Joint Tissues Research Articles

Osteoarthritis year in review 2024: Biology

Osteoarthritis (OA) research is a fast-growing and extremely wide field, in which a substantial increase in knowledge has been achieved over the last year. It covers many different topics, however, a PubMed search using the terms 'osteoarthritis' and 'biology' resulted in only a limited number of studies that were published between April 2023 and April 2024. In order to identify OA-relevant studies that focus on mechanistic studies of biological processes at the tissue, cellular, and molecular level, the following keywords were included as search terms: tissue interactions, single cell sequencing, transcriptomics, extracellular matrix, signaling, ion channels, and pain. The final selection of publications presented in this 'year in review' was influenced by the personal preferences of the authors, and eventually three larger key themes emerged: 1) Joint tissue interactions covering meniscus, subchondral bone, fat tissue, synovium, and synovial fluid. 2) Degeneration of the cartilage extracellular matrix and generation of bioactive fragments. 3) Receptors, ion channels, signaling pathways, and cellular metabolism. Many of the studies summarized here identified novel potential targets for OA treatment, and promising results were already obtained addressing these targets in different animal models. It will be exciting to see which findings can be translated into future clinical studies and eventually lead to novel treatment approaches for human OA.

Immune cells and tryptophan metabolism in the joint capsule tissue in rheumatoid arthritis

To the present day, many links in the pathogenesis of rheumatoid arthritis remain unclear, which leads to unsatisfactory results in its therapy.The aim. To study the cells involved in immune reactions and tryptophan metabolites in the joint capsule in rheumatoid arthritis.Materials and methods. The experiments were carried out on 40 Wistar rats. Rheumatoid arthritis was induced by intraperitoneal injection of a solution of type 2 collagen (Chondrex Inc., USA) in incomplete Freund’s adjuvant. On the days 7, 14 and 21, the content of tryptophan, kynurenine, 3-hydrokenurinine, L-5-hydrotryptophan in the joint capsule was determined using high-performance liquid chromatography. Cells with CD3, CD20 and CD68 in joint tissues were studied at the same time using the streptavidin-biotin-peroxidase method. We used enzyme-linked immunosorbent method to determine antibodies to citrulline-containing peptide. Statistical analysis was performed using the Jamovi, version 2.3 software.Results. The content of cells carrying CD3, CD20 and CD68 markers in the joint was high in experimental rheumatoid arthritis. In joint tissues, the content of tryptophan metabolites along the kynurenine pathway also increases and the concentration of metabolites along the serotonin pathway decreases. Direct positive correlations of cells carrying CD3, CD20 and CD68 differential clusters with the content of tryptophan metabolites along the kynurenine pathway and negative correlations with metabolites of the serotonin pathway were established.Conclusions. Cells carrying CD3, CD20 and CD68 markers and tryptophan metabolites – kynurenine and L-5-hydrotryptophan – play an important role in the pathogenesis of rheumatoid arthritis.

Report of the German Society of Pathology Working Group on Bone, Joint, and Soft Tissue Pathology

Report of the German Society of Pathology Working Group on Bone, Joint, and Soft Tissue Pathology

Functional benefit of joint surgery in patients with non-vascular Ehlers-Danlos syndrome: results of a retrospective study

BackgroundEhlers-Danlos syndrome (EDS) is a hereditary disease characterised by joint hypermobility, skin hyperextensibility and tissue fragility. Hypermobile EDS (hEDS is the more frequent subtype. Joint surgery may benefit certain patients after failure of medical treatments, but there is no consensus on the optimal surgical management of patients with hEDS. The aims of this retrospective study were to chart the surgical management of patients with hEDS, to determine the role of arthroscopy and to evaluate the functional results of joint surgery, including the reintervention rates.ResultsA total of 69 patients with non-vascular EDS were evaluated (60 female; 87%). Mean (SD) age at first surgery was 25.6 ± 11.1 years. Among the 69 patients, first surgeries were carried out on the knee (n = 50; 39.4%), ankle (n = 28; 22.0%), shoulder (n = 22; 17.3%), wrist (n = 18; 14.2%) and elbow (n = 9; 7.1%). One-fifth of all first operations (20.8%) were carried out by arthroscopy, most often on the knee (36% of knee surgery cases). At the time of primary surgery, the surgeon was alerted to the diagnosis or suspicion of hEDS in only 33.9% of patients. The rate of reoperations (2 to ≥ 5) was 35.7% (10/28) for the ankle, 40.9% (9/22) for the shoulder, 44.4% (4/9) for the elbow, 50% (9/18) for the wrist and 60% (30/50) for the knee. Local or regional anaesthesia was badly tolerated or ineffective in 27.8%, 36.4% and 66.6% of operations on the wrist, shoulder and elbow, respectively. Overall, the majority of patients (> 70%) were satisfied or very satisfied with their surgery, particularly on the non-dominant side. The lowest satisfaction rate was for shoulder surgery on the dominant side (58.3% dissatisfied).ConclusionsSurgery for joint instability has a greater chance of success when it is carried out in patients with a known diagnosis of EDS before surgery. The majority of patients were satisfied with their surgery and, with the exception of the knee, there was a low rate of reoperations (≤ 50%). Arthroscopic procedures have an important role to play in these patients, particularly when surgery is performed on the knee.

Collagen-based 3D printed poly (glycerol sebacate) composite scaffold with biomimicking mechanical properties for enhanced cartilage defect repair

Cartilage defect repair with optimal efficiency remains a significant challenge due to the limited self-repair capability of native tissues. The development of bioactive scaffolds with biomimicking mechanical properties and degradation rates matched with cartilage regeneration while simultaneously driving chondrogenesis, plays a crucial role in enhancing cartilage defect repair. To this end, a novel composite scaffold with hierarchical porosity was manufactured by incorporating a pro-chondrogenic collagen type I/II-hyaluronic acid (CI/II-HyA) matrix to a 3D-printed poly(glycerol sebacate) (PGS) framework. Based on the mechanical enforcement of PGS framework, the composite scaffold exhibited a compressive modulus of 167.0 kPa, similar to that of native cartilage, as well as excellent fatigue resistance, similar to that of native joint tissue. In vitro degradation tests demonstrated that the composite scaffold maintained structural, mass, and mechanical stability during the initial cartilage regeneration period of 4 weeks, while degraded linearly over time. In vitro biological tests with rat-derived mesenchymal stem cell (MSC) revealed that, the composite scaffold displayed increased cell loading efficiency and improved overall cell viability due to the incorporation of CI/II-HyA matrix. Additionally, it also sustained an effective and high-quality MSC chondrogenesis and abundant de-novo cartilage-like matrix deposition up to day 28. Overall, the biomimetic composite scaffold with sufficient mechanical support, matched degradation rate with cartilage regeneration, and effective chondrogenesis stimulation shows great potential to be an ideal candidate for enhancing cartilage defect repair.

Mechanics- and Behavior-Related Temporomandibular Joint Differences

Fatigue of temporomandibular joint (TMJ) tissues reflects the effects of magnitude (energy density; ED) and frequency of loading (jaw muscle duty factor; DF). This observational study measured these variables and tested for differences in mechanobehavior scores (MBS = ED2 × DF) and component variables in subjects with and without TMJ disc displacement (±D). In accordance with Institutional Review Board and STROBE guidelines, written informed consent was obtained, and examination and imaging protocols identified eligible adult subjects. Specifically, magnetic resonance imaging was used to assign subjects’ TMJs to ±D groups. Subjects were trained to record in-field jaw muscle activities, from which DFs (percentage of recording time) were determined. EDs (mJ/mm3) were estimated using modeled TMJ loads and in vivo dynamic stereometry. Multivariate analysis of variance, post hoc independent t tests, and K-means cluster analysis identified significant group differences (P < 0.05). Of 242 individuals screened, 65 females (TMJs: 78 +D, 52 −D) and 53 males (TMJs: 39 +D, 67 −D) participated. Subjects produced 312 daytime and 319 nighttime recordings of average duration 6.0 ± 0.2 h and 7.6 ± 0.1 h, respectively, and 219 (114 right, 105 left) intact dynamic stereometry recordings. Average EDs were 2-fold and significantly larger in +D than −D TMJs (P < 0.0001). DFs were on average 3-fold larger during the daytime versus nighttime for both masseter and temporalis muscles and 1.8- and 3.0-fold larger for the masseter versus temporalis muscle during the daytime and nighttime, respectively. Daytime masseter MBSs for +D TMJs in females were the largest overall at 621 ± 212 (mJ/mm3)2% and 2- to 43-fold larger versus −D TMJs in both sexes during daytime and nighttime. Cluster analysis (P < 0.0001) identified groups 2 and 3, which comprised 87% +D TMJs and had average MBSs 21-fold larger than group 1. The results show MBS as a potential biomarker to predict homeostasis versus progression or reversal of degenerative TMJ structural changes.

Transformable peptide blocks NF-κB/IκBα pathway through targeted coating IκBα against rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive effects. Although current therapies utilizing antibodies against inflammatory cytokines have shown some success, the inhibition of a single inflammatory molecule may not suffice to impede the progression of RA due to the intricate pathogenesis involving multiple molecules. In this study, we have developed an intelligent transformable peptide, namely BP-FFVLK-DSGLDSM (BFD). BFD has the ability to self-assemble into spherical nanoparticles in water or in the blood circulation to facilitate their delivery and distribution. When endocytosed into immune cells, BFD can identify and attach to phosphorylation sites on IκBα and in situ transform into a nanofibrous network coating NF-κB/IκBα complexes, blocking the phosphorylation and degradation of IκBα. As a result, BFD enables decreasing expression of proinflammatory mediators. In the present study, we demonstrate that BFD exhibits notable efficacy in alleviating arthritis-related manifestations, such as joints and tissues swelling, as well as bone and cartilage destruction on the collagen-induced arthritis (CIA) rat model. The investigation of intracellular biodistribution, phosphorylation of IκBα, and cytokine detection in culture medium supernatant, joint tissue, and serum exhibits strong associations with therapeutic outcomes. The utilization of transformable peptide presents a novel approach for the management of inflammatory diseases.

Enhancing Cartilage Repair: Surgical Approaches, Orthobiologics, and the Promise of Exosomes.

Treating cartilage damage is challenging as its ability for self-regeneration is limited. Left untreated, it can progress to osteoarthritis (OA), a joint disorder characterized by the deterioration of articular cartilage and other joint tissues. Surgical options, such as microfracture and cell/tissue transplantation, have shown promise as techniques to harness the body's endogenous regenerative capabilities to promote cartilage repair. Nonetheless, these techniques have been scrutinized due to reported inconsistencies in long-term outcomes and the tendency for the defects to regenerate as fibrocartilage instead of the smooth hyaline cartilage native to joint surfaces. Orthobiologics are medical therapies that utilize biologically derived substances to augment musculoskeletal healing. These treatments are rising in popularity because of their potential to enhance surgical standards of care. More recent developments in orthobiologics have focused on the role of exosomes in articular cartilage repair. Exosomes are nano-sized extracellular vesicles containing cargo such as proteins, lipids, and nucleic acids, and are known to facilitate intercellular communication, though their regenerative potential still needs to be fully understood. This review aims to demonstrate the advancements in cartilage regeneration, highlight surgical and biological treatment options, and discuss the recent strides in understanding the precise mechanisms of action involved.

The rice R2R3 MYB transcription factor FOUR LIPS connects brassinosteroid signaling to lignin deposition and leaf angle.

Leaf angle is an important agronomic trait for crop architecture and yield. In rice (Oryza sativa), the lamina joint is a unique structure connecting the leaf blade and sheath that determines leaf angle. Brassinosteroid (BR) signaling involving GLYCOGEN SYNTHASE KINASE-3 (GSK3)/SHAGGY-like kinases and BRASSINAZOLE-RESISTANT1 (BZR1) has a central role in regulating leaf angle in rice. In this study, we identified the atypical R2R3-MYB transcription factor FOUR LIPS (OsFLP), the rice homolog of Arabidopsis (Arabidopsis thaliana) AtFLP, as a participant in BR-regulated leaf angle formation. The spatiotemporal specificity of OsFLP expression in the lamina joint was closely associated with lignin deposition in vascular bundles and sclerenchyma cells. OsFLP mutation caused loose plant architecture with droopy flag leaves and hypersensitivity to BRs. OsBZR1 directly targeted OsFLP, and OsFLP transduced BR signals to lignin deposition in the lamina joint. Moreover, OsFLP promoted the transcription of the phenylalanine ammonia-lyase family genes OsPAL4 and OsPAL6. Intriguingly, OsFLP feedback regulated OsGSK1 transcription and OsBZR1 phosphorylation status. In addition, an Ala-to-Thr substitution within the OsFLP R3 helix-turn-helix domain, an equivalent mutation to that in Osflp-1, affected the DNA-binding ability and transcriptional activity of OsFLP. Our results reveal that OsFLP functions with OsGSK1 and OsBZR1 in BR signaling to maintain optimal leaf angle by modulating the lignin deposition in mechanical tissues of the lamina joint.

Osteochondral Tissue-On-a-Chip: A Novel Model for Osteoarthritis Research.

The existing in vitro and in vivo models for studying osteoarthritis have significant limitations in replicating the complexity of joint tissues. This research aims to validate a Tissue-On-a-Chip system for osteoarthritis research. Osteochondral tissues obtained from knee replacement surgeries of patients with osteoarthritis were cultured in an Organ-On-a-Chip system. This system was designed to supply oxygen and glucose to the cartilage from the bone. The distribution of oxygen and glucose was evaluated by fluorescence using Image-iT Green Hypoxia and 2-NBDG, respectively. Cytotoxicity was measured using lactate dehydrogenase (LDH) levels in chip cultures compared to plate cultures (12 tissues per method). Glycosaminoglycans (GAGs), alkaline phosphatase (ALP), Coll2-1, and procollagen type II N-terminal propeptide (PIINP) were measured in the perfused medium of the Tissue-On-a-Chip over a period of 70 days. Fluorescence of Image-iT Green Hypoxia was observed only in the cartilage area, while 2-NBDG was distributed throughout the tissue. An increase in LDH levels was noted in the plate cultures on day 24 and in the Tissue-On-a-Chip cultures on day 63. Compared to the start of the culture, GAG content increased on day 52, while ALP showed variations. A notable increase in GAG, ALP, and Coll2-1 levels was observed on day 59. PIINP levels remained stable throughout the experiment. The validated osteochondral Tissue-On-a-Chip system can replicate the joint microenvironment, with hypoxic conditions in cartilage and normoxic conditions in bone. Tissue survival and component stability were maintained for approximately two months. This platform is a useful tool for evaluating new drugs and represents a viable alternative to animal models.

A point-of-research decision in synovial tissue engineering: Mesenchymal stromal cells, tissue derived fibroblast or CTGF-mediated mesenchymal-to-fibroblast transition

Rheumatoid arthritis (RA) and osteoarthritis (OA) are prevalent inflammatory joint diseases characterized by synovitis, cartilage, and bone destruction. Fibroblast-like synoviocytes (FLSs) of the synovial membrane are a decisive factor in arthritis, making them a target for future therapies. Developing novel strategies targeting FLSs requires advanced in vitro joint models that accurately replicate non-diseased joint tissue. This study aims to identify a cell source reflecting physiological synovial fibroblasts. Therefore, we newly compared the phenotype and metabolism of “healthy” knee-derived FLSs from patients with ligament injuries (trauma-FLSs) to mesenchymal stromal cells (MSCs), their native precursors. We differentiated MSCs into fibroblasts using connective tissue growth factor (CTGF) and compared selected protein and gene expression patterns to those obtained from trauma-FLSs and OA-FLSs. Based on these findings, we explored the potential of an MSC-derived synovial tissue model to simulate a chronic inflammatory response akin to that seen in arthritis. We have identified MSCs as a suitable cell source for synovial tissue engineering because, despite metabolic differences, they closely resemble human trauma-derived FLSs. CTGF-mediated differentiation of MSCs increased HAS2 expression, essential for hyaluronan synthesis. It showed protein expression patterns akin to OA-FLSs, including markers of ECM components and fibrosis, and enzymes leading to a shift in metabolism towards increased fatty acid oxidation. In general, cytokine stimulation of MSCs in a synovial tissue model induced pro-inflammatory and pro-angiogenic gene expression, hyperproliferation, and increased glucose consumption, reflecting cellular response in human arthritis. We conclude that MSCs can serve as a proxy to study physiological synovial processes and inflammatory responses. In addition, CTGF-mediated mesenchymal-to-fibroblast transition resembles OA-FLSs. Thus, we emphasize MSCs as a valuable cell source for tools in preclinical drug screening and their application in tissue engineering.

PIEZO1 variants that reduce open channel probability are associated with familial osteoarthritis.

The synovial joints senses and responds to a multitude of physical forces to maintain joint homeostasis. Disruption of joint homeostasis results in development of osteoarthritis (OA), a disease characterized by loss of joint space, degeneration of articular cartilage, remodeling of bone and other joint tissues, low-grade inflammation, and pain. How changes in mechanosensing in the joint contribute to OA susceptibility remains elusive. PIEZO1 is a major mechanosensitive cation channel in the joint directly regulated by mechanical stimulus. To test whether altered PIEZO1 channel activity causes increased OA susceptibility, we determined whether variants affecting PIEZO1 are associated with dominant inheritance of age-associated familial OA. We identified four rare coding variants affecting PIEZO1 that are associated with familial hand OA. Single channel analyses demonstrated that all four PIEZO1 mutant channels act in a dominant-negative manner to reduce the open probability of the channel in response to pressure. Furthermore, we show that a GWAS mutation in PIEZO1 associated with reduced joint replacement results in increased channel activity when compared with WT and the mutants. Our data support the hypothesis that reduced PIEZO1 activity confers susceptibility to age-associated OA whereas increased PIEZO1 activity may be associated with reduced OA susceptibility.

Modulatory effects of miRNAs in doxorubicin resistance: A mechanistic view.

MicroRNAs (miRNAs) are a group of small non-coding RNAs and play an important role in controlling vital biological processes, including cell cycle control, apoptosis, metabolism, and development and differentiation, which lead to various diseases such as neurological, metabolic disorders, and cancer. Chemotherapy consider as gold treatment approaches for cancer patients. However, chemotherapeutic is one of the main challenges in cancer management. Doxorubicin (DOX) is an anti-cancer drug that interferes with the growth and spread of cancer cells. DOX is used to treat various types of cancer, including breast, nervous tissue, bladder, stomach, ovary, thyroid, lung, bone, muscle, joint and soft tissue cancers. Also recently, miRNAs have been identified as master regulators of specific genes responsible for the mechanisms that initiate chemical resistance. miRNAs have a regulatory effect on chemotherapy resistance through the regulation of apoptosis process. Also, the effect of miRNAs p53 gene as a key tumor suppressor was confirmed via studies. miRNAs can affect main biological pathways include PI3K pathway. This review aimed to present the current understanding of the mechanisms and effects of miRNAs on apoptosis, p53 and PTEN/PI3K/Akt signaling pathway related to DOX resistance.

Synergistic effects of biological stimuli and flexion induce microcavities promote hypertrophy and inhibit chondrogenesis during in vitro culture of human mesenchymal stem cell aggregates.

Interzone/cavitation are key steps in early stage joint formation that have not been successfully developed in vitro. Further, current models of endochondral ossification, an important step in early bone formation, lack key morphology morphological structures such as microcavities found during development in vivo. This is possibly due to the lack of appropriate strategies for incorporating chemical and mechanical stimuli that are thought to be involved in joint development. We designed a bioreactor system and investigated the synergic effect of chemical stimuli (chondrogenesis-inducing [CIM] and hypertrophy-inducing medium [HIM]) and mechanical stimuli (flexion) on the growth of human mesenchymal stem cells (hMSCs) based linear aggregates under different conditions over 4 weeks of perfusion culture. Computational studies were used to evaluate tissue stress qualitatively. After harvesting, both Safranin-O and hematoxylin & eosin (H&E) staining histology demonstrated microcavity structures and void structures in the region of higher stresses for tissue aggregates cultured only in HIM under flexion. In comparison to either HIM treatment or flexion only, increased glycosaminoglycan (GAG) content in the extracellular matrix (ECM) at this region indicates the morphological change resembles the early stage of joint cavitation; while decreased type II collagen (Col II), and increased type X collagen (Col X) and vascular endothelial growth factor (VEGF) with a clear boundary in the staining section indicates it resembles the early stage of ossification. Further, cell alignment analysis indicated that cells were mostly oriented toward the direction of flexion in high-stress region only in HIM under flexion, resembling cell morphology in both joint cavitation and hypertrophic cartilage in growth plate. Collectively, our results suggest that flexion and HIM inhibit chondrogenesis and promote hypertrophy and development of microcavities that resemble the early stage of joint cavitation and endochondral ossification. We believe the tissue model described in this work can be used to develop in vitro models of joint tissue for applications such as pathophysiology and drug discovery.

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.

Relationship between autophagy and NLRP3 inflammasome during articular cartilage degradation in oestrogen-deficient rats with streptozotocin-induced diabetes

BackgroundEstrogen deficiency and Diabetes mellitus (DM) cause joint tissue deterioration, although the mechanisms are uncertain. This study evaluated the immunoexpression of autophagy and NLRP3-inflammasome markers, in rat articular cartilage with estrogen deficiency and DM. MethodsTwenty rats were sham-operated (SHAM) or ovariectomized (OVX) and equally allocated into four groups: SHAM and OVX groups administered with vehicle solution; SHAM and OVX groups treated with 60mg/kg/body weight of streptozotocin, intraperitoneally, to induce DM (SHAM-DM and OVX-DM groups). After seven weeks, the rats were euthanized, and their joint knees were processed for paraffin embedding. Sections were stained with haematoxylin-eosin, toluidine blue, safranin-O/fast-green or subjected to picrosirius-red-polarisation method; immunohistochemistry to detect beclin-1 and microtubule-associated protein 1B-light chain 3 (autophagy markers), NLRP3 and interleukin-1β (IL-1β) (inflammasome activation markers), along with matrix metalloproteinase-9 (MMP-9), Nuclear factor-kappa B (NFκB), and Vascular endothelial growth factor A (VEGF-A) were performed. ResultsDeterioration of articular cartilage and subchondral bone were greater in SHAM-DM and OVX-DM groups. Higher percentages of immunolabeled chondrocytes to NLRP3, IL-1β, MMP-9, NFκB, and VEGF-A, as well as lower percentages of chondrocytes immunolabeled to autophagy markers, were noticed in estrogen-deficient and diabetic groups. These differences were greater in the OVX-DM group. Percentages of immunolabeled chondrocytes showed negative correlation between autophagy markers v.s IL-1β, NLRP-3, MMP-9, NFκB, and VEGF-A, along with positive correlation between VEGF-A vs. MMP-9, NFκB, IL-1β, and NLRP3, and MMP-9 vs. NFκB. ConclusionsIn conclusion, autophagy reduction and NLRP3 inflammasome activation in chondrocytes may be implicated in articular cartilage degradation, under estrogen-deficient and DM conditions. Moreover, the combination of estrogen deficiency and DM may potentiate those effects.

Artesunate attenuates osteoarthritis in mice by promoting MTA1 transcription through a USP7/FoxO1 axis

Artesunate (ART) is a derivative of artemisinin and has anti-inflammatory, anti-tumor, and anti-angiogenic properties. Although ART has been implicated in osteoarthritis (OA), the mechanism needs to be further dissected. Here, we explored the effects of ART on the development of OA and the underlying mechanism using destabilization of the medial meniscus (DMM) surgical instability model. Mice with OA were developed using DMM and treated with ART. The pathological morphology of knee joint tissues was examined, and the degeneration of joint cartilage was assessed. Mouse knee chondrocytes were isolated and induced with IL-1β, followed by ART treatment. ART alleviates OA in mice by elevating ubiquitin carboxyl-terminal hydrolase 7 (USP7) expression, and USP7 inhibitor (P22077) treatment mitigated the protective effects of ART on chondrocytes. We also showed that USP7 mediated the deubiquitination of forkhead box protein O1 (FoxO1), while FoxO1 alleviated chondrocyte injury. In addition, FoxO1 promoted metastasis-associated protein MTA1 (MTA1) transcription, and downregulation of MTA1 exacerbated chondrocyte injury. Our study identifies that USP7/FoxO1/MTA1 is a key signaling cascade in the treatment of ART on OA.

Platelet lysate does not have an anti-inflammatory effect on monoiodoacetic acid-induced equine persistent synovitis.

To clarify the anti-inflammatory effect of platelet lysate (PL) on equine persistent synovitis by using a model of synovitis induced by monoiodoacetic acid (MIA). Nonseptic synovitis was induced by administering MIA into both antebrachiocarpal joints of 6 clinically healthy horses on day 0. On days 23, 30, and 37, carpal circumference measurement and synovial fluid collection for assays (leucocytes, LDH, tumor necrosis factor-α, and TGF-β1) were performed, after which PL was injected into 1 antebrachiocarpal joint and saline into the contralateral joint. Synovium and synovial fluid were obtained on day 44 for histological analysis and quantification of inflammation-related genes (matrix metalloproteinase-13, a disintegrin and metalloproteinase with thrombospondin motifs 4, receptor activator of nuclear factor κ-Β ligand, and collagen type I α2 chain) and the abovementioned proteins. The LDH level on day 44 was significantly lower in the PL-injected joint than in the saline-treated one. However, no significant differences were found in the other indices quantified, including osteoclast counts on the synovium. Multiple IA administration of PL does not exert anti-inflammatory effects on the equine persistent synovitis induced by MIA. Intra-articular PL administration did not alter many inflammatory biomarkers, suggesting that PL does not have a direct anti-inflammatory effect. However, the reduction in synovial LDH levels suggests that PL promoted joint tissue repair and may consequently alleviate inflammation at the site of administration.

Critical evaluation of the current role of SYSADOA in the management of osteoarthritis (literature review)

Background. Osteoarthritis is a common chronic disease characterized by progressive degradation of all joint components and inflammation. The priority issue in the management of OA is sear­ching for drugs that simultaneously relieve symptoms, modify the course of the disease, and are safe for use. Symptoma­tic slow-ac­ting drugs (SYSADOA) are of considerable interest due to their potential to slow cartilage degeneration and potential osteoarthritis di­sease mo­difying effect. The purpose of the study was to ana­lyze current literature data on several types of SYSADOA, their biological role, mecha­nisms of effect on joints, effectiveness and safetye. ­Materials and methods. An analytical review of literature data was conducted using the ana­lysis of scientific databases PubMed, Web of Science, Scopus, Google Scholar for the period 2005–2024, the search was conducted using the keywords “osteoarthritis”, “SYSADOA”, “DMOAD”, “effectiveness”, “safety”. Results. Glucosamine salts (GA) and chondroitin sulfate (CS) are the most stu­died slow-acting drugs and have positive biological effects on joint tissues. Prescription salts of GA and CS have effect of pain relieve and joint function improvement as separate agents and also potentiate the effect in combination. Studies revealed limiting of cartilage volume loss and joint space narrowing – a potential DMOAD effect of these drugs. GA salts and CS drugs are safe, as they have no difference in the frequency of side effects compared to placebo. The quality of drugs largely depends on the type of raw materials and technological production process, which are not standardized now. Conclusions. The role of SYSADOA in the treatment of OA has not been definitively determined, and studies on the effectiveness of drugs such as SYSADOA and the study of their DMOAD effect are still ongoing. Further stu­dies should focus on the use of pharmacological class SYSADOA that have been properly purified and quality strictly supervised.

Intra-Articular Delivery of an AAV-Anti-TNF-α Vector Alleviates the Progress of Arthritis in a RA Mouse Model.

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease marked by joint destruction and functional impairment. Tumor necrosis factor (TNF) plays a critical role in RA pathogenesis. Although TNF-targeting drugs are clinically effective, their need for frequent and long-term administration often results in poor patient adherence and suboptimal outcomes. This study developed a gene therapy approach using engineered adeno-associated virus (AAV) vectors to deliver an anti-TNF agent directly into the joint cavity of RA animal models. Animals receiving this therapy demonstrated sustained improvement in clinical scores, inflammatory markers, and joint tissue health. Immunofluorescence staining revealed that AAV vectors could transduce various cell types, including T cells, type A synoviocytes, and dendritic cells. Our results indicate that a single administration of this gene therapy provided long-term efficacy. This suggests that AAV-mediated anti-TNF gene therapy can offer prolonged relief from clinical symptoms and reduce inflammatory damage in a mouse model of RA. This innovative approach presents a promising new therapy with significant clinical prospects to treat patients with RA.