Cartilage Degradation Research Articles

Regenerative Effect of Mesenchymal Stem Cell on Cartilage Damage in a Porcine Model.

Osteoarthritis (OA) is a major public and animal health challenge with significant economic consequences. Cartilage degradation plays a critical role in the initiation and progression of degenerative joint diseases, such as OA. Mesenchymal stem cells (MSCs) have become increasingly popular in the field of cartilage regeneration due to their promising results. The objective of this preclinical study was to evaluate the regenerative effects of mesenchymal stem cells (MSCs) in the repair of knee cartilage defects using a porcine model. Seven healthy LYD breed white pigs, aged 9-10 weeks and weighing approximately 20 ± 3 kg, were used in the experimental protocol. Full-thickness defects measuring 8 mm in diameter and 5 mm in depth were induced in the lateral femoral condyle of the posterior limbs in both knee joints using a sterile puncture technique while the knee was maximally flexed. Following a 1-week induction phase, the pig treatment groups received a 0.3 million/kg MSC transplant into the damaged knee region, while the placebo group received a control solution as a treatment. Magnetic resonance imaging (MRI), computerized tomography (CT), visual macroscopic examination, histological analysis, and cytokine concentration analysis were used to assess cartilage regeneration. The findings revealed that human adipose-derived mesenchymal stem cells (hADSCs) were more effective in repairing cartilage than pig umbilical cord-derived mesenchymal stem cells (pUCMSCs). These results suggest that MSC-based treatments hold promise as a treatment option for cartilage repair, which aid in the treatment of OA. However, further studies with larger sample sizes and longer follow-up periods are required to fully demonstrate the safety and efficacy of these therapies in both animals and humans.

Cartilaginous glycoprotein‑39 as laboratory marker of dynamics of course and effectiveness of treatment in patients with osteoarthritis

Backgrounds. Osteoarthritis (OA) occupies the first rank among diseases of the musculoskeletal system and accounts for 18.4% of the structure of this pathology. Currently, OA is considered as a disease in which there is a violation of the processes of remodeling (degradation and synthesis) of cartilage tissues, subchondral bone, joint capsule, tendon-ligamentous and muscular apparatus. An increased concentration of cartilage glycoprotein-39 (CGP-39) in the circulation is associated with inflammatory diseases and the processes of active tissue restructuring. To date, CGP-39 is a marker of chondrocyte activation and a sign of progressive OA, which determines its clinical significance. Along with this, the role of this biomarker in evaluating the effectiveness of anti-inflammatory therapy is relevant.The purpose. Comparative assessment of the quantitative content of CGP-39 in patients with knee joint OA, depending on the severity of inflammatory changes in the joints, the dynamics of the disease and the effectiveness of therapy.Methods. The study included 36 patients with OA and 30 practically healthy volunteers, identical in gender and age to the examined patients. The mean age of patients was 64 years, the average duration of the disease was 6 years. The diagnosis was determined according to the diagnostic criteria of the American College of Rheumatology (ACR, 1991). Along with the generally accepted clinical, laboratory and instrumental diagnosis of OA, in all patients and in control persons the levels of circulating CGP-39 were measured by enzyme immunoassay (ELISA). All examined patients received Ambene® Bio for 20 days, followed by repeated determination of the level of CGP-39. For statistical processing of the obtained data, we have used the programs Microsoft Excel 2007 and Statistica 10.0. Using the application program KRelRisk 1.1, the relative risk indicator for the studied factor was determined.Results. In the blood of patients with OA, a significant increase in the levels of CGP-39 has been found in comparison with the group of healthy individuals, which indicates increased degradation of articular cartilage in OA. As the severity of knee OA increased, the concentration of CGP-39 in the blood serum significantly raised, including in comparison with the control group. Reliable direct correlations were found between CGP-39 and clinical indices of knee OA severity. The content of CGP-39 in serum in patients with stage III radiological OA was significantly higher than in patients with stage I–II. The highest level of CGP-39 in patients with OA is associated with the presence of synovitis. TThe level of CGP-39 significantly decreased in patients with knee OA after a course of Ambene® Bio therapy, which confirms the participation of CGP-39 in inflammation on the one hand and the possibility of its use as an indicator of the effectiveness of anti-inflammatory therapy on the other hand.Conclusions. CGP-39 as a marker of inflammation and degradation of articular cartilage reflects the severity of the course of OA. The investigation of this biomarker is useful not only for diagnostic purposes, but also to assess the response to anti-inflammatory treatment in patients with knee OA.

Fundamentals of osteoarthritis: Inflammatory mediators in osteoarthritis

As more has become known of the pathophysiology of osteoarthritis (OA), evidence that inflammation plays a critical role in its development and progression has accumulated. Here, we aim to review current knowledge of the complex inflammatory network in the OA joint. This narrative review is presented in three main sections: local inflammation, systemic inflammation, and therapeutic implications. We focused on inflammatory mediators and their link to OA structural changes in the joint. OA is characterized by chronic and low-grade inflammation mediated mostly by the innate immune system, which results in cartilage degradation, bone remodeling and synovial changes. Synovitis is regarded as an OA characteristic and associated with increased severity of symptoms and joint dysfunction. However, the articular cartilage and the subchondral bone also produce several pro-inflammatory mediators thus establishing a complex interplay between the different tissues of the joint. In addition, systemic low-grade inflammation induced by aging, obesity and metabolic syndrome can contribute to OA development and progression. The main inflammatory mediators associated with OA include cytokines, chemokines, growth factors, adipokines, and neuropeptides. Future research is needed to deeper understand the molecular pathways mediating the inflammation in OA to provide new therapeutics that target these pathways, or to repurpose existing drugs.

Identification of Andrographolide as a novel FABP4 inhibitor for osteoarthritis treatment

Background and PurposeFatty acid binding protein 4 (FABP4) has been identified as a contributor to cartilage degradation in osteoarthritis (OA) patients, and inhibiting FABP4 using small molecules has emerged as a promising approach for developing OA drugs. Our previous research showed that Andrographis paniculata, a medicinal plant, strongly inhibits FABP4 activity. This led us to hypothesize that Andrographis paniculata ingredients might have protective effects on OA cartilage through FABP4 inhibition. MethodsWe analyzed scRNA-seq data from joint tissue of OA patients (GSE152805; GSE145286) using Scanpy 1.9.1 and Single Cell Portal. We conducted docking analysis of FABP4 inhibitors using Autodock Vina v.1.0.2. We evaluated the anti-FABP4 activity using a fluorescence displacement assay and measured the fatty acid oxidation (FAO) activity using the FAOBlue assay. We used H2DCF-DA to measure reactive oxygen species (ROS) levels. We studied signaling pathways using bulk RNA sequencing and western blot analysis in human C28/I2 chondrocytes. We evaluated anti-OA activity in monosodium iodoacetate (MIA)-induced rats. ResultsWe identified Andrographolide (AP) as a novel FABP4 inhibitor. Bulk RNA-sequencing analysis revealed that FABP4 upregulated FAO and ROS in chondrocytes, which was inhibited by AP. ROS generation activated the NF-κB pathway, leading to overexpression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), which is a responsible factor for cartilage degradation in OA patients. AP inhibited FABP4, thereby reducing the overexpression of ADAMTS4 by inhibiting the NF-κB pathway. In MIA rats, AP treatment reduced the overexpression of ADAMTS4, repaired cartilage and subchondral bone, and promoted cartilage regeneration. ConclusionOur results indicate that the inhibition of FABP4 activity by AP explains the anti-OA properties of Andrographis paniculata by protecting against cartilage degradation in OA patients. Additionally, our findings suggest that AP may be a promising therapeutic agent for OA treatment due to its ability to alleviate cartilage damage and bone erosion.

Identification of a novel cuproptosis-related gene signature for rheumatoid arthritis-A prospective study.

Rheumatoid arthritis (RA) is a multifactorial systemic autoimmune disease characterized by ongoing synovial inflammation, leading to the degradation of cartilage. Cuproptosis, as a newly characterized form of cell death, may influence RA progression by regulating immune cells and chondrocytes. This study sets out to identify the hub cuproptosis-related gene (CRG) associated with the pathogenesis of RA. A series of bioinformatic analyses were performed to evaluate the expression score of CRGs and the immune infiltration landscape between RA and normal samples. The hub gene was screened through the correlation analysis of CRGs, and the interaction network between the hub gene and transcription factors (TFs) was constructed. Finally, the hub gene was validated through quantitative real-time polymerase chain reaction (qRT-PCR) of patient samples and cell experiments. Drolipoamide S-acetyltransferase (DLAT) was screened as the hub gene. Correlation analysis between the hub gene and immune microenvironment demonstrated that DLAT had the highest correlation with T follicular helper cells. Eight pairs of DLAT-TF interaction networks were constructed. Single-cell sequencing showed that CRGs were highly expressed in RA chondrocytes, and chondrocytes could be classified into three different subsets. qRT-PCR was used to validate the above results. Dlat knockdown in immortalized human chondrocytes led to significantly improved mitochondrial membrane potentials and reduced levels of intracellular reactive oxygen species (ROS), mitochondrial ROS and apoptosis. This study rudimentarily demonstrates the correlation between CRGs and immune cell infiltration in RA. The biomarker DLAT may provide comprehensive insights into the pathogenesis and drug targets of RA.

Efficacy of a proprietary combination of Tamarindus indica seeds and Curcuma longa rhizome extracts in osteoarthritis: a clinical investigation.

NXT15906F6 (TamaFlex™) is a proprietary blend containing standardized Tamarindus indica seeds and Curcuma longa rhizome extracts. Earlier, NXT15906F6 supplementation demonstrated reduced knee joint pain and improved musculoskeletal functions in healthy and knee osteoarthritis (KOA) subjects. The present randomized, double-blind, placebo-controlled study was focused on validating the clinical efficacy of NXT15906F6 in a larger number of subjects with KOA. Male and female subjects (age: 40-70 years; body mass index [BMI]: 20-29 kg/m2] were randomized into three groups receiving placebo (n = 50), NXT15906F6 (n = 50) or a blend of C. longa and Boswellia serrata extracts (CLBS) (n = 50). Subjects consumed 250 mg NXT15906F6, 1,000 mg CLBS or a matched placebo daily after breakfast over a period of 30 consecutive days. The primary efficacy outcome was the improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and the secondary efficacy measures included various tests on joint pain and musculoskeletal functions and evaluations ofserum high-sensitivity C-reactive protein (hs-CRP) and a cartilage degradation marker, C-terminal telopeptide of type II collagen in urine (uCTX-II). NXT15906F6 significantly (P < 0.001) reduced the WOMAC scores and improved musculoskeletal function scores in the participants as compared with baseline and placebo. NXT15906F6 participants reduced knee pain and improved musculoskeletal functions as early as day 5 of supplementation. In contrast, CLBS supplementation failed to show early efficacies in pain and functional scores, except for 30s-CST and primary knee flexion. The NXT1506F6-supplemented participants significantly reduced serum hs-CRP and uCTX-II levels from baseline and as compared with the placebo. Both supplementations did not alter the subjects' clinical chemistry, hematology, and vital parameters. The anti-inflammatory botanical composition NXT15906F6 supplementation mitigated joint pain and improved musculoskeletal functions and joint motility in KOA subjects. This botanical composition was also well-tolerated by the volunteers.

Calcitriol-Loaded Multifunctional Nanospheres with Superlubricity for Advanced Osteoarthritis Treatment.

Osteoarthritis (OA) is characterized by the lubrication dysfunction of a cartilage sliding interface caused by chronic joint inflammation, and effective nonsurgical therapy for advanced OA remains lacking. Addressing chronic joint inflammation, lubrication dysfunction, and cartilage-tissue degradation simultaneously may hopefully tackle this challenge. Herein, we developed superlubricative zein@alginate/strontium@calcitriol (ZASC) nanospheres to treat advanced OA. ZASC was confirmed to significantly improve joint lubrication through traditional tribological tests and our proposed tribological experiment to mimic the intra-articular condition based on the human medial tibiofemoral joint tissues. This finding was attributed to the hydration lubrication formed around the alginate-strontium spheres that enabled ball-bearing lubrication and the filling of cartilage defects. Moreover, ZASCs that released calcitriol in a sustained manner showed proliferative, anti-inflammatory, and anti-apoptosis effects in vitro. Further experiments demonstrated that ZASC exerted chondroprotective effects by inhibiting the breakdown of the extracellular matrix in patient-derived OA cartilage explants. In vivo results demonstrated that ZASC can effectively maintain a normal gait to improve joint function, inhibit abnormal bone remodeling and cartilage degradation in early OA and can effectively reverse the advanced OA progression. Therefore, ZASC is a potentially nonsurgical therapeutic strategy for advanced OA treatments.

Research progress on the role of chondrocyte mitochondrial homeostasis imbalance in the pathogenesis of osteoarthritis

To summarize the role of chondrocyte mitochondrial homeostasis imbalance in the pathogenesis of osteoarthritis (OA) and analyze its application prospects. The recent literature at home and abroad was reviewed to summarize the mechanism of mitochondrial homeostasis imbalance, the relationship between mitochondrial homeostasis imbalance and the pathogenesis of OA, and the application prospect in the treatment of OA. Recent studies have shown that mitochondrial homeostasis imbalance, which is caused by abnormal mitochondrial biogenesis, the imbalance of mitochondrial redox, the imbalance of mitochondrial dynamics, and damaged mitochondrial autophagy of chondrocytes, plays an important role in the pathogenesis of OA. Abnormal mitochondrial biogenesis can accelerate the catabolic reaction of OA chondrocytes and aggravate cartilage damage. The imbalance of mitochondrial redox can lead to the accumulation of reactive oxygen species (ROS), inhibit the synthesis of extracellular matrix, induce ferroptosis and eventually leads to cartilage degradation. The imbalance of mitochondrial dynamics can lead to mitochondrial DNA mutation, decreased adenosine triphosphate production, ROS accumulation, and accelerated apoptosis of chondrocytes. When mitochondrial autophagy is damaged, dysfunctional mitochondria cannot be cleared in time, leading to ROS accumulation, which leads to chondrocyte apoptosis. It has been found that substances such as puerarin, safflower yellow, and astaxanthin can inhibit the development of OA by regulating mitochondrial homeostasis, which proves the potential to be used in the treatment of OA. The mitochondrial homeostasis imbalance in chondrocytes is one of the most important pathogeneses of OA, and further exploration of the mechanisms of mitochondrial homeostasis imbalance is of great significance for the prevention and treatment of OA.

MicroRNA-224-5p nanoparticles balance homeostasis via inhibiting cartilage degeneration and synovial inflammation for synergistic alleviation of osteoarthritis

MicroRNAs play a crucial role in regulating cartilage extracellular matrix (ECM) metabolism and are being explored as potential therapeutic targets for osteoarthritis (OA). The present study indicated that microRNA-224-5p (miR-224-5p) could balance the homeostasis of OA via regulating cartilage degradation and synovium inflammatory simultaneously. Multifunctional polyamidoamine dendrimer with amino acids used as efficient vector to deliver miR-224-5p. The vector could condense miR-224-5p into transfected nanoparticles, which showed higher cellular uptake and transfection efficiency compared to lipofectamine 3000, and also protected miR-224-5p from RNase degradation. After treatment with the nanoparticles, the chondrocytes showed an increase in autophagy rate and ECM anabolic components, as evidenced by the upregulation of autophagy-related proteins and OA-related anabolic mediators. This led to a corresponding inhibition of cell apoptosis and ECM catabolic proteases, ultimately resulting in the alleviation of ECM degradation. In addition, miR-224-5p also inhibited human umbilical vein endothelial cells angiogenesis and fibroblast-like synoviocytes inflammatory hyperplasia. Integrating the above synergistic effects of miR-224-5p in regulating homeostasis, intra-articular injection of nanoparticles performed outstanding therapeutic effect by reducing articular space width narrowing, osteophyte formation, subchondral bone sclerosis and inhibiting synovial hypertrophy and proliferation in the established mouse OA model. The present study provides a new therapy target and an efficient intra-articular delivery method for improving OA therapy. Statement of significanceOsteoarthritis (OA) is the most prevalent joint disease worldwide. Gene therapy, which involves delivering microRNAs, has the potential to treat OA. In this study, we demonstrated that miR-224-5p can simultaneously regulate cartilage degradation and synovium inflammation, thereby restoring homeostasis in OA gene therapy. Moreover, compared to traditional transfection reagents such as lipofectamine 3000, G5-AHP showed better efficacy in both microRNA transfection and protection against degradation due to its specific surface structure. In summary, G5-AHP/miR-224-5p was developed to meet the clinical needs of OA patients and the high requirement of gene transfection efficiency, providing a promising paradigm for the future application and development of gene therapy.

Human Osteoarthritic Chondrocytes Express Nineteen Different TRP-Genes-TRPA1 and TRPM8 as Potential Drug Targets.

Transient receptor potential (TRP) ion channels are expressed in neuronal and some non-neuronal cells and are involved particularly in pain and thermosensation. We previously showed that TRPA1 is functionally expressed in human osteoarthritic (OA) chondrocytes and mediates inflammation, cartilage degradation, and pain in monosodium-iodoacetate-induced experimental OA. In the present study, we explored the expression of TRP-channels in primary human OA chondrocytes and investigated whether drugs used in the treatment of OA, ibuprofen and glucocorticoids, have effects on TRP-channel expression. OA cartilage was obtained from knee replacement surgery and chondrocytes were isolated with enzyme digestion. NGS analysis showed the expression of 19 TRP-genes in OA chondrocytes, with TRPM7, TRPV4, TRPC1, and TRPM8 having the highest counts in unstimulated cells. These results were verified with RT-PCR in samples from a different group of patients. Interleukin-1β (IL-1β) significantly increased TRPA1 expression, while TRPM8 and TRPC1 expression was decreased, and TRPM7 and TRPV4 expression remained unaffected. Furthermore, dexamethasone attenuated the effect of IL-1β on TRPA1 and TRPM8 expression. The TRPM8 and TRPA1 agonist menthol increased the expression of the cartilage-degrading enzymes MMP-1, MMP-3, and MMP-13 and the inflammatory factors iNOS and IL-6 in OA chondrocytes. In conclusion, human OA chondrocytes express 19 different TRP-genes, of which the significant TRPM8 expression is a novel finding. Dexamethasone attenuated IL-1β-induced TRPA1 expression. Interestingly, the TRPM8 and TRPA1 agonist menthol increased MMP expression. These results support the concept of TRPA1 and TRMP8 as potential novel drug targets in arthritis.

Meloxicam emulgel potently suppressed cartilage degradation in knee osteoarthritis: Optimization, formulation, industrial scalability and pharmacodynamic analysis

Background and objectiveMeloxicam (MLX) is prescribed for the management of pain and inflammation allied with osteoarthritis (OA). However, MLX causes intestinal damage in long term administration. Hence, meloxicam loaded emulgel (MLX-emulgel) was optimized, formulated and examined under stringent parameters in monosodium-iodoacetate (MIA) induced knee OA in Wistar rats. Methods and resultsNanoemulsion of MLX was fabricated by ultrasonication and microfluidization method with a droplet size of 66.81 ± 5.31-nm and zeta potential of −24.6 ± 0.72-mV. Further, MLX nanoemulsion was optimized with centrifugation, heating-cooling cycles and transmittance parameters in addition to scale-up feasibility with microfluidizer. Post optimization, MLX-nanoemulsion was tailored as emulgel with Carbopol Ultrez 10 NF and assessed for pH, rheology, textural properties, assay and stability features. The in-vitro release study revealed the Korsmeyer-Peppas release kinetics and ex-vivo skin permeation was improved by 6.71-folds. The skin distribution of MLX-emulgel evinced the transfollicular mode of permeation. In-vivo study indicated the protective action of MLX-emulegl expressed in terms of inflammatory cyctokines level, X-ray analysis of knee joints of rats, histopathology and OARSI (Osteoarthritis Research Society International) scoring. MLX-emulgel treated group displayed lower (P < 0.001) level of COX-2 intensity as compared to positive control group. However, it was comparable (P > 0.05) to the normal control group, MLX oral dispersion, i.v. solution and etoricoxib gel groups. MLX-emulgel showcased an alternative to the long term usage of analgesics for relieving the symptoms of knee OA. ConclusionMLX-emulgel may be a potential candidate for translating in to a clinically viable dosage form in the management of knee OA.

Triptoquinone A and B exercise a therapeutic effect in systemic lupus erythematosus by regulating NLRC3.

The autoimmune disorder systemic lupus erythematosus (SLE) is multifaceted, with limited therapeutic alternatives and detrimental side effects, particularly on bones and joints. This research endeavors to examine the curative potential and underlying mechanisms of in addressing SLE-associated bone and joint complications. Triptoquinone A and triptoquinone B, constituents of Tripterygium wilfordii polyglycoside tablets (TGTs), exhibit antioxidant and anti-inflammatory attributes; nonetheless, its function in SLE therapy remains elusive. This investigation delves into the role of oxidative stress in systemic lupus erythematosus (SLE) and probes the prospective remedial effects of triptoquinone A and triptoquinone B on inflammation and cartilage deterioration in SLE-affected joints. Employing bioinformatics analyses, differentially expressed genes (DEGs) and protein-protein interactions were discerned in SLE, rheumatoid arthritis (RA), and osteoarthritis (OA) datasets. Enrichment analyses unveiled shared genes implicated in immune system regulation and toll-like receptor signaling pathways, among others. Subsequent examination of triptoquinone A and triptoquinone B revealed their capacity to diminish NLRC3 expression in chondrocytes, resulting in decreased pro-inflammatory cytokine levels and cartilage degradation enzyme expression. Suppression of NLRC3 augmented the protective effects of triptoquinone A and B, implying that targeting NLRC3 may constitute a potential therapeutic strategy for inflammation and cartilage degeneration-associated conditions in SLE patients. Our discoveries indicate that triptoquinone A and triptoquinone B may impede SLE progression via the NLRC3 axis, offering potential benefits for SLE-affected bone and joint health.

Extracts of Oldenlandia diffusa protects chondrocytes via inhibiting apoptosis and associated inflammatory response in osteoarthritis

Ethnopharmacological relevanceOsteoarthritis (OA) is a type of joint disorder that is marked by the gradual breakdown of cartilage and persistent inflammation of the synovial membrane, and is a leading cause of disability among elderly people worldwide. Oldenlandia diffusa (OD) is a member of the Rubiaceae family, and various researches have revealed that it possesses antioxidant, anti-inflammatory, and anti-tumor properties. Extracts of Oldenlandia diffusa is commonly used in traditional oriental medicine to treat various illnesses, including inflammation and cancer. Aim of the studyThis study is aimed at investigating the anti-inflammatory and anti-apoptosis effects of OD and its potential mechanisms on IL-1β-induced mouse chondrocytes, as well as its characteristics in a mouse osteoarthritis model. Materials and methodsIn this study, the key targets and potential pathways of OD were determined through network pharmacology analysis and molecular docking. The potential mechanism of OD in osteoarthritis was verified by in vitro and in vivo studies. ResultsThe results of network pharmacology showed that Bax, Bcl2, CASP3, and JUN are key candidate targets of OD for the treatment of osteoarthritis. There is a strong correlation between apoptosis and both OA and OD. Additionally, molecular docking results show that β-sitosterol in OD can strongly bind with CASP3 and PTGS2. In vitro experiments showed that OD pretreatment inhibited the expression of pro-inflammatory factors induced by IL-1β, such as COX2, iNOS, IL-6, TNF-α, and PGE2. Furthermore, OD reversed IL-1β-mediated degradation of collagen II and aggrecan within the extracellular matrix (ECM). The protective effect of OD can be attributed to its inhibition of the MAPK pathway and inhibition of chondrocyte apoptosis. Additionally, it was found that OD can alleviate cartilage degradation in a mouse model of knee osteoarthritis. ConclusionOur study showed that β-sitosterol, one of the active components of OD, could alleviate the inflammation and cartilage degeneration of OA by inhibiting chondrocyte apoptosis and MAPK pathway.

Autophagy and apoptosis: regulatory factors of chondrocyte phenotype transition in osteoarthritis.

Osteoarthritis (OA) is the main pathogenic factor in diseases that cause joint deformities. As the main manifestation of the progress of OA, cartilage degradation has been closely associated with the degeneration of chondrocytes, which is induced by inflammatory factors and other trauma factors. Autophagy and apoptosis are the main mechanisms for cells to maintain homeostasis and play crucial roles in OA. Under the influence of external environmental factors (such as aging and injury), the metabolism of cells can be altered, which may affect the extent of autophagy and apoptosis. With the progression of OA, these changes can alter the cell phenotypes, and the cells of different phenotypes display distinct differences in morphology and function. In this review, we have summarized the alteration in cell metabolism, autophagy, and the extent of apoptosis during OA progression and its effects on the cell phenotypes to provide new ideas for further research on the mechanisms of phenotypic transition and therapeutic strategies so as to reverse the cell phenotypes.

The Impact of Physiotherapy in the Management of Non-Operated Gonarthrosis in Mali

Introduction: According to the WHO, osteoarthritis is the result of mechanical and biological phenomena that destabilise the balance between the synthesis and degradation of cartilage and subchondral bone. Gonarthrosis is a genuine public health problem in developed countries due to its high frequency, the functional impotence it causes and its socio-economic impact [2, 3]. Its prevalence is estimated at between 7% and 17% in people aged over 45 [4]. This incidence has continued to increase over the last few decades due to the industrialisation of the world and the sedentary lifestyle of human beings. In the absence of any study on the role of physiotherapy in the management of gonarthrosis in Mali. We deemed it necessary to undertake a study whose aim was to evaluate the impact of physiotherapy in the management of non-operated gonarthrosis in the physiotherapy department of the Centre National d'Appareillage Orthopédique du Mali (C.N.A.O.M). Methods and Patients: This was a descriptive cross-sectional study over a period of one month. All patients seen in consultation with gonarthrosis and consenting were included. Results: In total, out of 561 patients seen in consultation at the C.N.A.O.M, we included 10 patients, i.e. 1.78%. Females accounted for 86%, with an average age of 55 years. Gonarthrosis was unilateral in 28.6% and bilateral in 71.4%. With the exception of one patient, all the other patients were overweight or obese. Apart from one patient, physiotherapy improved the symptoms in all our patients. Conclusion: Gonarthrosis is a very disabling condition. Our results are similar to those in the literature, i.e. it mainly affects obese adult women. Management is multidisciplinary. Physiotherapy plays a key role in the management of gonarthrosis. It significantly improves the clinical signs and quality of life of patients. A multicentre case-control study would be useful to assess the efficacy of physiotherapy alone in the management of gonarthrosis.

Protective and Pain-Killer Effects of AMC3, a Novel N-Formyl Peptide Receptors (FPRs) Modulator, in Experimental Models of Rheumatoid Arthritis.

Rheumatoid arthritis is an autoimmune disorder that causes chronic joint pain, swelling, and movement impairment, resulting from prolonged inflammation-induced cartilage and bone degradation. The pathogenesis of RA, which is still unclear, makes diagnosis and treatment difficult and calls for new therapeutic strategies to cure the disease. Recent research has identified FPRs as a promising druggable target, with AMC3, a novel agonist, showing preclinical efficacy in vitro and in vivo. In vitro, AMC3 (1-30 µM) exhibited significant antioxidant effects in IL-1β (10 ng/mL)-treated chondrocytes for 24 h. AMC3 displayed a protective effect by downregulating the mRNA expression of several pro-inflammatory and pro-algic genes (iNOS, COX-2, and VEGF-A), while upregulating genes essential for structural integrity (MMP-13, ADAMTS-4, and COLIAI). In vivo, AMC3 (10 mg kg-1) prevented hypersensitivity and restored postural balance in CFA-injected rats after 14 days. AMC3 attenuated joint alterations, reduced joint inflammatory infiltrate, pannus formation, and cartilage erosion. Chronic AMC3 administration reduced transcriptional changes of genes causing excitotoxicity and pain (EAATs and CCL2) and prevented morphological changes in astrocytes, including cell body hypertrophy, processes length, and thickness, caused by CFA in the spinal cord. This study demonstrates the usefulness of AMC3 and establishes the groundwork for further research.

Stevioside protects primary articular chondrocytes against IL-1β-induced inflammation and catabolism by targeting integrin.

Osteoarthritis (OA) is a common, progressive, and chronic disorder of the joints that is characterized by the inflammation and degradation of articular cartilage and is known to significantly impair quality of daily life. Stevioside (SVS) is a natural diterpenoid glycoside that has anti-inflammatory benefits. Hence, in the current research, it was hypothesized that SVS might exert anti-inflammatory effects on articular chondrocytes and alleviate cartilage degradation in mice with OA. The expression of inflammatory cytokines, like inducible nitric oxide synthase (iNOS), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), and cyclooxygenase-2 (COX-2) in chondrocytes after interleukin-1β (IL-1β) exposure, was inhibited by the pretreatment of SVS. As well, SVS inhibited the reduction of collagen II and sry-box transcription factor 9 (SOX9) in chondrocytes stimulated by IL-1β and suppressed the expression of MMP3 and MMP13. Further, after treatment with SVS, cell cytometry, autophagy flux, and related protein expression showed diminished cell apoptosis and reduced autophagy impairment. Moreover, SVS blocked the activation of phosphoinositide-3-kinase/Akt/nuclear factor-kappa beta (PI3K/Akt/NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways stimulated by IL-1β. This resulted in decreased cellular inflammation. In vivo experiments with intra-articular injections of SVS in mice with the DMM mouse model demonstrated a decrease in cartilage degradation and an improvement in subchondral bone remodeling. After the integrin αVβ3-related knockdown using siRNA, a reversed effect was observed on the anti-inflammatory, anabolic promoting, catabolic blocking, and NF-κB and MAPK signaling pathway inhibition of SVS on chondrocytes treated with IL-1β. The above findings highlighted that SVS blocked IL-1β, triggered an inflammatory response in mice chondrocytes, and prevented cartilage degradation in vivo through integrin αVβ3. This suggested that SVS might serve as a novel therapeutic option for OA.

CircSFMBT2-OA alleviates chondrocyte apoptosis and extracellular matrix degradation through repressing NF-κB/NLRP3 inflammasome activation

BackgroundIntra-articular inflammation and cartilage degradation are the major pathological characteristics of osteoarthritis (OA). Mounting studies have revealed that circular RNAs (circRNAs) act as an important regulatory role in inflammatory diseases and are frequently dys-expressed in OA cartilage tissues. ObjectiveHere, a dys-regulated cicrRNA (has_circ_0017636, termed circSFMBT2-OA) was identified, and its role in regulating lipopolysaccharide (LPS)-induced chondrocyte injury was next investigated. MethodsCHON-001 chondrocytes were treated with LPS, and then the levels of circSFMBT2-OA, cartilage-related genes, and pro-inflammatory cytokines were measured using quantitative real-time PCR (qRT-PCR) and Western blot analysis. CHON-001 cell viability, proliferation, and apoptosis were assayed using Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EDU), and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, respectively. ResultsCircSFMBT2-OA level was significantly down-regulated in OA cartilage tissues and LPS-treated CHON-001 cells. Functionally, circSFMBT2-OA overexpression accelerated cell proliferation, and suppressed cell apoptosis, pro-inflammatory cytokines production, matrix-degrading enzymes expression, and ECM degradation in CHON-001 cells. Inversely, circSFMBT2-OA depletion decreased cell viability and increased matrix-degrading enzymes expression and ECM degradation. Mechanistically, circSFMBT2-OA inhibited LPS-induced NF-κB/NOD-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome activation in CHON-001 cells. Consequently, NLRP3 activator reversed the effect of circSFMBT2-OA on repressing LPS-induced CHON-001 cell injury. ConclusionThese data reveal a vital effect of a novel circSFMBT2-OA on repressing OA progression and provide a promising target to treat OA.

Human placental extract: a potential therapeutic in treating osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease marked by cartilage degradation and loss of function. Recently, there have been increased efforts to attenuate and reverse OA by stimulating cartilage regeneration and preventing cartilage degradation. Human placental extract (HPE) may be an option due to its anti-inflammatory, antioxidant, and growth stimulatory properties. These properties are useful in preventing cell death and senescence, which may optimize in-situ cartilage regeneration. In this review, we discuss the anatomy and physiology of the placenta, as well as explore in vivo and in vitro studies assessing its effects on tissue regeneration. Finally, we assess the potential role of HPE in cartilage regenerative medicine and OA. The Medline database was utilized for all studies that involved the use of HPE or human placenta hydrolysate. Exclusion criteria included articles not written in English, conference reviews, editorials, letters to the editor, surveys, case reports, and case series. HPE had significant anti-inflammatory and regenerative properties in vitro and in vivo. Furthermore, HPE had a role in attenuating cellular senescence and cell apoptosis via reduction of reactive oxidative species both in vitro and in vivo. One study explored the effects of HPE in OA and demonstrated reduction in cartilage catabolic gene expression, indicating HPE's effect in attenuating OA. HPE houses favorable properties that can attenuate and reverse tissue damage. This may be a beneficial therapeutic in OA as it creates a more favorable environment for in-situ cartilage regeneration. More well designed in-vitro and in-vivo studies are needed to define the role of HPE in treating OA.

Simiao pill attenuates collagen-induced arthritis and bleomycin-induced pulmonary fibrosis in mice by suppressing the JAK2/STAT3 and TGF-β/Smad2/3 signalling pathway.

Simiao Pill (SM) as a classic prescription of traditional Chinese medicine treatment of damp-heat arthralgia, the earliest from 'Cheng Fan Bian Du ', written by the Qing Dynasty doctor Zhang Bingcheng. Previous studies have shown that SM has obvious curative effect on rheumatoid arthritis, which provides a basis for the application of SM in rheumatoid arthritis related complications. Interstitial lung disease (ILD), as the most severe complication of rheumatoid arthritis (RA), lacks effective clinical treatments and a corresponding animal model. Simiao pill (SM) is a traditional Chinese medicine prescription extensively used as a complementary and alternative treatment for RA. However, the effect and mechanism of SM on RA-ILD have not yet been reported. This study aimed to investigate an appropriate animal model that can simulate RA-ILD, and the efficacy, safety, and mechanism of SM on RA-ILD. Collagen-induced arthritis (CIA) and bleomycin-induced pulmonary fibrosis model were combined to construct the CIA-BLM model. After the intervention of SM, the protective effects of SM on RA-ILD were determined by detecting the CIA mouse arthritis index (AI), Spleen index, and the extent of pulmonary fibrosis. The joint inflammation and pulmonary fibrosis were detected by immunohistochemistry, H&E staining, safranin- O fast green Sirius red staining, trap staining, and Masson staining. Finally, the mechanism was verified by Western blot and immunohistochemistry. Our work showed that SM significantly reduced joint swelling, arthritis index, pulmonary fibrosis score, and spleen index in CIA mice. The pathological examination results indicated Si-Miao Pill suppressed inflammation, pulmonary fibrosis, bone erosion, and cartilage degradation of the ankle joint. Besides, SM up-regulated expressions of E-cadherin, whereas down-regulated expressions of α-SMA. Further studies confirmed that SM regulated JAK2/STAT3 and TGF-β/SMAD2/3. SM can not only effectively improve joint inflammation by JAK2/STAT3 Pathway but also inhibit pulmonary fibrosis by TGF-β/SMAD2/3. The fibrosis induced by CIA-BLM model was more stable and obvious than that induced by CIA model alone.