Osteoarthritis Animal Research Articles

Co-delivery of IL-1Ra and SOX9 via AAV inhibits inflammation and promotes cartilage repair in surgically induced osteoarthritis animal models.

Osteoarthritis (OA), a prevalent joint disorder, can lead to disability, with no effective treatment available. Interleukin-1 (IL-1) plays a crucial role in the progression of OA, and its receptor antagonist (IL-1Ra), a natural IL-1 inhibitor, represents a promising therapeutic target by obstructing the IL-1 signaling pathway. This study delivered IL-1Ra via adeno-associated virus (AAV), a gene therapy vector enabling long-term protein expression, to treat knee osteoarthritis (KOA) in animal models. scAAV-oIL-1Ra-I1/2 injected directly into the joint in both MMT/ACLT-induced KOA model rat improved abnormal gait (increasing footprint area and pressure), subchondral bone lesions, and significantly reduced cartilage wear and pathological scores. In the MMT-induced KOA rabbit model, weight-bearing asymmetry (indicating pain) improved after 8 weeks of scAAV-oIL-1Ra-I1/2 administration, and X-ray showed decreased K-L scores (severity grade), reduced cartilage loss, and lower pathology scores compared to untreated animals. Additionally, sex-determining region Y-type high mobility group box 9 (SOX9) was co-delivered with IL-1Ra via AAV in ACLT + MMT-induced KOA rats. The combined treatment significantly alleviated subchondral bone lesions, cartilage destruction, synovial inflammation, and pathological scores, demonstrating superior efficacy compared to either treatment administered alone. Co-delivering IL-1Ra and SOX9 inhibited IL-1 mediated inflammatory signaling, maintained cartilage homeostasis, and promoted its repair in KOA models, suggesting potential for clinical use.

Danggui niantong decoction attenuates synovial fibrosis through regulating PI3k/AKT signaling pathway.

Danggui Niantong Decoction (DGNTD) is a traditional Chinese medicine compound formula that has been demonstrated to possess efficacy in the treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), as well as for dispelling moisture and relieving pain. As mentioned before, DGNTD is essential for synovial inflammation in RA. The primary features of the OA synovial membrane are low-grade inflammation, hyperplasia with enhanced fibroblast-like synoviocytes (FLS) proliferation, and fibrosis, which can cause pain and stiffness. However, it is still unknown how DGNTD functions in the OA synovium. Clarify the influence of DGNTD on OA synovium and investigate potential mechanisms of action. The principal constituents of DGNTD were detected using liquid chromatography-mass spectrometry (LC-MS) analysis. To evaluate the effect of DGNTD on synovial inflammation and fibrosis, a transforming growth factor beta (TGF-β)-stimulated rat FLS cell model and a rat OA animal model based on anterior cruciate ligament transection (ACLT) and partial medial meniscectomy (MMx) were employed. Our results showed that 322 components were detected using LC-MS. In vivo, DGNTD therapy reduced pain, synovial inflammation, and fibrosis. The therapy significantly reduced levels of pain-related molecules, specifically calcitonin gene-related peptide (CGRP) and inducible nitric oxide synthase (iNOS), as well as fibrotic markers, including alpha smooth muscle actin (α-SMA) and type III collagen alpha-1 (Col3a1), in the synovium. A proteomics study demonstrated that DGNTD decreased the fibrotic protein Col3a1. DGNTD reduced the mRNA expression of pro-inflammatory and fibrotic markers (tumor necrosis factor alpha (TNF-α), interleukin-1 beta(IL-1β), interleukin-6(IL-6), α-SMA, Col3a1and TGF-β) in TGF-β-induced FLS. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and validation results revealed that DGNTD inhibits synovial fibrosis via the phosphatidylinositol 3-kinase (PI3K)/protein Kinase B (AKT) signaling pathway. DGNTD partially relieves pain, synovitis, and synovial fibrosis by regulating the PI3K/AKT pathway. These findings provide fresh information about the underlying mechanisms and successful therapy of OA, as well as a theoretical and experimental foundation for the clinical management of OA using DGNTD.

Polydatin retards the progression of osteoarthritis by maintaining bone metabolicbalance and inhibiting macrophage polarization.

Polydatin (PD), also known as tiger cane glycoside, is a natural compound extracted from the Japanese knotweed plant, which is often referred to as white resveratrol. It exhibits anti-inflammatory, antioxidant, and anti-apoptotic effects in the treatment of various diseases. However, the potential molecular mechanisms of PD in osteoarthritis have not been clearly elucidated. Anterior cruciate ligament transection (ACLT) surgery was performed to establish an osteoarthritis animal model. Female mice at the age of 12weeks were intraperitoneally injected with different concentrations of PD (20 and 40mg/kg). In vitro models were established by isolating mouse articular chondrocytes, which were subsequently treated with lipopolysaccharide or IL-1β for 24h for subsequent experiments. In addition, different concentrations of PD were administered for 12h. Morphological changes were observed by toluidine blue staining, joint bone metabolism changes were observed by tartrate-resistant acid phosphatase staining, immunohistochemistry was used to observe the expression levels of inflammatory factors and extracellular matrix. MicroCT analysis was conducted to assess changes in the microstructure of subchondral bone trabeculae, and Western blot was performed to measure the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and markers of M1 polarization in macrophages. PD significantly delays the progression of osteoarthritis induced by ACLT, effectively inhibits IL-1β-induced joint inflammation, bone metabolic remodeling and extracellular matrix degradation. In addition, paeoniflorin markedly suppresses the transmission of the NF-κB signaling pathway and reverses M1 polarization in macrophages induced by IL-1β. Taken together, PD might be a potential therapeutic agent for the prevention and treatment of osteoarthritis.

Hck promotes IL-1β-induced extracellular matrix degradation, inflammation, and apoptosis in osteoarthritis via activation of the JAK-STAT3 signaling pathway

We investigated role of haematopoietic cell kinase (Hck) in osteoarthritis (OA) and to explore the underlying mechanisms driving its effects. An OA animal model was established and after OA induction, rats received intra-articular injections of lentivirus twice a week for four weeks. Rats were divided into four groups: control (healthy rats without OA), OA model (rats with induced OA), OA + Len-si-NC (OA rats treated with a non-targeting control lentivirus), and OA + Len-si-Hck (OA rats treated with lentivirus targeting Hck). Blood samples were collected, and serum cytokine levels were measured using ELISA. Afterward, the rats were sacrificed for histological analysis and TUNEL assay. In vitro, IL-1β-treated human chondrocytes were transfected with Hck, and the effects on cell viability, apoptosis, ECM degradation, and JAK-STAT3 signaling were assessed. Colivelin, a JAK-STAT3 agonist, was used to confirm the pathway’s involvement. Results indicated increased Hck expression in the cartilage tissues of OA rats and in IL-1β-stimulated chondrocytes. Silencing Hck in vivo reduced IL-6 and TNF-α levels, apoptosis, and preserved cartilage structure. In vitro, Hck knockdown in IL-1β-treated chondrocytes resulted in enhanced cell viability, reduced apoptosis, and decreased ECM degradation. Notably, the expression of MMP3 and MMP13 was significantly lowered, while collagen II and aggrecan levels were restored. Additionally, Hck knockdown inhibited JAK-STAT3 activation, which was evident from reduced levels of phosphorylated JAK1 and STAT3. The addition of colivelin reversed these effects, confirming that Hck mediates its effects through the JAK-STAT3 pathway. Overall, our findings indicate that Hck is critical in OA progression by promoting inflammation, apoptosis, and ECM degradation through the JAK-STAT3 signaling pathway activation.

Targeting Long Noncoding RNA H19 in Subchondral Bone Osteocytes and the Alleviation of Cartilage Degradation in Osteoarthritis.

Emerging evidence suggests long noncoding RNA H19 is associated with osteoarthritis (OA) pathology. However, how H19 contributes to OA has not been reported. This study aims to investigate the biologic function of H19 in OA subchondral bone remodeling and OA progression. Clinical joint samples and OA animal models induced by surgical destabilization of the medial meniscus (DMM) were used to verify the causal relationship between osteocyte H19 and OA subchondral bone and cartilage changes. MLO-Y4 osteocyte cells subjected to fluid shear stress were used to verify the mechanism underlying H19-mediated mechanoresponse. Finally, the antisense oligonucleotide (ASO) against H19 was delivered to mice knee joints by magnetic metal-organic framework (MMOF) nanoparticles to develop a site-specific delivery method for targeting osteocyte H19 for OA treatment. Both clinical OA subchondral bone and wildtype mice with DMM-induced OA exhibit aberrant higher subchondral bone mass, with more H19 mice expressing osteocytes. On the contrary, mice with osteocyte-specific deletion of H19 are less vulnerable to DMM-induced OA phenotype. In MLO-Y4 cells, H19-mediated osteocyte mechanoresponse through PI3K/AKT/GSK3signal activation by EZH2-induced H3K27me3 regulation on protein phosphatase 2A inhibition. Targeted inhibition of H19 (using ASO-loaded MMOF) substantially alleviates subchondral bone remodeling and OA phenotype. In summary, our results provide new evidence that the elevated H19 expression in osteocytes may contribute to aberrant subchondral bone remodeling and OA progression. H19 appears to be required for the osteocyte response to mechanical stimulation, and targeting H19 represents a new promising approach for OA treatment.

Osteoarthritis early-, mid- and late-stage progression in the rat medial meniscus transection model.

Osteoarthritis is a degenerative disease of synovial joints affecting all tissues, including articular cartilage and subchondral bone. Osteoarthritis animal models can recapitulate aspects of human disease progression and are used to test efficacy of drugs, biomaterials, and cell therapies. The rat medial meniscus transection (MMT) model is a surgically induced posttraumatic osteoarthritis model commonly used for preclinical therapeutic screening. We describe herein, the qualitative and quantitative changes to articular cartilage, subchondral bone, and formation of osteophytes at early-, mid-, and late-stages of osteoarthritis progression. Tibia of MMT-operated animals showed proteoglycan loss and fibrillation along articular cartilage surfaces as early as 3-weeks post-surgery. With contrast-enhanced micro-CT technique, quantitative, 3-dimensional analysis of the tibia showed that the articular cartilage thickened at 3- and 6-weeks post-surgery and decreased at 12-weeks post-surgery. This decreased cartilage thickness corresponded with increased lesions in the articular cartilage that led to its full degradation and exposing the subchondral bone layer. Further, subchondral bone thickening was significant at 6-weeks post-surgery and followed cartilage damage. Osteophytes were found as early as 3-weeks post-surgery and coincided with articular cartilage degradation. Cartilaginous osteophytes preceded mineralization, suggesting endochondral ossification. The rat MMT model has predominantly been used out to 3-weeks, and most studies determined the effect of therapies to delay or prevent the onset of osteoarthritis. We provide evidence that an extension of the rat MMT model out to 6- and 12-weeks more resembled severe phenotypes of human osteoarthritis. Thus, evaluating novel therapeutics at late-stage will be important for eventual clinical translation.

METTL14-mediated lncRNA-FAS-AS1 promotes osteoarthritis progression by up-regulating ADAM8.

Osteoarthritis (OA) is a prevalent degenerative disease. We explored the role and regulatory mechanisms of lncRNA-FAS-AS1 in OA progression. We exposed human immortalized chondrocytes to IL-1β for 24 h to induce an OA cell model. The target molecule levels were assessed using western blot and quantitative real-time PCR (RT-qPCR). Cell viability and apoptosis were measured using CCK-8 and flow cytometry. The m6A modification of FAS-AS1 was determined using MeRIP. We examined the binding relationships between FAS-AS1, Fragile X mental retardation 1 (FMR1), and A disintegrin and metalloproteinase 8 (ADAM8) using RIP and RNA pull-down. The OA animal model was established by separating the medial collateral ligament and medial meniscus. Safranin-O staining and Mankin's scale were employed to evaluate pathological changes within the cartilage. FAS-AS1, METTL14, and ADAM8 were upregulated, and the JAK/STAT3 signaling pathway was activated in OA mice and IL-1β-induced chondrocytes. FAS-AS1 knockdown inhibited extracellular matrix degradation in IL-1β-induced chondrocytes; however, ADAM8 overexpression reversed this effect. FAS-AS1 maintained the stability of ADAM8 mRNA by recruiting FMR1. METTL14 knockdown repressed FAS-AS1 expression in an m6A-dependent manner. FAS-AS1 overexpression reversed the inhibitory effects of METTL14 knockdown on JAK/STAT3 signaling and cartilage damage in the OA model both invitro and invivo. METTL14-mediated FAS-AS1 promotes OA progression through the FMR1/ADAM8/JAK/STAT3 axis.

PP2Ac Regulates Autophagy via Mediating mTORC1 and ULK1 During Osteoclastogenesis in the Subchondral Bone of Osteoarthritis.

The molecular mechanism underlying abnormal osteoclastogenesis triggering subchondral bone remodeling in osteoarthritis (OA) is still unclear. Here, single-cell and bulk transcriptomics sequencing analyses are performed on GEO datasets to identify key molecules and validate them using knee joint tissues from OA patients and rat OA models. It is found that the catalytic subunit of protein phosphatase 2A (PP2Ac) is highly expressed during osteoclastogenesis in the early stage of OA and is correlated with autophagy. Knockdown or inhibition of PP2Ac weakened autophagy during osteoclastogenesis. Furthermore, the ULK1 expression of the downstream genes is significantly increased when PP2Ac is knocked down. PP2Ac-mediated autophagy is dependent on ULK1 phosphorylation activity during osteoclastogenesis, which is associated with enhanced dephosphorylation of ULK1 Ser637 residue regulating at the post-translational level. Additionally, mTORC1 inhibition facilitated the expression level of PP2Ac during osteoclastogenesis. In animal OA models, decreasing the expression of PP2Ac ameliorated early OA progression. The findings suggest that PP2Ac is also a promising therapeutic target in early OA.

Dental pulp stem cells-loaded kartogenin-modified hydrogel microspheres with chondrocyte differentiation property for cartilage repair

Stem cell-based regimens have evolved as a promising approach to cartilage reparations. Research efforts in this realm aim to enhance the therapeutic capabilities of stem cells and develop more effective cell delivery strategies. Herein, we present novel dental pulp stem cells (DPSCs)-loaded kartogenin-modified hydrogel microspheres with chondrocyte differentiation property for temporomandibular joint (TMJ) osteoarthritis treatment. Leveraging microfluidic technology, DPSCs were successfully encapsulated in hydrogel microspheres, serving as the pivotal contributors to cartilage repair. By modifying the hydrogel with kartogenin, these microspheres facilitated sustained stimulation of DPSCs’ chondrogenic differentiation. In vitro experimental results revealed that the DPSCs exhibited advanced cartilage-forming differentiation, as evidenced by the up-regulation of relative gene expressions and protein markers. Additionally, the DPSCs-loaded microspheres system displayed a capacity to regenerate and repair tissue at the cartilage defects in a TMJ osteoarthritis animal model. Thus, the DPSCs-loaded kartogenin-modified hydrogel microspheres exhibit significant promise for cartilage repair, showcasing the substantial potential for future clinical applications.

The Implications of Brain-Derived Neurotrophic Factor in the Biological Activities of Platelet-Rich Plasma.

Platelet-rich plasma (PRP) is a biological blood-derived therapeutic obtained from whole blood that contains higher levels of platelets. PRP has been primarily used to mitigate joint degeneration and chronic pain in osteoarthritis (OA). This clinical applicability is based mechanistically on the release of several proteins by platelets that can restore joint homeostasis. Platelets are the primary source of brain-derived neurotrophic factor (BDNF) outside the central nervous system. Interestingly, BDNF and PRP share key biological activities with clinical applicability for OA management, such as anti-inflammatory, anti-apoptotic, and antioxidant. However, the role of BDNF in PRP therapeutic activities is still unknown. Thus, this work aimed to investigate the implications of BDNF in therapeutic outcomes provided by PRP therapy in vitro and in-vivo, using the MIA-OA animal model in male Wistar rats. Initially, the PRP was characterized, obtaining a leukocyte-poor-platelet-rich plasma (LP-PRP). Our assays indicated that platelets activated by Calcium release BDNF, and suppression of M1 macrophage polarization induced by LP-PRP depends on BDNF full-length receptor, Tropomyosin Kinase-B (TrkB). OA animals were given LP-PRP intra-articular and showed functional recovery in gait, joint pain, inflammation, and tissue damage caused by MIA. Immunohistochemistry for activating transcriptional factor-3 (ATF-3) on L4/L5 dorsal root ganglia showed the LP-PRP decreased the nerve injury induced by MIA. All these LP-PRP therapeutic activities were reversed in the presence of TrkB receptor antagonist. Our results suggest that the therapeutic effects of LP-PRP in alleviating OA symptoms in rats depend on BDNF/TrkB activity.

Metabolomics in Osteoarthritis Knee: A Systematic Review of Literature.

Osteoarthritis (OA) is a common degenerative disorder of the synovial joints and is usually an age-related disease that occurs due to continuous wear and tear of the cartilage in the joints. Presently, there is no proven medical management to halt the progression of the disease in the early stages. The purpose of our systematic review is to analyze the possible metabolites and metabolic pathways that are specifically involved in OA pathogenesis and early treatment of the disease. The articles were collected from PubMed, Cochrane, Google Scholar, Embase, and Scopus databases. "Knee", "Osteoarthritis", "Proteomics", "Lipidomics", "Metabolomics", "Metabolic Methods", and metabolic* were employed for finding the articles. Only original articles with human or animal OA models with healthy controls were included. From the initial screening, a total of 458 articles were identified from the 5 research databases. From these, 297 articles were selected in the end for screening, of which 53 papers were selected for full-text screening. Finally, 50 articles were taken for the review based on body fluid: 6 urine studies, 15 plasma studies, 16 synovial fluid studies, 11 serum studies, 4 joint tissue studies, and 1 fecal study. Many metabolites were found to be elevated in OA. Some of these metabolites can be used to stage the OA Three pathways that were found to be commonly involved are the TCA cycle, the glycolytic pathway, and the lipid metabolism. All these studies showed a vast array of metabolites and metabolic pathways associated with OA. Metabolites like lysophospholipids, phospholipids, arginine, BCCA, and histidine were identified as potential biomarkers of OA but a definite association was not identified, Three pathways (glycolytic pathway, TCA cycle, and lipid metabolic pathways) have been found as highly significant in OA pathogenesis. These metabolic pathways could provide novel therapeutic targets for the prevention and progression of the disease. The online version contains supplementary material available at 10.1007/s43465-024-01169-5.

Recent Trends in Adipose Tissue-Derived Injectable Therapies for Osteoarthritis: A Scoping Review of Animal Models.

Background and Objectives: This scoping review investigates recent trends in adipose tissue-derived injectable therapies for osteoarthritis (OA) in animal models, focusing on minimally manipulated or lightly processed adipose tissue. By evaluating and examining the specific context in which these therapies were investigated across diverse animal OA models, this review aims to provide valuable insights that will inform and guide future research and clinical applications in the ongoing pursuit of effective treatments for osteoarthritis. Materials and Methods: This research conducted a comprehensive literature review of PubMed and Embase to determine studies about minimally manipulated adipose tissue-derived injectable therapies for osteoarthritis investigated using animal models. The primary search found 530 results. After excluding articles that focused on spontaneous osteoarthritis; on transfected, preconditioned, cultured, or co-cultured adipose-derived stem cells; and articles with unavailable full text, we included 11 articles in our review. Results: The examined therapies encompassed mechanical micro-fragmented adipose tissue (MFAT) and stromal vascular fraction (SVF) obtained via collagenase digestion and centrifugation. These interventions were evaluated across various animal models, including mice, rats, rabbits, and sheep with induced OA. Notably, more studies concentrated on surgically induced OA rather than chemically induced OA. The assessment of these therapies focused on elucidating their protective immunomodulatory, anti-inflammatory, and chondroregenerative potential through comprehensive evaluations, including macroscopic assessments, histological analyses, immunohistochemical examinations, and biochemical assays. Conclusions: This review provides a comprehensive analysis of adipose tissue-derived injectable therapies for osteoarthritis across diverse animal models. While revealing potential benefits and insights, the heterogeneity of data and the limited number of studies highlight the need for further research to formulate conclusive recommendations for clinical applications.

Changes in the Serum Metabolome in an Inflammatory Model of Osteoarthritis in Rats.

Osteoarthritis (OA) is a pathology of great impact worldwide. Its physiopathology is not completely known, and it is usually diagnosed by imaging techniques performed at advanced stages of the disease. The aim of this study was to evaluate early serum metabolome changes and identify the main metabolites involved in an inflammatory OA animal model. This study was performed on thirty rats. OA was induced in all animals by intra-articular injection of monoiodoacetate into the knee joint. Blood samples were taken from all animals and analyzed by mass spectrometry before OA induction and 28, 56, and 84 days following induction. Histological evaluation confirmed OA in all samples. The results of this study allow the identification of several changes in 18 metabolites over time, including organic acids, benzenoids, heterocyclic compounds, and lipids after 28 days, organic acids after 56 days, and lipid classes after 84 days. We conclude that OA induces serological changes in the serum metabolome, which could serve as potential biomarkers. However, it was not possible to establish a relationship between the identified metabolites and the time at which the samples were taken. Therefore, these findings should be confirmed in future OA studies.

Baccharis dracunculifolia DC Consumption Improves Nociceptive and Depressive-like Behavior in Rats with Experimental Osteoarthritis.

Osteoarthritis (OA) persistently activates nociceptors, leading to chronic pain, which is often accompanied by the comorbid development of emotional impairments (anxiety and depression), an effect associated with microgliosis. Baccharis dracunculifolia DC (Asteraceae), a Brazilian edible plant, is an important source of active compounds with anti-inflammatory abilities. Thus, we evaluated its ability to reverse OA-induced nociceptive and emotional-like impairments in osteoarthritic ovariectomized female rats using the kaolin/carrageenan (K/C) model. Four weeks after OA induction, mechanical hyperalgesia was confirmed, and the treatment started. Control animals (SHAMs) were treated with phosphate-buffered saline (PBS), while arthritic animals (ARTHs) either received PBS or B. dracunculifolia 50 mg/kg (Bd50) and 100 mg/kg (Bd100), via gavage, daily for five weeks. At the end of the treatment, anxiety-like behavior was assessed using the Open Field Test (OFT), anhedonia was assessed using the Sucrose Preference Test (SPT), and learned helplessness was assessed using the Forced Swimming Test (FST). After occision, microglia were stained with IBA-1 and quantified in brain sections of target areas (prefrontal cortex, amygdala, and periaqueductal grey matter). Treatment with B. dracunculifolia extract reversed OA-induced mechanical hyperalgesia and partly improved depressive-like behavior in OA animals' concomitant to a decrease in the number of M1 microglia. Our findings suggest that B. dracunculifolia extracts can potentially be used in the food industry and for the development of nutraceuticals and functional foods.

Collagen type II solution extracted from supercritical carbon dioxide decellularized porcine cartilage: regenerative efficacy on post-traumatic osteoarthritis model

Osteoarthritis (OA) of the knee is a common degenerative articular disorder and is one of the main causes of pain and functional disability. Cartilage damage is frequently linked to elevated osteoarthritis incidence. Supercritical carbon dioxide (scCO2) decellularized cartilage graft produced from the porcine cartilage is an ideal candidate for cartilage tissue engineering. In the present study, we derived collagen type II (Col II) solution from the scCO2 decellularized porcine cartilage graft (dPCG) and compared its efficacy with hyaluronic acid (HA) in the surgical medial meniscectomy (MNX) induced post-traumatic osteoarthritis (PTOA) model. Dose-dependent attenuation of the OA (12.3 ± 0.8) progression was observed in the intra‐articular administration of Col II solution (7.3 ± 1.2) which significantly decreased the MNX-induced OA symptoms similar to HA. The pain of the OA group (37.4 ± 2.7) was attenuated dose-dependently by Col II solution (45.9 ± 4.1) similar to HA (43.1 ± 3.5) as evaluated by a capacitance meter. Micro‐CT depicted a dose-dependent attenuation of articular cartilage damage by the Col II solution similar to HA treatment. A significant (p < 0.001) dose-dependent elevation in the bone volume was also observed in Col II solution-treated OA animals. The protective competence of Col II solution on articular cartilage damage is due to its significant (p < 0.001) increase in the expression of type II collagen, aggrecan and SOX‐9 similar to HA. To conclude, intra‐articular administration of type II collagen solution and HA reestablished the injured cartilage and decreased osteoarthritis progression in the experimental PTOA model.Graphical

Analysis of joint protein expression profile in anterior disc displacement of TMJ with or without OA.

Anterior disc displacement (ADD) is a common clinical issue and may cause osteoarthritis (OA). However, the research of protein changes in synovial fluid as disease development marker and potential treatment clue is still insufficient. We conducted the high-resolution mass spectrometry (MS) of synovial fluid collected from 60 patients with normal disk position to ADD and ADD with osteoarthritis (OA). The proteins with significant changes among the 3 groups were analyzed by biological information and further validated by in primary rat condyle chondrocytes and OA animal model. FGL2, THBS4, TNC, FN1, OMD etc. were significantly increased in ADD without OA (p < 0.05), which reflected the active extracellular matrix and collagen metabolism. FGFR1, FBLN2, GRB2 etc. were significantly increased in ADD with OA group (p < 0.05), which revealed an association with apoptosis and ferroptosis. Proteins such as P4HB, CBLN4, FHL1, VIM continuously increase in the whole disease progress (p < 0.05). Both the invitro and invivo results are consistent with protein changes detected in MS profile. This study firstly provides the expression changes of proteins from normal disc condyle relationship toward ADD with OA, which can be selected and studied further as disease progress marker and potential treatment targets.

Network analysis of monoamines involved in anxiety-like behavior in a rat model of osteoarthritis.

Chronic pain is a major health problem that affects a significant number of patients, resulting in personal suffering and substantial health care costs. One of the most commonly reported causal conditions is osteoarthritis (OA). In addition to sensory symptoms, chronic pain shares an inherent overlap with mood or anxiety disorders. The involvement of the frontal cortex, striatum and nucleus accumbens, in the affective processing of pain is still poorly understood. Male Wistar rats were divided into two groups: MIA (monoiodoacetate injected into the knee-model of OA) and sham (NaCl). Behavioral tests assessing pain, anxiety, and depressive behavior were performed at week 1, 3, 4, 6, 8, and 10. Neurochemical assays were conducted at weeks 3, 6, and 10 post-MIA injection, followed by the neurotransmitters and their metabolites correlation matrix and network analysis. OA animals developed rapid pain phenotype, whereas anxiety-like behavior accompanied the development of a pain phenotype from 6week post-MIA injection. We did not detect any depressive-like behavior. Instead, immobility time measured in the forced swimming test transiently decreased at 3weeks post-MIA in the OA group. We detected changes in noradrenaline and serotonin levels in analyzed structures at distinct time points. Network analysis revealed noradrenaline and serotonin neurotransmission changes in the nucleus accumbens, confirming it to be the key structure affected by chronic pain. Animals with chronic pain exhibit symptoms of anxiety-like behavior and we identified underlying neurochemical changes using network analysis.

The Immunological Facets Of Chondrocytes In Osteoarthritis: A Narrative Review.

Osteoarthritis (OA) is a disease in which the pathogenesis affects the joint and its surrounding tissues. Cartilage degeneration is the main hallmark of OA and chondrocytes within the cartilage regulate matrix production and degradation. In OA patients and animal models of OA, the pathology of the disease relates to disequilibrium between anabolic and catabolic states of the cartilage. Moreover, chondrocyte phenotype and function are also immunologically altered. Under inflammatory conditions, chondrocytes increase production levels of inflammatory cytokines and cartilage-degrading enzymes, which further drive cartilage destruction. Chondrocytes also have an innate immune function and respond to DAMPs and cartilage fragments via innate immune receptors. In addition, chondrocytes play a role in adaptive immune responses by acting as antigen presenting cells and presenting cartilaginous antigens to T cells. Indirectly, chondrocytes are stimulated by pathogen-associated molecular patterns (PAMPs) present in the joints, a result of the microbiota in the host. Chondrocytes have both direct and indirect relationships with immune cells and the immune compartment of OA patients. Therefore, chondrocytes serve as a target for immunotherapeutic approaches in OA. In this narrative review, we cover the aforementioned immune-related aspects of chondrocytes in OA.

Sarsasapogenin inhibits YAP1-dependent chondrocyte ferroptosis to alleviate osteoarthritis

The involvement of chondrocyte ferroptosis in the development of osteoarthritis (OA) has been observed, and Sarsasapogenin (Sar) has therapeutic promise in a variety of inflammatory diseases. This study investigates the potential influence of Sar on the mechanism of chondrocyte ferroptotic cell death in the progression of osteoarthritic cartilage degradation. An in vivo medial meniscus destabilization (DMM)-induced OA animal model as well as an in vitro examination of chondrocytes in an OA microenvironment induced by interleukin-1β (IL-1β) exposure were employed. Histology, immunofluorescence, quantitative RT-PCR, Western blot, cell viability, and Micro-CT analysis were utilized in conjunction with gene overexpression and knockdown to evaluate the chondroprotective effects of Sar in OA progression and the role of Yes-associated protein 1 (YAP1) in Sar-induced ferroptosis resistance of chondrocytes. In this study we found Sar reduced chondrocyte ferroptosis and OA progression. And Sar-induced chondrocyte ferroptosis resistance was mediated by YAP1. Furthermore, infection of siRNA specific to YAP1 in chondrocytes reduced Sar's chondroprotective and ferroptosis-suppressing effects during OA development. The findings suggest that Sar mitigates the progression of osteoarthritis by decreasing the sensitivity of chondrocytes to ferroptosis through the promotion of YAP1, indicating that Sar has the potential to serve as a therapeutic approach for diseases associated with ferroptosis.

Activities of sondhep herbs to cause changes in IL-1β in an osteoarthritis rat model

Background: Osteoarthritis (OA) is a slowly progressive and degenerative joint disease. Symptoms of pain and inflammation are influenced by IL-1β, which increases COX-2 enzyme activity and PGE2 production. Sumenep Sondhep herbs are used by the community for joint pain. Objective: To evaluate the activities of the Sumenep Sondhep herb in reducing the cytokine IL-1β in the OA rats model. Methods: Monosodium iodoacetate (MIA) induction was carried out on animal OA models. Rats were treated with Sondhep extract for 28 days. Knee diameter and hyperalgesia responses were recorded every week until the 7th week. The IL-1β levels were observed on the 21st and 49th days using the ELISA method. Results: There was a significant difference in decreasing the diameter of the rat's knee (p &lt; 0.05), increasing the hyperalgesia test in the rats (p &lt; 0.05), and decreasing IL-1β levels between before and after treatment (p &lt; 0.05). Conclusion: The Sondhep Sumenep herb has activity against osteoarthritis by reducing pro-inflammatory cytokine IL-1β in OA rat models.