this study we tested the hypothesis that a novel JDNI8 replication-defective herpes simplex-1 viral vector (rdHSV) incorporating a modified carbonic anhydrase-8 transgene (CA8*) produces analgesia and treats monoiodoacetate-induced (MIA) chronic knee pain due to OA. We observed transduction of lumbar DRG sensory neurons with these viral constructs (vHCA8*) (~40% of advillin-positive cells and ~ 50% of TrkA-positive cells colocalized with V5-positive cells) using the intra-articular (IA) knee joint (KJ) route of administration. vHCA8* inhibited chronic mechanical OA knee pain induced by MIA was dose- and time-dependent. Mechanical thresholds returned to Baseline by D17 after IA KJ vHCA8* treatment, and exceeded Baseline (analgesia) through D65, whereas negative controls failed to reach Baseline responses. Weight-bearing and automated voluntary wheel running were improved by vHCA8*, but not negative controls. Kv7 voltage-gated potassium channel-specific inhibitor XE-991 reversed vHCA8*-induced analgesia. Using IHC, IA KJ of vHCA8* activated DRG Kv7 channels via dephosphorylation, but negative controls failed to impact Kv7 channels. XE-991 stimulated Kv7.2-7.5 and Kv7.3 phosphorylation using western blotting of differentiated SH-SY5Y cells, which was inhibited by vHCA8* but not by negative controls. The observed prolonged dose-dependent therapeutic effects of IA KJ administration of vHCA8* on MIA-induced chronic KJ pain due to OA is consistent with the specific activation of Kv7 channels in small DRG sensory neurons. Together, these data demonstrate for the first-time local IA KJ administration of vHCA8* produces opioid-independent analgesia in this MIA-induced OA chronic pain model, supporting further therapeutic development.

In vitro and in vivo studies of the therapeutic potential of Tinospora crispa extracts in osteoarthritis: Targeting oxidation, inflammation, and chondroprotection

Ethnopharmacological relevanceThe increasing incidence of osteoarthritis (OA), especially among the elderly population, highlights the need for more efficacious treatments that go beyond mere symptomatic relief. Tinospora crispa (L.) Hook. f. & Thomson (TC) boasts a rich traditional heritage, widespread use in Ayurveda, traditional Chinese medicine (TCM), and diverse indigenous healing practices throughout Southeast Asia for treating arthritis, rheumatism, fever, and inflammation. Aim of the studyThis study investigates the anti-inflammatory and chondroprotective potential of TC stem extracts, including ethanolic TC extract (ETCE) and aqueous TC extract (ATCE), in modulating OA pathogenesis through in vitro and in vivo approaches. Materials and methodsThe study utilized LC-MS/MS to identify key compounds in TC stem extracts. In vitro experiments assessed the antioxidative and anti-inflammatory properties of ETCE and ATCE in activated macrophages, while an in vivo monoiodoacetate (MIA)-induced OA rat model evaluated the efficacy of ETCE treatment. Key markers of oxidative stress, such as superoxide dismutase (SOD) and catalase (CAT), were assessed alongside pro-inflammatory cytokines TNF-α and IL-1β, and matrix-degrading enzymes, matrix metalloproteinase (MMP 13 and MMP 3), to evaluate the therapeutic effects of TC stem extracts on OA. ResultsChemical profiling of the extracts was conducted using LC-MS/MS in positive ionization, identifying seven compounds, including pseudolaric acid B, stylopine, and reticuline, which were reported for the first time in this species. The study utilized varying concentrations of TC stem extracts, specifically 6.25–25 μg/mL for in vitro assays and 500 mg/kg for in vivo studies. Our findings also revealed that both ETCE and ATCE exhibit dose-dependent reduction in reactive oxygen species (41%–52%) and nitric oxide (NO) levels (50% and 72%), with ETCE displaying superior antioxidative efficacy and marked anti-inflammatory properties, significantly reducing TNF-α and IL-6 at concentrations above 12.5 μg/mL. In the MIA-induced OA rat model, ETCE treatment notably outperformed ATCE, markedly lowering TNF-α (1.91 ± 0.37 pg/mL) and IL-1β (26.30 ± 3.68 pg/mL) levels and effectively inhibiting MMP 13 and MMP 3 enzymes. Furthermore, macroscopic and histopathological assessments, including ICRS scoring and OARSI grading, indicate that TC stem extracts reduce articular damage and proteoglycan loss in rat knee cartilage. These results suggest that TC stem extracts may play a role in preventing cartilage degradation and potentially alleviating inflammation and pain associated with OA, though further studies are needed to confirm these effects. ConclusionThis study highlights the potential of TC stem extracts as a novel, chondroprotective therapeutic avenue for OA management. By targeting oxidative stress, pro-inflammatory cytokines, and cartilage-degrading enzymes, TC stem extracts promise to prevent cartilage degradation and alleviate inflammation and pain associated with OA.

Impact of Cuminaldehyde and Indomethacin Co-Administration on Inflammatory Responses in MIA-Induced Osteoarthritis in Rats.

Osteoarthritis (OA) remains a chronic incurable condition, presenting substantial challenges in treatment. This study explores a novel strategy by investigating the concurrent use of cuminaldehyde, a natural compound, with indomethacin in animal models of MIA-induced OA. Our results demonstrate that the co-administration of cuminaldehyde and indomethacin does indeed produce a superior effect when compared to these compounds individually, significantly enhancing therapeutic outcomes. This effect is evidenced by a marked reduction in pro-inflammatory cytokines IL-6 and IFN-γ, alongside a significant increase in the anti-inflammatory cytokine IL-10, compared to treatments with each compound alone. Radiographic analyses further confirm the preservation of joint integrity and a reduction in osteoarthritic damage, highlighting the association's efficacy in cartilage-reducing damage. These findings suggests that the association of cuminaldehyde and indomethacin not only slows OA progression but also offers enhanced cartilage-reducing damage and fosters the production of protective cytokines. This study underscores the potential benefits of integrating natural products with pharmaceuticals in OA management and stresses the importance of further research to fully understand the mechanisms underlying the observed potentiated effects.

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

BackgroundThis study aimed to investigate the analgesic impact of S(+)-ketamine on pain behavior and synovial inflammation in an osteoarthritis (OA) model. MethodsAnimals 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. ResultsS(+)-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. ConclusionLow Intra-articular (IA) doses of S(+)-ketamine reduced MIA-induced OA pain but did not reverse synovial histopathological changes. IRB approval number23115 012030/2009-05.

Curcuma longa L. extract exhibits anti-inflammatory and cytoprotective functions in the articular cartilage of monoiodoacetate-injected rats.

Osteoarthritis (OA), the most prevalent form of arthritis, is a degenerative joint disease marked by the progressive deterioration of articular cartilage, leading to clinical manifestations such as joint pain. This study investigated the effects of Curcuma longa L. extract (CL) containing curcumin, demethoxycurcumin, and bisdemethoxycurcumin on monosodium iodoacetate (MIA)-induced OA rats. Sprague-Dawley rats with MIA-induced OA received CL supplementation at doses of 5, 25, and 40 mg/kg body weight. CL extract administration suppressed mineralisation parameters and morphological modifications and decreased arachidonate5-lipoxygenase and leukotriene B4 levels in articular cartilage. Additionally, it decreased serum prostaglandin E2, NO, and glycosaminoglycanlevels as well as the protein expression of phosphorylated inhibitor kappa B-alpha, phosphorylated p65, cyclooxygenase-2, and inducible nitric oxide synthase in the cartilage of MIA-injected rats. Furthermore, it also reduced matrix metalloproteinases and elevated SMAD family member 3 phosphorylation, tissue inhibitor of metalloproteinases, aggrecan, collagen type I, and collagen type II levels in the articular cartilage of MIA-induced OA rats. This study's findings suggest that CL supplementation helps prevent OA development and is an effective therapy for OA.

Evaluating the Anti-Osteoarthritis Potential of Standardized Boswellia serrata Gum Resin Extract in Alleviating Knee Joint Pathology and Inflammation in Osteoarthritis-Induced Models.

Osteoarthritis is a widespread chronic degenerative disease marked by the deterioration of articular cartilage, modifications in subchondral bone, and a spectrum of symptoms, including pain, stiffness, and disability. Ultimately, this condition impairs the patient's quality of life. This study aimed to evaluate the therapeutic efficacy of standardized Boswellia serrata gum resin extract (BSRE) in a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis. A total of 60 rats were allocated into six groups: normal control group (NC), osteoarthritis control (injected with MIA, OC), O + B50 (injected with MIA and treated with 50 mg/kg body weight (BW) BSRE), O + B75 (injected with MIA and treated with 75 mg/kg BW BSRE), O + B100 (injected with MIA and treated with 100 mg/kg BW BSRE), and O + M (injected with MIA and treated with 150 mg/kg BW methyl sulfonyl methane). Several parameters, including knee joint swelling, histopathological changes, and the expression of collagen type II alpha 1 (COL2A1) and aggrecan, were comprehensively assessed. Concurrently, the serum levels and mRNA expression of inflammatory mediators, cytokines, and matrix metalloproteinases (MMPs) were analyzed in both the serum and knee joint synovium. The results demonstrated that BSRE significantly mitigated knee joint swelling, cartilage destruction, and tissue deformation. Notably, BSRE administration markedly upregulated the expression of COL2A1 and aggrecan while concurrently reducing levels of nitric oxide, prostaglandin E2, leukotriene B4, interleukin (IL)-6, and tumor necrosis factor (TNF)-α. Furthermore, a substantial decrease was observed in the mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, 5-lipoxygenase, IL-6, TNF-α and MMP-3 and -13, thereby indicating promising therapeutic implications for osteoarthritis. In conclusion, BSRE exhibited anti-inflammatory properties and inhibited cartilage matrix degradation in a rat model of MIA-induced osteoarthritis, with the O + B100 group showing significant reductions in swelling and notable improvements in joint cartilage damage. These findings illuminate the preventive and therapeutic potential of BSRE for osteoarthritis treatment, emphasizing the criticality of exhaustive evaluation of novel compounds.

Comparison of the protective effect of the upper zone of the growth plate and unique cartilage matrix-associated protein with hyaluronic acid and corticosteroids on an experimental rat osteoarthritis model.

This study sought to compare the protective effect of the upper zone of the growth plate and unique cartilage matrix-associated protein (UCMA) with hyaluronic acid (HA) and corticosteroids (CS) in a rat model of osteoarthritis (OA). In the experimental animal study, 40 adult male rats were randomly assigned into five groups: control, monosodium iodoacetate (MIA) + vehicle (MIA+V), MIA+HA, MIA+CS, and MIA+UCMA. The OA model was induced by an intra-articular MIA injection to the right knee, and intra-articular injections into the right knee were performed on the treatment groups seven times every three days for 21 days. The knee joints were taken for histopathology and immunohistochemistry (IHC) analyses after the rats were sacrificed. All sections were stained with hematoxylin-eosin, safranin O and fast green FCF, and toluidine blue, and bone morphogenetic protein 2 (BMP-2) and nuclear factor-kappa B (NF-κB) expressions were analyzed with IHC. The Mankin scoring was utilized to determine the histopathological changes in the joint tissues. Mankin score was significantly higher in the MIA group compared to the control group. Histopathologically, in the UCMA-, HA-, and CS-treated groups, degenerations in the articular cartilage were milder than in the MIA+V group. Mankin score was found to be decreased significantly in the UCMA-, HA-, and CS-treated groups compared to the MIA group. Furthermore, IHC analyses revealed that NF-κB and BMP-2 expressions elevated in the MIA-induced OA model, while they were downregulated after UCMA, HA, and CS treatments. Our data revealed that UCMA could be used as a potential protective molecule in the prevention and treatment of OA. Furthermore, the protective effect of UCMA was similar to HA and CS, and its possible beneficial roles against OA may be linked to the reduced BMP-2 and NF-κB levels. Further experimental research would make significant contributions to a better understanding of the therapeutic effect of UCMA on degenerative cartilage tissues.

Moderate mechanical stress suppresses chondrocyte ferroptosis in osteoarthritis by regulating NF-κB p65/GPX4 signaling pathway

Ferroptosis is a recently identified form of programmed cell death that plays an important role in the pathophysiological process of osteoarthritis (OA). Herein, we investigated the protective effect of moderate mechanical stress on chondrocyte ferroptosis and further revealed the internal molecular mechanism. Intra-articular injection of sodium iodoacetate (MIA) was conducted to induce the rat model of OA in vivo, meanwhile, interleukin-1 beta (IL-1β) was treated to chondrocytes to induce the OA cell model in vitro. The OA phenotype was analyzed by histology and microcomputed tomography, the ferroptosis was analyzed by transmission electron microscope and immunofluorescence. The expression of ferroptosis and cartilage metabolism-related factors was analyzed by immunohistochemical and Western blot. Animal experiments revealed that moderate-intensity treadmill exercise could effectively reduce chondrocyte ferroptosis and cartilage matrix degradation in MIA-induced OA rats. Cell experiments showed that 4-h cyclic tensile strain intervention could activate Nrf2 and inhibit the NF-κB signaling pathway, increase the expression of Col2a1, GPX4, and SLC7A11, decrease the expression of MMP13 and P53, thereby restraining IL-1β-induced chondrocyte ferroptosis and degeneration. Inhibition of NF-κB signaling pathway relieved the chondrocyte ferroptosis and degeneration. Meanwhile, overexpression of NF-κB by recombinant lentivirus reversed the positive effect of CTS on chondrocytes. Moderate mechanical stress could activate the Nrf2 antioxidant system, inhibit the NF-κB p65 signaling pathway, and inhibit chondrocyte ferroptosis and cartilage matrix degradation by regulating P53, SLC7A11, and GPX4.

Protective and Anti-Inflammatory Effects of Avocado and Soybean Unsaponifiables in Primary Rat Chondrocytes and an MIA-Induced Osteoarthritis Model

Protective and Anti-Inflammatory Effects of Avocado and Soybean Unsaponifiables in Primary Rat Chondrocytes and an MIA-Induced Osteoarthritis Model

Ameliorative effects of undifferentiated and differentiated BM-MSCs in MIA-induced osteoarthritic Wistar rats: roles of NF-κB and MMPs signaling pathways.

Osteoarthritis (OA) is a degenerative joint condition that is persistent. OA affects millions of people throughout the world. Both people and society are heavily economically burdened by osteoarthritis. There is currently no medication that can structurally alter the OA processes or stop the disease from progressing. Stem cells have the potential to revolutionize medicine due to their capacity to differentiate into chondrocytes, capacity to heal tissues and organs including osteoarthritic joints, and immunomodulatory capabilities. Therefore, the goal of the current investigation was to determine how bone marrow-derived mesenchymal stem cells (BM-MSCs) and chondrogenic differentiated mesenchymal stem cells (CD-MSCs) affected the treatment of OA in rats with monosodium iodoacetate (MIA)-induced osteoarthritis. Male Wistar rats were injected three times with MIA (1 mg)/100 µL isotonic saline to induce osteoarthritis in the ankle joint of the right hind leg. Following the MIA injection, the osteoarthritic rats were given weekly treatments of 1 × 106 BM-MSCs and CD-MSCs into the tail vein for three weeks. The obtained results showed that in osteoarthritic rats, BM-MSCs and CD-MSCs dramatically decreased ankle diameter measurements, decreased oxidized glutathione (GSSG) level, and boosted glutathione peroxidase (GPx) and glutathione reductase (GR) activities. Additionally, in rats with MIA-induced OA, BM-MSCs and CD-MSCs dramatically boosted interleukin-10 (IL-10) serum levels while considerably decreasing serum anticitrullinated protein antibodies (ACPA), tumour necrosis factor-α (TNF-α), and interleukin-17 (IL-17) levels as well as ankle transforming growth factor-β1 (TGF-β1) expression. Analysis of histology, immunohistochemistry, and western blots in osteoarthritic joints showed that cartilage breakdown and joint inflammation gradually decreased over time. It is possible to conclude from these results that BM-MSCs and CD-MSCs have anti-arthritic potential in MIA-induced OA, which may be mediated via inhibitory effects on oxidative stress, MMPs and inflammation through suppressing the NF-κB pathway. In osteoarthritis, using CD-MSCs as a treatment is more beneficial therapeutically than using BM-MSCs.

Serum Metabolomic Alteration in Rats with Osteoarthritis Treated with Palm Tocotrienol-Rich Fraction Alone or in Combination with Glucosamine Sulphate.

Osteoarthritis (OA) is a degenerative joint condition with limited disease-modifying treatments currently. Palm tocotrienol-rich fraction (TRF) has been previously shown to be effective against OA, but its mechanism of action remains elusive. This study aims to compare serum metabolomic alteration in Sprague-Dawley rats with monosodium iodoacetate (MIA)-induced OA which were treated with palm TRF, glucosamine sulphate, or a combination of both. This study was performed on thirty adult male rats, which were divided into normal control (n = 6) and OA groups (n = 24). The OA group received intra-articular injections of MIA and daily oral treatments of refined olive oil (vehicle, n = 6), palm TRF (100 mg/kg, n = 6), glucosamine sulphate (250 mg/kg, n = 6), or a combination of TRF and glucosamine (n = 6) for four weeks. Serum was collected at the study's conclusion for metabolomic analysis. The findings revealed that MIA-induced OA influences amino acid metabolism, leading to changes in metabolites associated with the biosynthesis of phenylalanine, tyrosine and tryptophan as well as alterations in the metabolism of phenylalanine, tryptophan, arginine and proline. Supplementation with glucosamine sulphate, TRF, or both effectively reversed these metabolic changes induced by OA. The amelioration of metabolic effects induced by OA is linked to the therapeutic effects of TRF and glucosamine. However, it remains unclear whether these effects are direct or indirect in nature.

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 β3) 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.

The Synergistic Effects of Corbicula fluminea and Sarcodia montagneana on Alleviating Systemic Inflammation and Osteoarthritis Progression.

Osteoarthritis (OA) is a progressive disease that causes pain, stiffness, and inflammation in the affected joints. Currently, there are no effective treatments for preventing the worst outcomes, such as synovitis or cartilage degradation. Sarcodia montagneana and Corbicula fluminea are common species found in the ocean or in freshwater areas. Their extracts are demonstrated to possess both antioxidative and anti-inflammatory functions. This study aimed to investigate the synergistic effects of the extracts of Sarcodia montagneana (SME) and Corbicula fluminea (FCE) on reducing local and systemic inflammation, as well as their efficacy in OA symptom relief. An in vitro monocytic LPS-treated THP-1 cell model and in vivo MIA-induced mouse OA model were applied, and the results showed that the combinatory usage of SME and FCE effectively suppressed IFN-γ and TNF-α production when THP-1 cells were treated with LPS. SME and FCE also significantly decreased the systemic TNF-α level and joint swelling and prevented the loss of proteoglycan in the cartilage within the joints of OA mice. The data shown here provide a potential solution for the treatment of osteoarthritis.

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.

L-Carnitine augments probenecid anti-inflammatory effect in monoiodoacetate-induced knee osteoarthritis in rats: involvement of miRNA-373/P2X7/NLRP3/NF-κB milieu

Osteoarthritis (OA) is a degenerative joint disease, whereas the underlying molecular trails involved in its pathogenesis are not fully elucidated. Hence, the current study aimed to investigate the role of miRNA-373/P2X7/NLRP3/NF-κB trajectory in its pathogenesis as well as the possible anti-inflammatory effects of probenecid and l-carnitine in ameliorating osteoarthritis via modulating this pathway. In the current study, male Sprague Dawley rats were used and monoiodoacetate (MIA)-induced knee osteoarthritis model was adopted. Probenecid and/or L-carnitine treatments for 14 days succeeded in reducing OA knee size and reestablishing motor coordination and joint mobility assessed by rotarod testing. Moreover, different treatments suppressed the elevated serum levels of IL-1β, IL-18, IL-6, and TNF-α via tackling the miRNA-373/P2X7/NLRP3/NF-κB, witnessed as reductions in protein expressions of P2X7, NLRP3, cleaved caspase-1 and NF-κB. These were accompanied by increases in procaspase-1 and IκB protein expression and in miRNA-373 gene expression OA knee to various extents. In addition, different regimens reversed the abnormalities observed in the H and E as well as Safranin O-Fast green OA knees stained sections. Probenecid or l-carnitine solely showed comparable results on the aforementioned parameters, whereas the combination therapy had the most prominent effect on ameliorating the aforementioned parameters. In conclusion, l-carnitine augmented the probenecid’s anti-inflammatory effect to attenuate MIA-induced osteoarthritis in rats by provoking the miRNA-373 level and inhibiting the P2X7/NLRP3/NF-κB milieu, leading to the suppression of serum inflammatory cytokines: IL-1β, IL-18, IL-6, and TNF-α. These findings suggest the possibility of using probenecid and l-carnitine as a useful therapeutic option for treatment of osteoarthritis.Graphical abstract

Exploring rutinoside's impact on inflammation in a rat knee OA model induced by monosodium iodoacetate (MIA)

Link of Video Abstract: https://youtu.be/Dl8sYvPfd6o Introduction: Osteoarthritis (OA) is a common joint disease characterized by persistent inflammation and cartilage breakdown. Monosodium iodoacetate (MIA) is often used to generate OA in rats. This study aims to explore the anti-inflammatory benefits of rutinoside, a natural flavonoid glycoside, in rats with MIA-induced knee OA. Methods: The male Wistar rats were divided into five groups (n = 6) and randomly allocated to one of five treatments: control, OA, rutinoside, glucosamine sulfate, and sodium diclofenac-treated group. 3 mg of monosodium iodoacetate (MIA) was injected intra-articularly into the knee joints of rats to induce osteoarthritis. Rutinoside, glucosamine sulfate, and sodium diclofenac were given daily for four weeks. Body weight, joint swelling, knee bend score, interleukin-1 (IL-1) levels, interleukin-8 (IL-8) levels, and C-terminal telopeptide type II collagen (CTX-II) levels were all assessed. Result: Rutinoside significantly decreased body weight loss, joint edema, and knee bend test scores compared to the untreated OA group. Furthermore, rutinoside was equally effective as glucosamine sulfate and sodium diclofenac in these parameters. The rutinoside, glucosamine sulfate, and sodium diclofenac groups had significantly lower IL-1, IL-8, and CTX-II levels than the untreated OA group. Conclusion: Rutinoside reduced inflammatory responses, lowered joint edema, and improved knee bend test scores in a rat model of MIA-induced osteoarthritis. Its efficacy in preventing illness was comparable to glucosamine sulfate and sodium diclofenac. More study is needed to better understand rutinoside's underlying mechanisms and long-term consequences for treating osteoarthritis.