Per- and polyfluoroalkyl substances (PFASs) have garnered considerable research attention due to their potential adverse effects on human health. Epidemiological studies have indicated a possible association between PFASs exposure and the prevalence of osteoarthritis (OA). However, the presence of PFASs in the synovial fluid of OA patients and the distribution of PFASs across the blood-joint barrier remains unreported. This study identified significant differences in PFASs profiles between patients and controls, with a markedly higher PFOS-to-PFOA ratio observed in patients. Additionally, the blood-joint transfer efficiency of PFOS was significantly greater in patients than in controls (0.75 vs. 0.53, p < 0.05). Furthermore, PFOS levels were elevated in patients with advanced OA compared to those in the early stages. Positive correlations were observed between synovial fluid PFOS and inflammatory markers C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α), implying that inflammation may facilitate the distribution of PFOS across the joint barrier. This study represents the first documented evidence of the human joint exposure to PFASs and their blood-joint transfer abilities.

Cobalt-chromium-molybdenum (CoCrMo) femoral components are widely used in total knee arthroplasty (TKA). However, recent retrospective clinical trials associate moderate adverse local tissue reactions with CoCrMo release in the knee. Additionally, gaps persist in our understanding of the fundamental corrosion processes that occur at the CoCrMo-synovial fluid interface. In this study, we investigated the electrochemical behavior of CoCrMo in human synovial fluid obtained at the time of primary TKA, using CoCrMo in phosphate-buffered saline (PBS) as a comparison. Synovial fluid was collected from 118 patients immediately before arthroplasty, then transferred to a three-electrode electrochemical cell with a wrought CoCrMo alloy working electrode. To quantify electrochemical properties, open circuit potential (OCP), electrochemical impedance spectroscopy, and linear polarization tests were run. Generally, the properties varied on a patient-by-patient basis and significantly differed (p < 0.05) from comparison tests performed in PBS. In human synovial fluid, we measured OCPs between a range of -0.38 and 0.15 V and corrosion potentials (Ecorr) between -0.95 and -0.2 V. Additionally, we reported instantaneous corrosion rates (1/Rp) spanning nearly four orders of magnitude. The variability we documented suggested that the electrochemical properties of CoCrMo implants may depend on the patient's local physiological environment, influenced by the biological and chemical components of synovial fluid. Statement of Clinical Significance: This study shows that human synovial fluid affects the electrochemical behavior of CoCrMo, evidenced by the variation on a patient-by-patient basis. This study may have implications for long-term biological response to orthopaedic implants, including total knee arthroplasty.

Previous study has observed the clinical relationship between affective disorders such as depression and anxiety and osteoarthritis (OA), however the gene causal effect was still unclear. The objective of this study was to evaluate the genetic causal effect of emotions on OA using bidirectional Mendelian randomization (MR), which is a novel methodology elucidating the causal relationship between diseases and screening for the potential driver genes. A bidirectional MR study was conducted to assess the causal effect of emotion on OA. The instrumental variables were selected from publicly available Genome-Wide Association Study summary datasets based on a P-value threshold (P < 5e-8) and linkage disequilibrium clumping criteria (r² < 0.001, window size = 10,000 kb). The robustness of the findings across different MR methods was validated by Cochran Q test, MR-Egger intercept test, MR_PRESSO, F-statistic, and statistical power. The inverse-variance weighted method was employed as the primary analysis due to its weighting approach, which minimizes variance and yields the most precise estimation of causal effects. While MR-Egger (assessed and accounted Pleiotropy), Weighted Median (adjusted for the potential confounding pleiotropy of instrumental variables), Weighted and Simple Mode (identified the effect clusters) methods were used as supplementary analyses to complement the outcome. The main genetic data source consisted of 10,083 participants obtained from publicly accessible repository. The emotions of depression, anxiousness, and hurt were found to have a genetic influence on the development of OA. Specifically, anxiousness was associated with a reduced risk of OA (odds ratio [OR] = 0.486, 95% confidence interval [CI] = 0.260-0.908, P = .024). On the other hand, depression (OR = 2.157, 95% CI = 1.605-2.899, P = 3.4e-07) and hurt (OR = 1.731, 95% CI = 1.092-2.745, P = .020) were identified as genetic factors that increased the susceptibility to OA. The statistical power of depression, anxious and feeling hurt on OA were > 0.99, 0.29, and > 0.99. These findings suggest that genetic factors underlying emotions, particularly depression and emotional distress, significantly influence susceptibility to OA, underscoring the potential for targeted mental health interventions in OA management.

Knee osteoarthritis (OA) is a major cause of pain and disability. Genicular artery embolization (GAE) is a promising alternative for patients unresponsive to conservative treatment or unsuitable for total knee replacement. GAE may alleviate knee pain by reducing synovitis and by causing ischemia to pathologic knee nerves. However, outcomes vary based on baseline MRI and radiographic findings, making patient selection challenging. Recently, reduction in synovitis on contrast-enhanced MRI has been associated with pain relief post-GAE. Novel OA phenotypes (inflammatory, cartilage, bone, and atrophic) can aid in patient selection by using imaging and molecular biomarkers. Moreover, imaging features such as cartilage defects, bone marrow lesions, and synovitis may predict symptomatic outcomes. This review explores OA pathophysiology, focusing on radiographic, biochemical, and imaging biomarkers in evaluating GAE for knee OA treatment.

The skeletal system is responsible for the body's support and motor functions, and can be pathologically affected by factors, such as metabolism, autoimmune inflammation, tumors, and infections. Regarding tissue localization and biological function, the immune system is deeply involved in the physiological and pathological processes of the skeletal system. As a regulator and effector cell of the innate immune system, natural killer (NK) cells can exert cytotoxic effects through cell contact and immunomodulatory effects through cytokine secretion. In the past 30 years, many advances have been made regarding the role of NK cells and their derived cytokines on bone and joints. In this review, the role of NK cells in the physiological activities of bone remodeling is summarized first, focusing on osteoclast differentiation and function. Subsequently, the roles of NK cells in osteoarthritis, bone tumors, and bone diseases caused by microbial infections are described, meanwhile, some conflicting research results are discussed. By reviewing the state-of-the-art progress of NK cells in the above-mentioned bone physiological and pathological processes, it is helpful to clarify the blind spots of current research and provide some references for the integrated evaluation of immune factors in the study of skeletal system diseases.

Late-life diseases result from the poorly understood process of senescence (aging), which is largely genetically determined. According to a recently proposed evolutionary physiology-based account, the multifactorial model, senescence is largely caused by evolved but non-adaptive programmatic mechanisms specified by the wild-type (i.e. normal) genome. These act together with disruptions to wild-type function (due e.g. to infectious pathogens, mechanical injury and malnutrition) in a variety of combinations to generate diverse late-life diseases. Here, I explore the utility of this model by testing its capacity to provide an account of one complex, late-life disease, osteoarthritis (OA), and suggest a framework for understanding OA etiology. In this cartilage-focused framework, a core OA disease mechanism is a futile (non-adaptive) developmental program of endochondral ossification, in which hypertrophic articular cartilage chondrocytes alter joint architecture. Programmatic changes prime chondrocytes for futile program activation, which can be triggered by secondary causes of OA (e.g. joint mechanical injury). I suggest that an evolutionary cause of this priming, involving antagonistic pleiotropy, is selection to maximize early-life tissue repair benefits at the expense of late-life programmatic costs.

Chondrocyte senescence, synovitis, and decreased level of lubrication play pivotal roles in the pathogenesis of age-related osteoarthritis (AROA). However, there are currently no effective therapeutic interventions capable of altering the progression of OA until it reaches advanced stages, necessitating joint replacement. In this study, lubricious and drug-loaded hydrogel microspheres were designed and fabricated by utilizing microfluidic technology for radical polymerization of chondroitin sulfate methacrylate and incorporating nicotinamide adenine dinucleotide (NAD)-loaded liposomes modified with lactoferrin that are positively charged. Mechanical, tribological, and drug release analyses demonstrated enhanced lubrication properties and an extended drug dissemination time for the NAD@NPs@HM microspheres. In vitro assays unveiled the ability of NAD@NPs@HM to counteract chondrocyte senescence. RNA sequencing analysis, untargeted metabolomics analysis, and in vitro experiments on macrophages revealed that NAD@NPs@HM can regulate the metabolic reprogramming of synovial macrophages, promoting their repolarization from the M1 to M2 phenotype, thereby alleviating synovitis. Intra-articular injection of NAD@NPs@HM in aged mice reduced the mechanisms associated with AROA. These results suggest that NAD@NPs@HM may provide extended drug release, improved joint lubrication leading to better gait, and attenuation of AROA pathogenic processes, indicating its potential as a therapeutic approach for AROA.

The use of nanoparticles in nuclear medicine is paradoxical. While several nanoformulations, such as 99mTc colloids, have been used for diagnosis for decades, only a few new radionanomedicines have been able to reach the market, despite extensive preclinical efforts. This contradiction is dictated by the unique features of nanoparticles, such as (potential) prolonged circulation times, slow compartment exchanges, and large accumulations in the mononuclear phagocyte system, which allow for certain specific applications while preventing others. In this review, we discuss the development and clinical application of radiolabeled nanoparticles as imaging agents for disease diagnosis and patient stratification, as well as their promise and potential to be used as next-generation formulations to improve the efficacy of radiotherapy.

Osteoarthritis (OA) is a low-grade inflammatory disease that is highly associated with severe hyperplasia of the synovial membrane and the degeneration of cartilage. Interleukin-10 (IL-10), has been extensively studied, while its receptor, IL-10Rα, has not been widely mentioned in the context of OA. A significant difference is found in the expression of IL-10Rα in synovial macrophages from normal and OA patients, along with a marked increase in the glycolytic activity of synovial macrophages. In IL-10RαLysm OA mice, the specific deficiency of IL-10Rα exacerbated the progression of OA. Mechanistically, hypoxia-inducible factor-1α (HIF-1α) is identified as a key transcription factor, and its inhibition significantly weakened the glycolytic process. Additionally, differences in ferroptosis of chondrocytes are observed. After co-culturing the two types of cells in vitro, a significant connection is found between the glycolytic state of synovial macrophages and the ferroptosis of chondrocytes. To achieve targeted therapy, MI@UN, a biomimetic nanoparticle encapsulating NO-prednisolone in UIO-66-NH2, surface-modified with IL-10, and coated with macrophage membranes (MM), is developed. It significantly slows osteoarthritis progression in mice. This offers new insights into OA pathogenesis, highlighting IL-10Rα as a therapeutic target and supporting MI@UN's translational use for OA treatment.

As people age, degenerative bone and joint diseases (DBJDs) become more prevalent. When middle-aged and elderly people are diagnosed with one or more disorders such as osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IVDD), it often signals the onset of prolonged pain and reduced functionality. Chronic inflammation has been identified as the underlying cause of various degenerative diseases, including DBJDs. Recently, excessive activation of pyroptosis, a form of programed cell death (PCD) mediated by inflammasomes, has emerged as a primary driver of harmful chronic inflammation. Consequently, pyroptosis has become a potential target for preventing and treating DBJDs.

This review explored the physiological and pathological roles of the pyroptosis pathway in bone and joint development and its relation to DBJDs. Meanwhile, it elaborated the molecular mechanisms of pyroptosis within individual cell types in the bone marrow and joints, as well as the interplay among different cell types in the context of DBJDs. Furthermore, this review presented the latest compelling evidence supporting the idea of regulating the pyroptosis pathway for DBJDs treatment, and discussed the potential, limitations, and challenges of various therapeutic strategies involving pyroptosis regulation.

In summary, an interesting identity for the unregulated pyroptosis pathway in the context of DBJDs was proposed in this review, which was undertaken as a spoiler of peaceful coexistence between cells in a degenerative environment. Over the extended course of DBJDs, pyroptosis pathway perpetuated its activity through crosstalk among pyroptosis cascades in different cell types, thus exacerbating the inflammatory environment throughout the entire bone marrow and joint degeneration environment. Correspondingly, pyroptosis regulation therapy emerged as a promising option for clinical treatment of DBJDs.

To investigate the interaction among the cells thought to be foundational to inflammation, fibrosis, and angiogenesis in the synovial membrane.

We encapsulated fibroblasts, polarized macrophages, and endothelial cells in a 3D culture system. We used this model to determine the cellular transcriptional profiles, cytokine secretion, and vascular formation associated with different macrophage phenotype conditions.

Neo-angiogenesis reached its maximum level at approximately day 21 in the presence of pro-inflammatory macrophages conditions, but was sustained in the presence of anti-inflammatory macrophages. RNA sequencing revealed an influence of macrophage phenotype on gene expression associated with fibrosis and angiogenesis. Furthermore, by including lipopolysaccharides-coated polyethylene particles (lcPE), an inflammatory stimulus replicating wear debris from joint replacements into our system, insights into the local reaction to byproducts of different biomaterials can be ascertained.

Chronic inflammation and fibrosis of the synovial membrane are often present in osteoarthritis and post-total joint arthroplasty. Our results suggest that the progression of inflammatory synovial diseases is influenced by macrophage phenotypes.

This systematic review aimed to investigate in animal models the presence of disease-modifying effects driven by non-bone marrow-derived and non-adipose-derived products, with a particular focus on umbilical cord and placenta-derived cell-based therapies for the intra-articular injective treatment of osteoarthritis (OA).

A systematic review was performed on three electronic databases (PubMed, Web of Science and Embase) according to PRISMA guidelines. The results were synthesised to investigate disease-modifying effects in preclinical animal studies comparing injectable umbilical cord, placenta, and other sources-derived products with OA controls. The risk of bias was assessed using the SYRCLE tool.

A total of 80 studies were included (2314 animals). Cell therapies were most commonly obtained from the umbilical cord in 33 studies and placenta/amniotic tissue in 18. Cell products were xenogeneic in 61 studies and allogeneic in the remaining 19 studies. Overall, 25/27 (92.6%) of studies on umbilical cord-derived products documented better results compared to OA controls in at least one of the following outcomes: macroscopic, histological and/or immunohistochemical findings, with 19/22 of studies (83.4%) show positive results at the cartilage level and 4/6 of studies (66.7%) at the synovial level. Placenta-derived injectable products documented positive results in 13/16 (81.3%) of the studies, 12/15 (80.0%) at the cartilage level, and 2/4 (50.0%) at the synovial level, but 2/16 studies (12.5%) found overall worse results than OA controls. Other sources (embryonic, synovial, peripheral blood, dental pulp, cartilage, meniscus and muscle-derived products) were investigated in fewer preclinical studies. The risk of bias was low in 42% of items, unclear in 49%, and high in 9% of items.

Interest in cell-based injectable therapies for OA treatment is soaring, particularly for alternatives to bone marrow and adipose tissue. While expanded umbilical cord mesenchymal stem cells reported auspicious disease-modifying effects in preventing OA progression in animal models, placenta/amniotic tissue also reported deleterious effects on OA joints. Lower evidence has been found for other cellular sources such as embryonic, synovial, peripheral blood, dental-pulp, cartilage, meniscus, and muscle-derived products.

Level II.

Autologous protein solution (APS) has been shown to decrease lameness in horses with osteoarthritis (OA). Synovitis is an early driver of OA, providing an opportunity to intervene in the progression of disease via intra-articular (IA) therapeutics.

The objective of this study was to investigate the effects of a single IA APS injection in horses with interleukin-1β (IL-1β)-induced synovitis. We hypothesised that APS would decrease joint swelling and lameness, improve synovial fluid parameters and improve joint pathology scores in horses compared with untreated controls.

Randomised controlled in vivo experiment.

Synovitis was induced with IL-1β (65 ng) in one randomly selected tarsocrural joint. Twenty-four hours later, joints were treated with APS (Pro-Stride®) (n = 12) or left as untreated controls (n = 6). Lameness examinations and joint circumference measurements were performed on Days 0 (prior to IL-1β), 1 (prior to APS), 2, 4, 7 and 14. Synovial fluid, obtained on the same days, was analysed for protein concentration, nucleated cell count, and cytokine (IL-1β, TNF-α, IFN-γ, IL-6, IL-10) and prostaglandin E2 (PGE2) concentrations. Gross pathology and synovial membrane histopathology scoring was performed on APS-treated (n = 5), untreated control (n = 4) and normal (n = 9) tarsocrural joints.

APS did not decrease lameness or joint circumference compared with untreated controls. Synovial fluid parameters were not different between treatment groups. APS treatment did significantly decrease gross and histopathology scores.

Main limitations included the use of an induced model of the synovitis, inter-horse variability in the response to IL-1β and likely variability in the constituents of APS from individual horses.

APS treatment of tarsocrural joints with synovitis did not significantly improve lameness or alter synovial fluid parameters. APS did lead to significant improvement in gross joint appearance and synovial membrane histology suggesting that APS may have disease-modifying effects.

Metabolic Syndrome (MetS), as a syndrome characterized by low-grade inflammation and energy metabolism disorders, is considered to be an important systemic risk factor for knee osteoarthritis (KOA). Our previous study showed that the protein level of serum resistin was positively correlated with the degree of metabolic disorder in MetS-OA. However, whether Resistin promotes the progression of KOA synovitis and the underlying mechanisms remain unclear. This study mainly investigateswhether there were metabolism disorder which promote inflammatory and catabolic phenotype in fibroblast-like synoviocytes (FLS) from KOA patients with MetS (MetS-KOA-FLS), and the roles and mechanisim of resistin in MetS-KOA-FLS.

Comparative analysis of synovium and FLS from MetS-associated KOA (MetS-KOA) and non-MetS-associated KOA (nMetS-KOA) of females to detect the differences in inflammation, catabolism and glycolipid metabolism. Serum from MetS-KOA stimulated nMetS-KOA-FLS to detect the effect of MetS microenvironment on inflammation, catabolism and glycolipid metabolism of nMetS-KOA-FLS. Resistin stimulated MetS-KOA-FLS to explore the effect of resistin on inflammation and catabolism of MetS-KOA-FLS and its specific mechanism.

Compared with nMetS-KOA-FLS, MetS-KOA-FLS expressed higher inflammatory related factors, catabolic enzymes, and showed stronger adhesive and invasive ability. Resistin was found to be an important factor in the serum and internal environment of MetS-KOA patients, and it mediated the differences in fatty acid oxidation (FAO) between the two groups. Resistin activated the PKA/CREB pathway through CAP1 and upregulated FAO, promoting the inflammatory and catabolic phenotype of MetS-KOA-FLS.

This study clarifies the mechanism by which MetS causes synovitis from a metabolic perspective and provides new ideas for further research and treatment of MetS-KOA.

Although biomaterials strategies have been regarded as a promising approach for the treatment of osteoarthritis (OA), identifying novel drugs to be delivered for modulate macrophage polarization is still unclear. As a commonly used non-steroidal anti-inflammatory drug for OA, Imrecoxib may be a novel drug to direct and sustain macrophage phenotype. However, the specific protective mechanism of Imrecoxib in OA remains unclear. This study aims to investigate whether Imrecoxib would treat OA by regulating synovial macrophage polarization.

The research involves constructing mouse destabilization of medial meniscus (DMM) model to assess the changes in pain, bone destruction, cartilage degeneration, and synovial macrophage phenotypes following Imrecoxib treatment. Additionally, the effects of macrophage conditioned medium (CM) pretreated with Imrecoxib on the chondrocyte apoptosis, inflammation and degeneration-related factor expression were evaluated. The role of COX-2/PGE2 signaling pathway in the macrophage phenotype changes was further investigated.

We found that Imrecoxib alleviated pain, cartilage degeneration and synovitis, promoted polarization of M1 macrophages toward M2 phenotype in vivo and in vitro. In vitro experiments, Imrecoxib-CM protected chondrocyte by modulating macrophage polarization. Furthermore, Imrecoxib regulates macrophage polarization through the COX-2/PGE2 pathway.

This study unravels that Imrecoxib protects joint cartilage and attenuates osteoarthritis by modulating synovial macrophage polarization through inactivating COX-2/PGE2 signaling pathway, providing new drug delivery strategy for the clinical treatment of OA.

Osteoarthritis (OA) is a ubiquitous problem affecting dog joints, particularly the hip, elbow, stifle, and spine. OA most often results from developmental orthopedic problems such as hip dysplasia, elbow dysplasia, and patellar luxation and from injuries to the cranial cruciate ligament. Several management approaches have been proposed to manage OA, including steps to modulate growth, physical activity, and exercise, nutrition and nutritional supplementation, medications, physical rehabilitation, and surgical procedures. This article is the first in a series of articles that propose steps for practical OA management in dogs at various life stages. The review presented here focuses on growing dogs. The text describes the early pathophysiology and diagnosis of OA. The physical, nutritional, analgesic, and surgical management options of OA in growing dogs are presented. The application of these management options is described for three dogs. The overall approach to the management of OA in growing dogs is discussed.

Regulatory T cells (Tregs) are the specific T cell population that suppress inflammatory immunity. Independent of their inhibitory activities, Tregs exhibit unique capacity to repair tissue damage. Rapid progresses are made in the processing and engineering of Tregs for clinical applications. Tregs have been used in the treatment of autoimmune diseases, transplantation rejection and graft-versus-host disease. Osteoarthritis is one of the major diseases that affect at least 600 million people worldwide. Osteoarthritis is characterized by physical erosion of cartilage, accompanied with chronic and low-grade inflammation. Tregs possess abilities to increase osteoclast differentiation and bone resorption, repair bone physical damage, and increase bone mass. Tregs are therefore candidate therapeutics for osteoarthritis for both inflammation resolution and tissue repairing. In this review, we will summarize the recent development in using Tregs in immunotherapy, and the potential of using Tregs in osteoarthritis.

We probed the roles of SNHG7, miR-146b, PCBP1, and IL-β in the development of osteoarthritis (OA).

OA models were established using anterior cruciate ligaments, and chondrocytes were obtained from mouse cartilage tissue. Cells were treated with 10 ng/ml Il-1β. RT-qPCR was used to detect the expression of SNHG7, miR-146b, PCBP1, and IL-β in tissues and cells. Safranin-O/Fast Green staining was performed to analyze the cartilage damage in each group of mice.

SNHG7 and PCBP1 expressions were down-regulated, and miR-146b expression was up-regulated in OA tissue and IL-1β-treated chondrocytes compared to normal cartilage tissue and chondrocytes. Forced SNHG7 expression improved cartilage structure, enhanced proliferative viability of chondrocytes, and inhibited apoptosis and IL-1β release in IL-1β-treated chondrocytes in OA mice. In contrast, miR-146b upregulation decreased proliferative viability and promoted apoptosis and IL-1β release in chondrocytes. Rescue assays showed that miR-146b attenuated the protective effects of SNHG7 on apoptosis and inflammation in IL-1β-treated chondrocytes, and activation of PCBP1 expression significantly inhibited the cytotoxic effects of miR-146b. Mechanistically, SNHG7 acted as a competitive endogenous RNA by targeting miR-146b to promote the expression of PCBP1.

This study confirms that SNHG7 inhibits IL-1β-mediated inflammatory responses in chondrocytes via the miR-146b/PCBP1 axis, thereby suppressing IL-1β-induced OA.

Osteoarthritis is a chronic and progressive joint disease accompanied by cartilage degeneration and synovial inflammation. It is associated with an imbalance of synovial macrophage M1/M2 ratio tilting more towards the pro-inflammatory M1 than the anti-inflammatory M2. The M1-macrophages rely on aerobic glycolysis for energy whereas the M2-macrophages derive energy from oxidative phosphorylation. Therefore, inhibiting aerobic glycolysis to induce metabolic reprogramming of macrophages and consequently promote the shift from M1 type to M2 type is a therapeutic strategy for osteoarthritis. Here we developed a macrophage-targeting strategy based on opsonization, using nanoparticles self-assembled to incorporate Chrysin (an anti-inflammatory flavonoid) and V-9302 (an inhibitor of glutamine uptake), and the outer layer modified by immunoglobulin IgG by electrostatic adsorption into IgG/Fe-CV NPs. In vitro studies showed that IgG/Fe-CV NPs effectively target M1 macrophages and inhibit HIF-1α and GLUT-1 essential for aerobic glycolysis and promote polarization from M1 to M2-type macrophages. In vivo, IgG/Fe-CV NPs inhibit inflammation and protect against cartilage damage. The metabolic reprogramming strategy with IgG/Fe-CV NPs to shift macrophage polarization from inflammatory to anti-inflammatory phenotype by inhibiting aerobic glycolysis and glutamine delivery may open up new avenues to treat osteoarthritis.

There is a clear relationship between osteoarthritis (OA) and micronutrients. Excessive accumulation of micronutrients may play a negative role in aggravating the symptoms of OA. This study aims to sort out the causal relationship between micronutrients (zinc, copper, magnesium, vitamins A, C, E, D, B6, and B12, folic acid, iron, carotene, selenium, calcium, and potassium) and OA. This study used Mendelian randomization (MR) to combining the causal relationship between micronutrients and the risk of OA. Micronutrient-related variants were extracted from a large-scale genome-wide association study (GWAS) database of circulating micronutrients in European populations. Outcome data were from the FINNGEN meta-analysis of OA in participants of European ancestry from the FinnGen Biobank in Finland. The primary analysis was performed using the inverse-variance weighted (IVW) method, and a series of sensitivity analyses and multi-dimensionality analyses were conducted to detect possible violations of the MR assumptions. This study used the IVW method to analyze the causal relationship between 15 micronutrients and OA. The results showed that copper (P = 0.535), selenium (P = 0.463), folic acid (P = 0.664), carotene (P = 0.706), potassium (P = 0.839), vitamin D (P = 0.941), vitamin C (P = 0.928), vitamin B12 (P = 0.859), iron (P = 0.496), vitamin E (P = 0.678), magnesium (P = 0.934), vitamin B6 (P = 0.027), calcium (P = 0.743), and vitamin A (P = 0.368) had no significant causal relationship with OA. Among them, vitamin B6 showed P < 0.05 in the pleiotropy test, indicating the presence of pleiotropy. In contrast, zinc exhibited a significant causal relationship with OA (P < 0.001, OR 95% CI = 1.044 [1.021-1.067]), with sensitivity analyses further validating the robustness and reliability of this finding. This study reveals a causal relationship between zinc and OA, identifying zinc as a risk factor for OA. It provides evidence of causality between zinc and OA, offering novel insights for clinical research, diagnosis, and treatment of OA.

This study describes a novel technique to analyze the extracellular vesicle (EV)-derived microRNA (miRNA) crosstalk between equine chondrocytes and synoviocytes. Donor cells (chondrocytes, n = 8; synoviocytes, n = 9) were labelled with 5-ethynyl uridine (5-EU); EVs were isolated from culture media and incubated with recipient cells (chondrocytes [n = 5] were incubated with synoviocyte-derived EVs, and synoviocytes [n = 4] were incubated with chondrocyte-derived EVs). Total RNA was extracted from recipient cells; the 5-EU-labelled RNA was recovered and sequenced. Differential expression analysis, pathway analysis, and miRNA target prediction were performed. Overall, 198 and 213 miRNAs were identified in recipient synoviocytes and chondrocytes, respectively. The top five most abundant miRNAs were similar for synoviocytes and chondrocytes (eca-miR-21, eca-miR-221, eca-miR-222, eca-miR-100, eca-miR-26a), and appeared to be linked to joint homeostasis. There were nine differentially expressed (p < 0.05) miRNAs (eca-miR-27b, eca-miR-23b, eca-miR-31, eca-miR-191a, eca-miR-199a-5p, eca-miR-143, eca-miR-21, eca-miR-181a, and eca-miR-181b) between chondrocytes and synoviocytes, which appeared to be linked to migration of cells, apoptosis, cell viability of connective tissue cell, and inflammation. In conclusion, the reported technique was effective in recovering and characterizing the EV-derived miRNA crosstalk between equine chondrocytes and synoviocytes and allowed for the identification of EV-communicated miRNA patterns potentially related to cell viability, inflammation, and joint homeostasis.

Combining artificial cellular compartmentalization and intelligent motion benefits of micro/nanomotors, light is used as energy input to construct an artificial cell-based micromotor capable of photosynthetic anabolism and intelligent directional movement. This system is assembled from phospholipids functionalized with F-ATP synthase and molybdenum disulfide (MoS2) nanoparticles (Vesical@MoS2-ATPase). The underlying mechanism involves the generation of protons (H+) through photo-hydrolysis of MoS2 nanoparticles within vesicles, which generates a local electroosmotic flow inside the vesicles and drives the negatively charged MoS2 toward light. The established proton gradient across the phospholipid membrane, in turn, drives the ATP synthase to catalyze ATP production. Both in vitro and in vivo models demonstrate that the micromotor can elevate local intracellular ATP levels upon light and improve the metabolism of denatured chondrocytes. This cell mimicry, with capabilities of migration and biosynthesis, emerges as a promising platform for the next generation of functional bio-interface.

Previous studies have suggested that women with higher follicle-stimulating hormone (FSH) levels have a greater incidence of osteoarthritis (OA) compared to women with lower FSH despite normal estrogen levels. Our previous studies also showed that FSH has a negative effect on cartilage in postmenopausal OA. However, no studies have investigated the effect of FSH on the synovium. Here, we showed that the FSH receptor (FSHR) is expressed on RAW264.7 cells and BMDM (Bone Marrow-Derived Macrophages), and found that FSH stimulation promotes the production and secretion of inflammatory cytokines in synovial macrophages. In RAW264.7 cells, FSH stimulation enhances phosphorylation and nuclear translocation of P65, suggesting the activation of NFκB signaling, while the knockdown of FSHR eliminates the proinflammatory effect of FSH. To further validate these results, we used an ovariectomy mouse model supplemented with FSH and estrogen, and a mouse model with FSH neutralization. We noted that FSHR was expressed on mouse synovial joint membranes. Furthermore, in ovariectomy mice supplemented with estrogen and treated with FSH, synovial macrophages were significantly increased, while the opposite was the case in the FSH neutralizing group, which suggest that FSH triggers an inflammatory response in the synovial tissue in mice. Taken together, our results indicate that FSH is an important regulator in synovial inflammation via NFκB signaling activation and, to some extent, appears to accelerate the development of osteoarthritis.

BackgroundKnee osteoarthritis is a debilitating disease with a complex pathogenesis. Synovitis, which refers to inflammation of the synovial membrane surrounding the joint, is believed to play an important role in the development and progression of knee osteoarthritis. To better understand the molecular mechanisms underlying knee osteoarthritis, we conducted a comprehensive analysis of gene expression in knee osteoarthritis synovium using machine learning.MethodsDifferentially expressed genes between knee osteoarthritis and control synovial tissues were analyzed using the GSE55235 dataset. We employed several machine learning algorithms, including least absolute shrinkage and selection operator and support vector machine-recursive feature elimination, to screen for key genes. Then, we validated the key genes using an external dataset (GSE51588) and an in vitro knee osteoarthritis animal model. CIBERSORT was used to compare immune cell infiltration levels between knee osteoarthritis and control synovial tissues and determine their relationship with the key genes. Finally, we performed a Connectivity Map analysis to screen for potential small-molecule compounds. Moreover, we conducted single-cell RNA sequencing analysis using knee joint tissues to annotate different subtypes of cells.ResultsA total of 930 differentially expressed genes were identified. Least absolute shrinkage and selection operator regression and support vector machine-recursive feature elimination identified FOSL2 and RHoBTB1 as key genes. The expression levels of both genes were further validated in the GSE51588 dataset as well as verified through an in vitro experiment involving a knee osteoarthritis mouse model. Multiple significant correlation pairs were found between the immune cell infiltration levels. We unveiled the genetic basis of knee osteoarthritis using genome-wide association study and specific signaling pathways through gene set enrichment analysis. The GeneCards database was used to obtain 3032 pathogenic genes associated with knee osteoarthritis, and we found that RHoBTB1 expression was significantly negatively correlated and FOSL2 expression was significantly positively correlated with interleukin-1β expression. We predicted several small-molecule compounds based on Connectivity Map analysis. Finally, single-cell RNA sequencing analysis revealed the expression levels of the two key genes in chondrocytes and tissue stem cells.ConclusionFOSL2 and RHoBTB1 may play key roles in the pathogenesis of knee osteoarthritis, exhibiting correlations with immune cell infiltration levels. These findings indicate that these genes have potential as therapeutic targets. However, further research and validation are necessary to confirm their exact roles and therapeutic potential in knee osteoarthritis.

Patients with systemic juvenile idiopathic arthritis (sJIA) exhibit highly heterogeneous pain manifestations, which significantly impact their quality of life and disease prognosis. An understanding of the pain phenotypes for this disorder and their influencing factors is crucial for individualized pain management.

To explore the pain phenotypes of newly diagnosed sJIA patients via latent class analysis (LCA), analyse the influencing factors of these phenotypes, and evaluate the impacts of different pain phenotypes on short-term inpatient outcomes.

A retrospective cohort study was conducted by collecting the electronic health records of 165 patients who were first diagnosed with sJIA at the Children's Hospital of Chongqing Medical University from January 2018 to July 2024. Patient pain characteristics, laboratory indicators, and inpatient outcome data were extracted. LCA was used to identify pain phenotypes, and multivariate logistic regression was used to analyse the influencing factors. The Lanza-Tan-Bray method and the data combination analysis technique were applied to evaluate the relationships between pain phenotypes and clinical outcomes.

LCA categorized the pain phenotypes of sJIA patients into three distinct classes, including (1) Class 1: inflammation-related moderate to severe pain with functional impairment (53.9% of patients); (2) Class 2: mild intermittent pain with extra-articular symptoms (19.4% of patients); and (3) Class 3: no joint pain with mild functional impairment (26.7% of patients). The analysis revealed that age (P = 0.023) and serum IL-10 levels (P = 0.047) were significant factors influencing pain phenotypes. Significant differences were observed among different pain phenotypes in terms of hospital stay duration, intrahospital department transfer rates, and pain status at discharge.

Pain in sJIA patients can be classified into three distinct phenotypes, which are influenced by factors such as age and IL-10 levels. The identification of these pain phenotypes has important clinical significance for developing individualized pain management strategies.

Osteoarthritis (OA) is a degenerative joint disease that can be aggravated by synovitis and synovial immune disorders (SID). However, the role of synovial SID-related genes in OA synovium remains poorly understood. OA synovial and peripheral blood datasets were obtained from the GEO database ( https://www.ncbi.nlm.nih.gov/ ). Immune-related genes ( https://reactome.org/ ) showing differential expression in peripheral blood were identified as immune disorder genes. Subsequently, differentially expressed immune disorder genes in OA synovium were further identified as SID genes. The Venn diagram, random forest, SVM-RFE algorithm, and multivariate analysis were employed to determine SID-related hub genes in OA synovium. Using the identified hub genes, we constructed and validated a diagnostic model for predicting OA occurrence. The correlation between hub gene expression and immune-related modules was explored using CIBERSORT and MCP-counter analyses. We identified three SID-related hub genes (ACAT1, SPHK1, and ACACB) in OA synovium. The diagnostic model incorporating these hub genes demonstrated reliable predictive accuracy (AUC = 0.939). Through qPCR analysis, we quantitated the expression levels of the hub genes and confirmed that three hub genes could serve as novel biomarkers for OA patients (AUC = 0.960). Furthermore, we observed a significant correlation between the expression of these hub genes and immune cell infiltration, as well as inflammatory cytokine levels in OA synovium. Our findings suggest that three SID-related hub genes have the potential to serve as diagnostic biomarkers for OA patients. These genes are associated with immune disorder and contribute to immune alterations within the OA synovium.

The progression of osteoarthritis (OA) is closely linked to synovial inflammation caused by an imbalance between M1 and M2 macrophages. To tackle this problem, we developed a liposome responsive to reactive oxygen species (ROS), modified with folic acid ligands to target M1-polarized macrophages, and loaded with the anti-inflammatory agent dimethyl fumarate (DMF). This liposome-based drug delivery system was designed to reprogram macrophage phenotype to remodel the inflammatory microenvironment in the joint cavity and alleviate OA degeneration. The liposome we prepared had a suitable size and negative zeta potential, with uniform size, good stability in aqueous solution, and excellent biocompatibility. Laboratory tests showed that these DMF-filled liposomes notably decreased high levels of ROS in M1-type macrophages and shifted macrophage polarization via the Nrf2/HO-1 pathway, which in turn lessened inflammation in chondrocytes and averted their apoptosis. Additionally, animal studies demonstrated that liposomes containing DMF exhibited notable anti-inflammatory properties, significantly reduced synovial inflammation, safeguarded injured cartilage, reversed changes in subchondral bone, and effectively slowed the progression of osteoarthritis in a mouse model induced by anterior cruciate ligament transection (ACLT). Therefore, ROS-responsive liposomes targeting M1-polarized macrophages represent a promising and valuable approach for OA treatment.

Osteoarthritis (OA) is a chronic joint disease that significantly impairs quality of life. Synovitis plays a pivotal role in OA progression, and pyroptosis, a form of programmed cell death associated with innate immune inflammation, may contribute to the pathogenesis of OA synovitis. Nevertheless, the precise role of pyroptosis in OA pathogenesis remains poorly understood.

We performed an analysis of bulk RNA sequencing data to examine the expression profiles of pyroptosis-related genes in the OA synovium. A LASSO-Cox regression model was employed to identify pivotal genes. Single-cell RNA sequencing data were used to validate the expression of these genes in specific synovial cell clusters. Differentially expressed genes (DEGs) in macrophages with high or low expression levels of core genes were subjected to enrichment analysis. A protein-protein interaction (PPI) network was constructed to identify hub genes, and potential therapeutic compounds were predicted. Consensus clustering analysis was performed to examine the correlations between hub genes and disease status. After identifying PYCARD as the core pyroptosis gene in OA macrophages, we assessed the expression levels of PYCARD in the OA synovium and validated the expression of PYCARD and its related core genes in M1 macrophages.

A total of twenty pyroptosis-related DEGs were identified, and six core genes were selected through LASSO regression. PYCARD was identified as the key pyroptosis gene in macrophages. Furthermore, 57 therapeutic compounds targeting these genes were predicted. Validation confirmed the upregulation of PYCARD in the OA synovium and M1 macrophages.

PYCARD was identified as the core pyroptosis gene in OA macrophages, and 57 potential therapeutic compounds were identified. This study offers valuable insights into potential treatment targets for OA.

In preclinical models of osteoarthritis (OA), histology is commonly used to evaluate joint remodeling. The current study introduces a deep learning driven histological analysis pipeline for the spatial evaluation of knee osteoarthritis (SEKO) focused on quantifying and visualizing joint remodeling in the medial compartment of rodent knees.

The SEKO pipeline contains both segmentation and visualization tools. For segmentation, two separate convolutional neural network architectures, HRNet and U-Net, were considered for identifying multiple regions of interest. Following segmentation, SEKO calculates multiple morphometric and location dependent measures to summarize joint-level changes. Additionally, SEKO generates probabilistic heat maps for visualization of the spatial aspects of joint remodeling.

SEKO incorporated the U-NET architecture - due to its higher prediction accuracy - and identified similar cartilage loss changes that were reported using by-hand segmentation in prior work. Additionally, SEKO enabled the detection of changes in subchondral bone area and location dependent bone remodeling. SEKO also enabled visualization of spatial changes in cartilage thinning and bone remodeling using probabilistic heat maps.

The SEKO pipeline offers the potential for objective comparison of OA progression and therapeutic interventions through visualization of spatial and morphometric changes. SEKO is provided as an open-source tool for the OA research community, facilitating collaborative research efforts and comprehensive analysis of knee joint histology.

Previous studies have reported that low-intensity pulsed ultrasound (LIPUS) can alleviate cartilage degradation in osteoarthritis (OA). However, the functions and mechanisms of LIPUS in synovial fibrosis with OA require further study. To investigate the role of the PI3K/AKT signaling pathway in synovial fibrosis and in LIPUS treatment in synovial fibrosis, a 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 used. The results revealed that LIPUS delayed the progression of OA. Masson staining revealed that LIPUS reduced the collagen deposition of synovial tissue in OA rats. Correspondingly, immunofluorescence demonstrated that LIPUS significantly downregulated the expression of α-SMA, Col1a1 and Col3a1 in OA rats. Moreover, TGF-β stimulation upregulated fibrosis markers at the mRNA and protein levels in FLS, as well as increased phosphorylation-dependent activation of the PI3K/Akt pathway. 740Y-P was found to promote the fibrotic change of FLS induced by TGF-β, but LY294002 reduced its expression. However, LIPUS inhibits the fibrotic change and activation of the PI3K/Akt pathway in FLS under stimulation of TGF-β. In conclusion, LIPUS alleviates synovial fibrosis by blocking the PI3K/AKT pathway.

This study was performed to compare the outcomes of adjunctive injections (injectable platelet-rich fibrin (iPRF), hyaluronic acid (HA)) and arthrocentesis only (AO) in the treatment of temporomandibular joint osteoarthritis. The study included 127 female patients (mean age 52.3 years). None of them had undergone prior occlusal splint therapy. The pain reduction (visual analogue scale) at 12 months post-treatment was the primary outcome variable, while maximum inter-incisal opening (MIO) at all follow-ups and pain at 1 and 6 months of follow-up were secondary outcome variables. All treatment groups showed significant improvements in pain and MIO at all postoperative follow-ups compared to baseline (P < 0.001). iPRF and HA resulted in significantly better pain relief than AO at all follow-ups (P < 0.01). There was no significant difference in pain alleviation between iPRF and HA. No differences were observed among the three groups in jaw mobility (MIO) at any follow-up. Since iPRF did not provide additional benefits over HA, the two treatments may be considered as alternatives, depending on cost considerations. Of note, the treatment objectives were achieved even without previous occlusal splint use.

This double-blind, trial sought to assess the effectiveness of intra-articular ozone therapy at concentrations of 20 µg/mL and 40 µg/mL in managing pain and enhancing functional mobility in patients with knee osteoarthritis (KOA).

This parallel, three-arm randomized controlled trial, conducted between 2022 and 2023, included 59 knee osteoarthritis (KOA) patients randomly allocated to one of three groups: the first group received 40 µg/mL ozone therapy, the second group received 20 µg/mL ozone therapy, and the control group received oxygen. Functional mobility was assessed through the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), knee flexion range of motion (FROM), the Timed Up and Go (TUG) test, and the six-minute walk test (6MWT). Pain intensity was measured using the Visual Analog Scale (VAS) and the pain subscale of the WOMAC. Intra-articular injections were administered weekly for four consecutive weeks, with assessments conducted pre-treatment, and at two weeks, one month, and two months post-intervention. One-way ANOVA was employed for normally distributed quantitative data, while the Kruskal-Wallis test was utilized for non-normally distributed data. Qualitative variables were analyzed using the Chi-squared or Fisher's exact test, as appropriate.

The groups receiving intra-articular ozone therapy exhibited notable reductions in mean VAS scores and improvement in functional mobility variables when compared to the control group (p < 0.05). However, post-hoc analysis indicated no statistically significant differences between the 40 µg/mL and 20 µg/mL ozone therapy groups regarding these parameters (VAS, FROM, TUG, 6MWT, or WOMAC scores) (p > 0.05).

Both 20 µg/mL and 40 µg/mL doses of intra-articular ozone therapy prove to be effective in reducing pain and enhancing functional mobility in patients with knee osteoarthritis (KOA). Nevertheless, there was no significant difference in the efficacy between the two ozone concentrations.

The trial is registered on us ClinicalTrials.gov in 2024-05-01 with the following ID code NCT06088706.

Osteoarthritis (OA) is associated with lost range of motion in the affected joint(s). Evidence suggests that this may be due to increased activity of posterior capsule fibroblasts, cells in turn derived from mesenchymal stromal cells (MSCs).

To test the hypotheses that (1) MSCs are more numerous in the posterior capsule of patients with knee flexion contracture (FC) and (2) in OA participants with knee FC, the MSC population in the posterior capsule differentiates toward a fibrotic phenotype. In order to complete these objectives, we looked for associations between capsule histologic and MSC outcomes with clinical outcomes.

Cross-sectional translational research design using data from the Ottawa Knee Osteoarthritis (OKOA) database.

A total of 71 OKOA database participants and their relevant clinical and laboratory outcomes were included. Associations were first tested with bivariate correlation, then for p < 0.10, tested using a linear model.

No lab-based differences between FC and no-FC groups we discovered. In the posterior capsule, there was an association between knee flexion and adipogenic capacity (p = 0.001), osteogenic capacity (p < 0.001), KL grade and percent "other" (mainly neurovascular) tissue (p = 0.039), visual analog scale pain, and percent fibrous tissue (p = 0.014). For the anterior capsule, there was an association between knee flexion (p = 0.002) and extension (p = 0.005) with MSC enumeration, KL grade with MSC fibrogenic capacity (p = 0.002), and Knee Injury and Osteoarthritis Outcome Score quality of life with chondrogenic capacity (p < 0.001).

Joint capsule composition, MSC enumeration, and function were associated with important clinical OA outcomes. These findings suggest that the entire joint capsule may play an important role in OA-related morbidity and progression and could represent an underappreciated target for OA treatment.

The medial meniscus extrusion (MME) is associated with increased stress on the knee joint, which leads to cartilage degeneration. To evaluate the etiology of knee osteoarthritis, it is extremely important to create animal models of the disease that more closely resemble actual clinical conditions in terms of symptomatology, molecular biology, and histology. This study aimed to create a clinically relevant model of MME in rats.

Behavioral, molecular biological, and histological changes in the newly developed rat MME model were compared with those in sham and medial meniscus transection and medial collateral ligament transection (MMT) models to examine the characteristics of this model.

In the MME rat model, behavioral evaluation shows abnormalities in gait compared with the other 2 groups, and molecular biological evaluation of the infrapatellar synovia of rats shows that gene expression of inflammatory cytokines, matrix-degrading enzymes, and pain-related nerve growth factor was increased compared with the sham group. Furthermore, histological evaluation reveals that cartilage degeneration was the most severe in the MME group.

The newly developed MME model reproduced the characteristic pathology of MME in clinical practice, such as severe pain, inflammation, and rapid progression of osteoarthritis. The MME model, which might more closely mimic human knee osteoarthritis (OA), could be a useful model for elucidating the pathophysiology and considering therapeutic management for knee OA.

The aging population has led to a global issue of osteoarthritis (OA), which not only impacts the quality of life for patients but also poses a significant economic burden on society. While biotherapy offers hope for OA treatment, currently available treatments are unable to delay or prevent the onset or progression of OA. Recent studies have shown that as nanoscale bioactive substances that mediate cell communication, exosomes from stem cell sources have led to some breakthroughs in the treatment of OA and have important clinical significance. This paper summarizes the mechanism and function of stem cell exosomes in delaying OA and looks forward to the development prospects and challenges of exosomes.

Osteoarthritis (OA) is a devastating whole-joint disease affecting a large population worldwide; the role of lipid dysregulation in OA and mechanisms underlying targeted therapy effect of lipid-lowering metformin on OA remains poorly defined.

To investigate the effects of lipid dysregulation on OA progression and to explore lipid dysregulation-targeting OA treatment of metformin.

RNA-Seq data, biochemical, and histochemical assays in human and murine OA cartilage as well as primary chondrocytes were utilized to determine lipid dysregulation. Effects of metformin, a potent lipid-lowering medication, on ACSL4 expression and chondrocyte metabolism were determined. Further molecular experiments, including RT-qPCR, western blotting, flow cytometry, and immunofluorescence staining, were performed to investigate underlying mechanisms. Mice with intra-articular injection of metformin were utilized to determine the effects on ACLT-induced OA progression.

ACSL4 and 4-HNE expressions were elevated in human and ACLT-induced mouse OA cartilage and IL-1β-treated chondrocytes (P < 0.05). Ferrostatin-1 largely rescued IL-1β-induced MDA, lipid peroxidation, and ferroptotic mitochondrial morphology (P < 0.05). Metformin decreased the levels of OA-related genes (P < 0.05) and increased the levels of p-AMPK and p-ACC in IL-1β-treated chondrocytes. Intra-articular injection of metformin alleviated ACLT-induced OA lesions in mice, and reverted the percentage of chondrocytes positive for MMP13, Col2a1, ACSL4 and 4-HNE in ACLT mice (P < 0.05). Ferroptotic chondrocytes promoted the recruitment and chemotaxis of RAW264.7 cells via CCL2, which was blocked by metformin in vitro (P < 0.05).

We establish a critical role of polyunsaturated fatty acids metabolic process in OA cartilage degradation and define metformin as a potential OA treatment. Metformin reshapes lipid availability and ameliorates chondrocyte ferroptosis sensitivity via the AMPK/ACC pathway. In the future, gene-edited animals and extensive omics technologies will be utilized to reveal detailed lipids' involvement in cartilage lesions.