To investigate the acute effects of short-term exposure to ambient air pollution on the risk of hospital admissions for osteoarthritis (OA) and its major subtypes.

Hospital admission data on OA and its major subtypes were sourced from two major urban medical insurance systems in China, covering the period from 2013 to 2017. A two-stage, time-stratified case-crossover design was used to investigate the acute effects of short-term exposure to ambient air pollutants on hospital admissions for OA across 278 Chinese cities with available hospital admission data over 50 cases. The conditional logistic regression model was utilized to assess city-specific associations, which were subsequently pooled by employing a random-effects model.

A total of 1,404,095 OA-related hospital admissions were included. At the main time windows, per interquartile range increases in PM2.5 (particulate matter with an aerodynamic diameter of ≤ 2.5 μm), PM10 (particulate matter with an aerodynamic diameter of ≤ 10 μm), NO2 (nitrogen dioxide), SO2 (sulfur dioxide), O3 (ozone), and CO (carbon monoxide) were associated with significant increases in OA-related admissions by 0.70 % (95 % CI: 0.12 %, 1.28 %), 1.08 % (95 % CI: 0.47 %, 1.69 %), 4.50 % (95 % CI: 3.36 %, 5.65 %), 2.75 % (95 % CI: 1.79 %, 3.72 %), 1.33 % (95 % CI: 0.57 %, 2.10 %) and 1.77 % (95 % CI: 0.76 %, 2.79 %), respectively. Short-term exposures to ambient air pollutants were also associated with increased hospital admissions for major OA subtypes, especially gonarthrosis. The attributable fractions of OA admissions ranged from 0.87 % for PM2.5 to 6.22 % for NO2.

Short-term exposure to ambient air pollution is significantly associated with an increased risk and burden of OA admissions.

Osteoarthritis (OA), a high-prevalence degenerative cartilage disease, urgently requires novel therapeutic strategies. M2 macrophage-derived exosomes (M2-Exo) demonstrate therapeutic potential for OA, though their regulatory mechanisms in chondrocyte-macrophage (Mφ) interactions remain to be elucidated. To investigate the regulatory effects of M2-Exo on chondrocytes and Mφ in vitro, and to evaluate the therapeutic effect of the M2-Exo-loaded hydrogel system (ALG-M2Exo) on cartilage damage in a rat OA model.

In the cell experiment, M2-Exo were extracted and characterized using ultracentrifugation. Different concentrations of M2-Exo were co-cultured with inflammatory chondrocytes or M1Mφ to evaluate their direct anti-inflammatory effects and the ability to promote M1Mφ repolarization to the M2 phenotype, using methods such as EdU, TUNEL, qRT-PCR, and Western blot. Then, the repolarized RM2Mφ were co-cultured with inflammatory chondrocytes to verify their anti-inflammatory efficacy, employing similar detection methods. In the in vivo experiment, sodium iodoacetate was injected to establish a rat knee OA model, followed by interventions including ALG-M2Exo. After 4 and 8 weeks, samples were collected for gross observation and histological staining to assess cartilage damage repair.

In the cell experiment, M2-Exo exhibited typical exosomal characteristics, directly promoting the proliferation of inflammatory chondrocytes, inhibiting their apoptosis, reducing the expression of TNF-α, iNOS, and MMP-13, and increasing the expression of IL-10 and COL II. RM2Mφ showed similar therapeutic effects on inflammatory chondrocytes as M2-Exo. In the in vivo experiment, the ALG-M2Exo group demonstrated superior repair effects on cartilage damage compared to other groups, with the treatment effect at 8 weeks being better than at 4 weeks.

ALG-M2Exo effectively promotes the repair of cartilage damage in OA through both a direct pathway by releasing M2-Exo that act on chondrocytes and an indirect pathway that facilitates the repolarization of M1Mφ to M2Mφ.

Osteoarthritis (OA) is a common degenerative joint disease characterized by the progressive degradation of articular cartilage, synovial inflammation, and subchondral bone remodeling. This review explores the interplay between aging, PANoptosis, and inflammation in OA progression. Age-related cellular and immune dysfunctions, including cellular senescence, senescence-associated secretory phenotypes (SASPs), and immunosenescence, significantly contribute to joint degeneration. In OA, dysregulated apoptosis, necroptosis, and pyroptosis, particularly in chondrocytes, exacerbate cartilage damage. Apoptosis, mediated by the JNK pathway, reduces chondrocyte density, while necroptosis and pyroptosis, involving RIPK-1/RIPK-3 and the NLRP3 inflammasome, respectively, amplify inflammation and cartilage destruction. Inflammatory cytokines and damage-associated molecular patterns (DAMPs) further enhance these PANoptotic pathways. Current therapeutic strategies primarily focus on anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, with growing interest in anti-senescence drugs targeting cellular senescence and SASP. Additionally, exploring PANoptosis mechanisms offers potential for innovative OA treatments.

This study explored the association between serum Hcy level and the all-cause mortality among osteoarthritis (OA) patients. This cohort study included patients diagnosed as OA from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. Abbott Homocysteine assay, a fully automated fluorescence polarization immunoassay (FPIA) method, was used to measure the level of serum Hcy. Covariates included sociodemographic information, lifestyles, history of diseases and medications were extracted from the database. The weighted univariate, multivariate Cox proportional hazard models and restricted cubic splines (RCS) were utilized to explore the association between Hcy level and all-cause mortality in OA patients, with hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analyses based on different age, gender, duration of OA, complications and C-reactive protein (CRP) were further assessed by this association. Totally 1384 OA patients were included in this study, of which 817 (59.03%) died by 31 December 2019. After adjusting all covariates, high Hcy level was associated with the high all-cause mortality among OA patients (HR=1.31, 95%CI: 1.02-1.67), especially in females (HR=1.43, 95%CI: 1.07-1.91), aged >60 years (HR=1.49, 95%CI: 1.14-1.94), duration of OA >10 years (HR=1.40, 95%CI: 1.01-1.95), with the history of hypertension (HR=1.37, 95%CI: 1.03-1.80), without the history of diabetes (HR=1.36, 95%CI: 1.01-1.82) or CRP >0.29 mg/l (HR=1.51, 95%CI: 1.04-2.19). High serum Hcy level was associated with high risk of all-cause mortality in OA patients. Our results suggest that serum Hcy is a promising biomarker for the prognosis of OA patients.

This study aims to explore the relationship between osteoarthritis and the trace elements zinc and copper and to provide a theoretical basis for research on the related mechanisms for the prevention, diagnosis, and treatment of osteoarthritis. We searched all the literature indexed in Web Of Science, Embase, and PubMed as of January 10, 2024, summarized the zinc and copper detection indexes in patients with osteoarthritis, obtained clinical data through literature screening, quality assessment, and data extraction, and analyzed the data using Revman 5.4. A total of 13 papers were included in this study, totaling 7983 study subjects. These were divided into osteoarthritis and healthy control groups. The results from the meta-analysis showed that in patients with osteoarthritis, circulating copper levels, but not zinc levels, were significantly higher compared to healthy individuals. The level of copper in the blood of patients with osteoarthritis is significantly higher than that of healthy people.

Osteoarthritis (OA), affecting > 500 million people worldwide, profoundly affects the quality of life and ability to work. The mitogen-activated protein kinase (MAPK) signaling pathway plays an essential role in OA. To address the lack of studies focused on synovial cells in OA, we evaluated the expression patterns and roles of the MAPK signaling pathway components in OA synovial tissues using bioinformatics. The JUN, MYC, and VEGFA expression levels were significantly higher in the synovial tissues of patients with OA than in control tissues. These loci were closely related to abnormal proliferation, inflammation, and angiogenesis in the synovial tissues of patients with OA. We speculate that Myc and VEGFA activate the p38-MAPK signaling pathway to further activate Jun, thereby promoting abnormal inflammation, proliferation, and angiogenesis in OA synovial tissue. The high MYC, JUN, and VEGFA expression was positively correlated with the patients' K-L score, pain time, and synovial score. Furthermore, the high p38-MAPK and P-p38-MAPK expression confirmed that the abnormal expression and activation of the MAPK signaling pathway occurred in the synovial tissue of patients with OA. Our findings may provide a new direction for the clinical diagnosis and treatment of OA and insights into its pathogenesis.

The primary clinical manifestations of osteoarthritis (OA) are joint pain and restricted movement capabilities. Synovial inflammation, serving as an initiator of OA progression, intensifies cartilage damage via the generation of various deleterious agents, including pro-inflammatory cytokines and nociceptive mediators. Despite extensive research on modulating synovial inflammation to retard OA progression, the underlying pathophysiological mechanisms of synovial inflammation in OA remain elusive. Interleukin-17A (IL-17A), a pro-inflammatory cytokine released by activated T lymphocytes, is a therapeutic target for numerous inflammatory and autoimmune pathologies. This study investigates the role and mechanism of IL-17A in OA synovial inflammation using both in vivo and in vitro models and examines the impact of the endoplasmic reticulum stress (ERS) inhibitor, 4-Phenylbutyric Acid (4-PBA). Our findings indicate that IL-17A may be implicated in synovial inflammation through ERS and suggest a potential therapeutic direction for mitigating synovial inflammation in OA.

Knee osteoarthritis (KOA) refers to a prevalent musculoskeletal disorder, frequently complicated by substantial pain and physical disability. Yougui Yin (YGY) is a classic Chinese herbal mixture which has demonstrated potential in treating KOA. Considering that, its cryptic mechanism warrants to be deciphered, which is the subject of our present research. In vivo, H&E staining, Alcian blue staining and Masson staining assessed the histomorphology. Commercial kits and ELISA evaluated oxidative stress markers. ELISA also assayed serum inflammatory cytokines. TUNEL staining appraised apoptosis. Western blotting examined cartilage matrix degradation, apoptotic and NLRP3 inflammasome proteins. Immunofluorescence assay estimated macrophage polarization. In vitro, ELISA assayed oxidative stress markers and inflammatory cytokines. Immunofluorescence and flow cytometry assay estimated macrophage polarization. MTT and flow cytometry assays severally measured cell viability and apoptosis. DCFH-DA probe detected ROS formation. RT-qPCR and Western blotting examined chondrocyte markers, apoptotic and pyroptotic genes. YGY significantly eased the histomorphological damage, apoptosis and pyroptosis in the cartilage tissues of KOA mice. Besides, YGY exerted anti-oxidant and anti-inflammatory activities and drove M1-to-M2 polarization of macrophages both in vitro and in vivo. Further, the co-culture of macrophages treated by LPS and serum containing YGY improved the viability, eliminated the apoptosis, pyroptosis, inflammation, oxidative stress and cartilage degradation in TNF-α-exposed chondrocytes co-cultured with LPS-intervened macrophages. Overall, YGY might mediate macrophage polarization to impede the advancement of KOA.

Extensor training improves the quadriceps contraction intensity of knee osteoarthritis. But the duration of effects is limited. This study aimed to assess whether electroacupuncture (EA) with extensor training (EA + E) has better short-and long-term effects than simple extensor training (E).

Fifty-four patients were categorized into EA + E and E groups. Elastic shear wave imaging was employed to ascertain the quadriceps elastic modulus values (EMV) at different time points and extension angles. WOMAC scale was used to measure knee function.

Compared to before EA, the vastus lateralis (VL) EMV with 180° knee extension immediately after EA increased significantly. After 1 month, the vastus medialis (VM) EMV with 180° extension increased and WOMAC scores decreased significantly than immediately after EA. The EMV of the VM and VL of group EA + E increased, and WOMAC scores decreased significantly compared to group E after 1 month. After 6 months, EMV of the VM and VL in EA + E group significantly increased, and WOMAC scores significantly decreased compared to E group.

In short- and long-term, EA with extensor training enhances the contraction strength of the quadriceps and knee function for OA.

This prospective single-center randomized controlled trial was approved by the Review Committee of the First Affiliated Hospital of Sun Yat-sen University (Registration date: 28/02/2023, Ethical Number: [2023] 005; The Clinical trial registration number: ChiCTR2300076651.

• The contraction strength of the quadriceps femoris muscle in OA was detected with shear wave elastic ultrasound, and electroacupuncture immediately enhanced the contraction strength. • After the completion of electroacupuncture treatment, the quadriceps strength and the function of knee joint in OA can be continuously improved, which will last for 6 months. • In short and long term, electroacupuncture with extensor training has better enhancement of quadriceps contraction strength of and knee function for OA than extention only.

Articular cartilage lesion frequently leads to dysfunction and the development of degenerative diseases, posing a significant public health challenge due to the limited self-healing capacity of cartilage tissue. Current surgical treatments, including marrow stimulation techniques and osteochondral autografts/allografts, have limited efficacy or have significant drawbacks, highlighting the urgent need for alternative strategies. Advances in 3D printing for cartilage regeneration have shown promising potential in creating cartilage-mimicking constructs, thereby opening new possibilities for cartilage repair. In this review, we summarize current surgical treatment methods and their limitations for addressing articular cartilage lesion, various 3D printing strategies and their features in cartilage tissue engineering, seed cells from different sources, and different types of biomaterials. We also explore the benefits, current challenges, and future research directions for 3D printing in the treatment of articular cartilage lesion within the field of cartilage tissue engineering.

The duration of sleep is linked to a range of disorders. Osteoarthritis (OA) stands as one of the most prevalent forms of arthritis and serves as a leading cause of disability. The correlation between the duration of sleep and OA remains ambiguous. Research indicates that waist circumference correlates with sleep duration and OA, respectively. This study aimed to investigate the association of sleep duration with OA and the mediated effect of waist circumference.

The study sample comprised adults who were participants in the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2018. Insufficient sleep is characterized by a duration of less than seven hours, whereas 7-8 h is considered appropriate, and 9 h or more is categorized as a long sleep duration. Three models were employed in this study. Model 1 was not adjusted for any covariates, while Model 2 was adjusted for sex, age, and race. Model 3 has been adjusted to account for all covariates. Utilizing multivariable logistic regression, subgroup analysis, interaction tests and smoothing curve fitting, the correlation between sleep duration and OA was explored. The mediating effect of waist circumference on the association between sleep duration and OA was investigated through mediation analysis.

In this study, 9380 did not have OA, while 2424 were diagnosed with the ailment. After multivariable adjustment, the odds ratios (OR) for OA were 1.19 (95% CI 1.06, 1.34; P = 0.0026) for people with insufficient sleep duration and 1.18 (95% CI 1.03, 1.35 P = 0.0142) for participants with long sleep duration. Sleep duration and the incidence of OA were found to be related in a U-shaped manner. Additionally, 12.1% of the correlation between sleep duration and OA appeared to be mediated by waist circumference.

Increased OA was found to be correlated in a U-shaped manner with sleep duration in the middle-aged and elderly cohorts. Both insufficient and long sleep duration contribute to an elevated risk of developing OA. A potential mediating factor in the association between OA and sleep duration is waist circumference. Focus on sleep health and visceral obesity in middle-aged and older adults is necessary.

The aberrant H-type vessel formation was found to be intimately linked to subchondral bone remodeling during osteoarthritis (OA) development. Herein, we investigated the role and mechanism of osteoblast-secreted slit guidance ligand 3 (Slit3) in H-type vessel formation during OA progression.

Slit3 protein levels in subchondral bone samples of OA patients were detected. The isolated osteoblasts were transfected with Slit3 overexpression or knockdown plasmids, and their conditioned medium was cultured with endothelial progenitor cells (EPCs). The migration, tube formation, VEGF, and H-type vessel marker protein CD31 and endomucin (EMCN) levels in EPCs were accessed. The interactions between Slit3 and roundabout (Robo) family members were validated by Co-IP assay. Besides, whether the Slit3/Robo signaling affects the transforming growth factor β1 (TGF-β1)/SMADs pathway was determined. Additionally, sh-Slit3 was injected into OA mice, followed by the detection of articular cartilage degradation, subchondral bone remodeling, and H-type vessel formation.

Slit3 was upregulated in subchondral bone tissues of OA patients. Slit3 overexpression in osteoblasts intensified the migration and H-type vessel formation of EPCs, while Slit3 knockdown showed the opposite results. Slit3 overexpression enhanced Robo1 protein level. Robo1 knockdown abrogated Slit3-mediated migration and H-type vessel formation in EPCs. Slit3 activated the TGF-β1/SMADs pathway in EPCs, which might be associated with H-type vessel formation in EPCs. Additionally, Slit3 silencing restrained articular cartilage degradation, aberrant subchondral bone formation, and H-type vessel formation in OA mice.

Inhibition of Slit3/Robo1 signaling alleviates osteoarthritis in mice by reducing abnormal H-type vessel formation in the subchondral bone.

Osteoarthritis (OA) is a degenerative joint disease prevalent in the elderly. Currently, the relationship between the senescence inhibitor Klotho and OA remains unclear. This study investigated the relationship between serum soluble Klotho (S-Klotho) and OA.

This cross-sectional study was based on the 2007-2016 National Health and Nutrition Examination Survey (NHANES). Three multifactorial logistic regression models were constructed to assess the association between serum Klotho and OA. Restricted cubic spline (RCS) curves were further used to assess whether there was a nonlinear relationship between serum Klotho and OA. Finally, stratified analyses and interaction tests were used to evaluate the association's stability. To further investigate the relationship between serum Klotho and OA, we recruited 107 patients for analysis at the First Affiliated Hospital of Guangxi Medical University.

The final 8,918 participants included in this study comprised 50.55% females and 49.45% males, with 18.10% of participants suffering from OA and a mean S-Klotho level of 846.41 (5.61) pg/ml. All three logistic regression models observed a negative association between continuous S-Klotho and OA risk. When S-Klotho was categorized into tertiles, the fully adjusted model showed that participants in the third tertile had a 17% lower risk of OA than those in the first tertile (OR = 0.83, 95% CI: 0.70, 0.99, P = 0.035). The RCS curves showed a linear negative association between S-Klotho and the incidence of OA (P for overall = 0.025; P for non-linearity = 0.667). Further subgroup analyses and interaction tests suggested that the negative association between S-Klotho and OA remained stable in different conditions. Research conducted in China has shown that the negative correlation between serum Klotho levels and the prevalence of OA remains evident among Chinese individuals (OR: 0.77, 95% CI: 0.66, 0.90, P<0.001).

Our study suggests that elevated levels of the senescence inhibitor S-Klotho may be a potential protective factor for OA, which may provide new insights into the diagnosis and treatment of OA.

Currently, approaches to personalized medicine are actively developing. For example, the use of platelet-rich plasma (PRP) is actively growing every year. As a result of activation, platelets release a wide range of growth factors, cytokines, chemokines, and angiogenic factors, after which these molecules regulate chemotaxis, inflammation, and vasomotor function and play a crucial role in restoring the integrity of damaged vascular walls, angiogenesis, and tissue regeneration. Due to these characteristics, PRP has a wide potential in regenerative medicine and gerontology. PRP products are actively used not only in esthetic medicine but also to stimulate tissue regeneration and relieve chronic inflammation. PRP therapy has a number of advantages, but the controversial results of clinical studies, a lack of standardization of the sample preparation of the material, and insufficient objective data on the evaluation of efficacy do not allow us to unambiguously look at the use of PRP for therapeutic purposes. In this review, we will examine the current clinical efficacy of PRP-based products and analyze the contribution of PRP in the therapy of diseases associated with aging.

Synovial inflammation is vital for the progression of osteoarthritis (OA). The objective of this study was to explore the effects and potential molecular mechanisms of sphingosine kinase 2 (SPHK2) on the proliferation and migration of fibroblast-like synoviocytes (FLS).

A TNF-α-stimulated FLS model and a papain-induced OA rat model were constructed. The functions of SPHK2 knockdown in OA were explored by a series of in vivo and in vitro assays. Downstream target genes of SPHK2 were investigated using transcriptome sequencing and validated by reverse transcription quantitative PCR (RT-qPCR). The effects of the SPHK2/IL-17 signaling pathway on inflammation, proliferation, and migration of OA-FLS were investigated using the IL-17 pathway inhibitor (secukinumab) and the activator (rhIL-17A).

TNF-α stimulation promoted SPHK2 expression at mRNA and protein levels in OA-FLS. SPHK2 knockdown reduced IL-1β, IL-6, MMP-2, MMP-9, cyclinD1, and PCNA levels and suppressed proliferation and migration of OA-FLS. SPHK2 knockdown alleviated cartilage damage and synovial inflammation in the OA rat model. LRRIQ3, H4C8, CXCL1, CABP4, COL23A1, and PROK2 expression levels were regulated by SPHK2. SPHK2 knockdown inhibited the protein levels of IL-17A, IL-17RA, and Act1. The IL-17 pathway inhibitor secukinumab enhanced the inhibitory effect of SPHK2 knockdown on the proliferation and migration of OA-FLS, while the IL-17 pathway activator rhIL-17A exerted the opposite effect.

SPHK2 knockdown inhibits proliferation and migration of OA-FLS by blocking the IL-17 pathway, which provides a novel approach to the OA treatment.

Osteoarthritis (OA) is a chronic joint disease with an unclear cause characterized by secondary osteophytes and degenerative changes in the articular cartilage. More than 250 million people are expected to be affected by it by 2050, putting a tremendous socioeconomic strain on the entire world. OA cannot currently be treated with any effective medications that change the illness. Over time, chondrocytes undergo gradual metabolic, structural, and functional changes as a result of aging or abuse. The degenerative progression of osteoarthritis is significantly influenced by the imbalance of chondrocyte homeostasis. By continuously recycling and rebuilding macromolecules or organelles, autophagy functions as a crucial regulatory system to maintain homeostasis during an individual's growth and development. This review uses chondrocytes as its starting point and establishes a strong connection between autophagy and osteoarthritis in order to thoroughly examine the mechanisms behind chondrocyte autophagy in osteoarthritis. Biomarkers of chondrocyte autophagy will be identified, and prospective targeted medications and novel treatment approaches for slowing or preventing the course of OA will be developed based on chondrocyte senescence, autophagy, and apoptosis in OA. KEY MESSAGES: Currently, OA has not been treated with any drugs that can effectively cure it. We hope that by exploring specific targets in the course of osteoarthritis, we can promote the progress of treatment strategies. The degenerative progression of osteoarthritis is significantly influenced by the imbalance of chondrocyte balance. Through the continuous recovery and reconstruction of macromolecules or organelles, autophagy is an important regulatory system for maintaining homeostasis during individual growth and development. In this paper, the close relationship between autophagy and osteoarthritis was established with chondrocytes as the starting point, in order to further explore the mechanism of chondrocyte autophagy in osteoarthritis. The development process of osteoarthritis was studied from the perspective of chondrocytes, and the change of autophagy level had a significant impact on osteoarthritis. Chondrocyte autophagy is mainly determined by intracellular mitochondrial autophagy, so we are committed to finding relevant molecules. Through PI3K/AKT- and MAPK-related pathways, the biomarkers of chondrocyte autophagy were identified, and chondrocyte senescence, autophagy, and apoptosis based on osteoarthritis provided a constructive idea for the development of prospective targeted drugs and new therapies to slow down or prevent the progression of osteoarthritis.

Osteoarthritis (OA) is a common joint disease associated with the aging of the population, and it reduces the quality of life of patients. It is characterized by the destruction of articular cartilage and the secretion of inflammatory cytokines. Owing to the unclear pathogenesis of OA, current treatment methods have significant limitations. Oxidative stress has been revealed to play an important role in the development of OA. Our experiments indicated that the levels of GSH decreased and the level of MDA increased in chondrocytes, which induced ferroptosis in chondrocytes in OA. We also revealed that ferroptosis was the main mechanism of cartilage destruction caused by the addition of the ferroptosis activator erastin and the ferroptosis inhibitor ferrostatin-1. NOX1 is the main modulator of oxidative stress by increasing the generation of reactive oxidative species (ROS). We suppressed the expression of NOX1 in chondrocytes through cell transfection. The expression of collagen II and MMP13, and the secretion of IL-1β and TNF-α were reversed. An increase in the mitochondrial membrane potential and a decrease in the level of intracellular ROS indicate an improvement in oxidative damage. Additionally, we determined the effect of the Nrf2/HO-1 pathway on NOX1-mediated chondrocyte injury. We found that NOX1 inhibited the expression of Nrf2/HO-1, but the activation of Nrf2 improved the oxidative damage to chondrocytes in vivo and vitro. This study revealed that NOX1-mediated oxidative stress induces chondrocyte ferroptosis by inhibiting the Nrf2/HO-1 pathway. Our findings contribute to revealing the pathogenesis of OA, providing targets for drug design and optimizing the clinical treatment of OA.

Musculoskeletal pain is a major burden in our society. Management of musculoskeletal pain or injuries includes both pharmacological and non-pharmacological approaches, including heat therapy (HT). HT is a well-established treatment option due to its ability to promote muscle relaxation, enhance blood circulation, and modulate nociceptors with a good safety profile. The main focus of this paper is to review the available literature about HT in knee pathologies (i.e., arthrosis, arthritis, traumatic pathologies in the subacute phase, muscle and tendon pathologies linked to fatigue, muscle tension and distractions) and to provide an expert opinion in case of lack of data.

Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.

Bone remodeling is the balance between osteoblasts and osteoclasts. Bone diseases such as osteoporosis and osteoarthritis are associated with imbalanced bone remodeling. Skeletal injury leads to limited motor function and pain. Neurophilin was initially identified in axons, and its various ligands and roles in bone remodeling, angiogenesis, neuropathic pain and immune regulation were later discovered. Neurophilin promotes osteoblast mineralization and inhibits osteoclast differentiation and its function. Neuropolin-1 provides channels for immune cell chemotaxis and cytokine diffusion and leads to pain. Neuropolin-1 regulates the proportion of T helper type 17 (Th17) and regulatory T cells (Treg cells), and affects bone immunity. Vascular endothelial growth factors (VEGF) combine with neuropilin and promote angiogenesis. Class 3 semaphorins (Sema3a) compete with VEGF to bind neuropilin, which reduces angiogenesis and rejects sympathetic nerves. This review elaborates on the structure and general physiological functions of neuropilin and summarizes the role of neuropilin and its ligands in bone and cartilage diseases. Finally, treatment strategies and future research directions based on neuropilin are proposed.

With rates growing quickly with age, osteoarthritis (OA) is the most common cause of chronic disability in aging persons. The discomfort and reduced motion associated with osteoarthritis have a significant impact on quality of life, and there is no known solution. Runt-related transcription factor 1(Runx1) has been shown to play a protective role in the development of osteoarthritis by promoting chondrogenesis. We had created models of ageing mice with osteoarthritis by anterior cruciate ligament transection (ACLT) and analyzed the effects of intra-articular injection of adeno-associated virus/Runx1 (AAV/Runx1) on the models. The results showed that the AAV/Runx1-group maintained better articular cartilage integrity and retained more proteoglycan than the OA group after injection of AAV-Runx1. The markers related to pathological changes in cartilage were downregulated, while the markers related to physiological changes in cartilage were upregulated. This suggests that Runx1 may impede OA progression on the knee joint of ageing mice, potentially playing a protective role in OA and becoming a probable treatment target for osteoarthritis among ageing patients in the future.

The discovery of non-coding RNAs (ncRNAs) has unveiled a wide range of transcripts that do not encode proteins but play key roles in several cellular and molecular processes. Long noncoding RNAs (lncRNAs) are specific class of ncRNAs that are longer than 200 nucleotides and have gained significant attention due to their diverse mechanisms of action and potential involvement in various pathological conditions. In the current review, the authors focus on the role of lncRNAs, specifically highlighting the Myocardial Infarction Associated Transcript (MIAT), in non-oncological context. MIAT is a nuclear lncRNA that has been directly linked to myocardial infarction and is reported to control post-transcriptional processes as a competitive endogenous RNA (ceRNA) molecule. It interacts with microRNAs (miRNAs), thereby limiting the translation and expression of their respective target messenger RNA (mRNA) and regulating protein expression. Yet, MIAT has been implicated in other numerous pathological conditions such as other cardiovascular diseases, autoimmune disease, neurodegenerative diseases, metabolic diseases, and many others. In this review, the authors emphasize that MIAT exhibits distinct expression patterns and functions across different pathological conditions and is emerging as potential diagnostic, prognostic, and therapeutic agent. Additionally, the authors highlight the regulatory role of MIAT and shed light on the involvement of lncRNAs and specifically MIAT in various non-oncological pathological conditions.

Osteoarthritis (OA) is a degenerative joint disease characterized by the destruction of the articular cartilage, resulting in a pro-inflammatory response. The progression of OA is multifactorial and is influenced by the underlying cause of inflammation, which includes but is not limited to trauma, metabolism, biology, comorbidities, and biomechanics. Although articular cartilage is the main tissue affected in osteoarthritis, the chronic inflammatory environment negatively influences the surrounding synovium, ligaments, and subchondral bone, further limiting their functional abilities and enhancing symptoms of OA. Treatment for osteoarthritis remains inconsistent due to the inability to determine the underlying mechanism of disease onset, severity of symptoms, and complicating comorbidities. In recent years, diet and nutritional supplements have gained interest regarding slowing the disease process, prevention, and treatment of OA. This is due to their anti-inflammatory properties, which result in a positive influence on pain, joint mobility, and cartilage formation. More specifically, omega-3 polyunsaturated fatty acids (PUFA) have demonstrated an influential role in the progression of OA, resulting in the reduction of cartilage destruction, inhibition of pro-inflammatory cytokine cascades, and production of oxylipins that promote anti-inflammatory pathways. The present review is focused on the assessment of evidence explaining the inflammatory processes of osteoarthritis and the influence of omega-3 supplementation to modulate the progression of osteoarthritis.

Ubiquitination (Ub) and deubiquitination are crucial post-translational modifications (PTMs) that precisely regulate protein degradation. Under the catalysis of a cascade of E1-E2-E3 ubiquitin enzymes, ubiquitination extensively regulates protein degradation exerting direct impact on various cellular processes, while deubiquitination opposes the effect of ubiquitination and prevents proteins from degradation. Notably, such dynamic modifications have been widely investigated to be implicated in cell cycle, transcriptional regulation, apoptosis and so on. Therefore, dysregulation of ubiquitination and deubiquitination could lead to certain diseases through abnormal protein accumulation and clearance. Increasing researches have revealed that the dysregulation of catalytic regulators of ubiquitination and deubiquitination triggers imbalance of cartilage homeostasis that promotes osteoarthritis (OA) progression. Hence, it is now believed that targeting on Ub enzymes and deubiquitinating enzymes (DUBs) would provide potential therapeutic pathways. In the following sections, we will summarize the biological role of Ub enzymes and DUBs in the development and progression of OA by focusing on the updating researches, with the aim of deepening our understanding of the underlying molecular mechanism of OA pathogenesis concerning ubiquitination and deubiquitination, so as to explore novel potential therapeutic targets of OA treatment.

Background: Osteoarthritis causes tremendous damage to the joints, reducing the quality of life and imposing significant financial burden. An implantable drug-delivery system can improve the symptomatic manifestations with low doses and frequencies. However, the free drug has short retention in the joint cavity. Materials & methods: This study used electrostatic spinning technology to create an implantable drug-delivery system loaded with celecoxib (celecoxib nanofibers [Cel-NFs]) to improve retention and bioavailability. Results: Cel-NFs exhibited good formability, hydrophilicity and tensile properties. Cel-NFs were able to continuously release drugs for 2 weeks and increase the uptake capacity of Raw 264.7 cells, ultimately ameliorating symptoms in osteoarthritis rats. Conclusion: These results suggest that Cel-NFs can effectively ameliorate cartilage damage, reduce joint pain and alleviate osteoarthritis progression.

Increasing age is associated with dysregulated immune function and increased inflammation-patterns that are also observed in individuals exposed to chronic social adversity. Yet we still know little about how social adversity impacts the immune system and how it might promote age-related diseases. Here, we investigated how immune cell diversity varied with age, sex and social adversity (operationalized as low social status) in free-ranging rhesus macaques. We found age-related signatures of immunosenescence, including lower proportions of CD20 + B cells, CD20 + /CD3 + ratio, and CD4 + /CD8 + T cell ratio - all signs of diminished antibody production. Age was associated with higher proportions of CD3 + /CD8 + Cytotoxic T cells, CD16 + /CD3- Natural Killer cells, CD3 + /CD4 + /CD25 + and CD3 + /CD8 + /CD25 + T cells, and CD14 + /CD16 + /HLA-DR + intermediate monocytes, and lower levels of CD14 + /CD16-/HLA-DR + classical monocytes, indicating greater amounts of inflammation and immune dysregulation. We also found a sex-dependent effect of exposure to social adversity (i.e., low social status). High-status males, relative to females, had higher CD20 + /CD3 + ratios and CD16 + /CD3 Natural Killer cell proportions, and lower proportions of CD8 + Cytotoxic T cells. Further, low-status females had higher proportions of cytotoxic T cells than high-status females, while the opposite was observed in males. High-status males had higher CD20 + /CD3 + ratios than low-status males. Together, our study identifies the strong age and sex-dependent effects of social adversity on immune cell proportions in a human-relevant primate model. Thus, these results provide novel insights into the combined effects of demography and social adversity on immunity and their potential contribution to age-related diseases in humans and other animals.

Osteoarthritis is a common joint disease characterized by damage to the joint cartilage that occurs throughout the entire joint tissue. This damage primarily manifests as pain in the affected area. In clinical practice, medication is commonly used to relieve pain, but the treatment's effectiveness is poor and recurrent attacks are likely. Schisandrin B is the most abundant biphenylcyclohexene lignan found in the traditional Chinese medicine Schisandra chinensis, and it possesses various pharmacological effects. This study aims to investigate the protective effect of Schisandrin B on mitochondrial damage in osteoarthritis (C28I2 cells) under an inflammatory environment induced by LPS. Cell proliferation and activity, scratch tests, and LDH release tests are utilized to assess cell growth and migration ability. The immunofluorescence assay was used to detect the expression levels of proliferation and apoptosis proteins. The Western Blot assay was used to detect the expression levels of mitochondrial fusion and division proteins. The JC-1 assay was used to detect changes in mitochondrial membrane potential. The mitochondrial fluorescence probe assay was used to detect mitochondrial activity. Through research, it was found that Schisandrin B promotes the proliferation, growth, and migration of C28I2 cells, reduces apoptosis of C28I2 cells, balances mitochondrial fusion and division, stabilizes mitochondrial membrane potential, and promotes mitochondrial activity in an LPS induced inflammatory environment.

Alternative splicing (AS) is a principal mode of genetic regulation and one of the most widely used mechanisms to generate structurally and functionally distinct mRNA and protein variants. Dysregulation of AS may result in aberrant transcription and protein products, leading to the emergence of human diseases. Although considered important for regulating gene expression, genome-wide AS dysregulation, underlying mechanisms, and clinical relevance in knee osteoarthritis (OA) remain unelucidated. Therefore, in this study, we elucidated and validated AS events and their regulatory mechanisms during OA progression.

In this study, we identified differentially expressed genes between human OA and healthy meniscus samples. Among them, the OA-associated genes were primarily enriched in biological pathways such as extracellular matrix organization and ossification. The predominant OA-associated regulated AS (RAS) events were found to be involved in apoptosis during OA development. The expression of the apoptosis-related gene BCL2L13, XAF1, and NF2 were significantly different between OA and healthy meniscus samples. The construction of a covariation network of RNA-binding proteins (RBPs) and RAS genes revealed that differentially expressed RBP genes LAMA2 and CUL4B may regulate the apoptotic genes XAF1 and BCL2L13 to undergo AS events during OA progression. Finally, RT-qPCR revealed that CUL4B expression was significantly higher in OA meniscus samples than in normal controls and that the AS ratio of XAF1 was significantly different between control and OA samples; these findings were consistent with their expected expression and regulatory relationships.

Differentially expressed RBPs may regulate the AS of apoptotic genes during knee OA progression. XAF1 and its regulator, CUL4B, may serve as novel biomarkers and potential therapeutic targets for this disease.

Chondrocytes are mechanosensitive cells able to sense and respond to external mechanical stimuli through the process of mechanotransduction. Previous studies have demonstrated that mechanical stimulation causes mitochondrial deformation leading to mitochondrial reactive oxygen species (ROS) release in a dose-dependent manner. For this reason, we focused on elucidating the role of mitochondrial ROS as anabolic signaling molecules in chondrocyte mechanotransduction. Chondrocyte-seeded agarose gels were subjected to mechanical stimuli and the effect on matrix synthesis, ROS production, and mitogen-activated protein kinases (MAPK) signaling was evaluated. Through the use of ROS-specific staining, superoxide anion was the primary ROS released in response to mechanical stimuli. The anabolic effect of mechanical stimulation was abolished in the presence of electron transport chain inhibitors (complexes I, III, and V) and superoxide anion scavengers. Subsequent studies were centered on the involvement of MAPK pathways (ERK1/2, p38, and JNK) in the mechanotransduction cascade. While disruption of the ERK1/2 pathway had no apparent effect, the anabolic effect of mechanical stimulation was abolished in the presence of p38 and JNK pathway inhibitors. This suggest the involvement of apoptosis stimulating kinase 1 (ASK1), an upstream redox-sensitive MAP3K shared by both the JNK and p38 pathways. Future experiments will focus on the involvement of the thioredoxin-ASK1 complex which disassociates in the presence of oxidative stress, allowing ASK1 to phosphorylate several MAP2Ks. Overall, these findings indicate superoxide anion as the primary ROS released in response to mechanical stimuli and that the resulting anabolic effect on chondrogenic matrix biosynthesis arises from the ROS-dependent activation of the p38 and JNK MAPKs.

This study aimed to evaluate age-stratified radiographic features in temporomandibular joint osteoarthritis using cone-beam computed tomography.

In total, 210 joints from 183 patients (144 females, 39 males, ranging from 12 to 88 years old with a mean age of 44.75±19.97 years) diagnosed with temporomandibular joint osteoarthritis were stratified by age. Mandibular condyle position and bony changes (flattening, erosion, osteophytes, subchondral sclerosis, and subchondral pseudocysts in both the condyle and articular eminence, thickening of the glenoid fossa, joint space narrowing, and joint loose bodies) were evaluated through cone-beam computed tomography. After adjusting for sex, the association between age groups and radiographic findings was analyzed using both a multiple regression model and a multinomial logistic regression model (α=0.05).

The prevalence of joint space narrowing and protruded condyle position in the glenoid fossa significantly increased with age (P<0.05). The risks of bony changes, including osteophytes and subchondral pseudocysts in the condyle; flattening, erosion, osteophyte, and subchondral sclerosis in the articular eminence; joint loose bodies; and thickening of the glenoid fossa, also significantly rose with increasing age (P<0.05). The number of radiographic findings increased with age; in particular, the increase was more pronounced in the temporal bone than in the mandibular condyle (P<0.05).

Increasing age was associated with a higher frequency and greater diversity of bony changes in the temporal bone, as well as a protruded condyle position in the glenoid fossa, resulting in noticeable joint space narrowing in temporomandibular joint osteoarthritis.

Osteoarthritis (OA) is the most common age-related chronic and disabling joint disease, frequently causing pain and disability in the adult population. Given that there are no proven disease-modifying drugs for OA, it is urgent to gain a deeper understanding of OA pathogenesis. This study intended to uncover the circFOXK2 regulation in OA.

First, an in vitro OA cell model was constructed by treating murine chondrocytes with interleukin (IL)-1β. Then, a series of functional assays were conducted to evaluate the effect of circFOXK2 on OA progression in murine chondrocytes. Bioinformatics analysis and mechanism investigations were performed to investigate the competitive endogenous ribonucleic acid (RNA) network of circFOXK2 in OA.

circFOXK2 is overexpressed in IL-1β-treated chondrocyte. We confirmed the cyclic structure and cytoplasmic distribution of circFOXK2. Functionally, circFOXK2 promotes chondrocyte apoptosis and extracellular matrix degradation but inhibits chondrocyte proliferation. Mechanically, circFOXK2 competitively binds to microRNA-4640-5p (miR-4640-5p) to enhance NOTCH2 expression in OA, affecting OA progression. Besides, circFOXK2 could motivate the NOTCH pathway to accelerate OA progression.

The circFOXK2/miR-4640-5p/NOTCH2 axis stimulates the NOTCH pathway to promote the transcription of inflammatory cytokines (IL33, IL17F, and IL6), consequently facilitating OA progression in murine chondrocytes.

Arthritis is the most prevalent joint disease and is characterized by articular cartilage degradation, synovial inflammation, and changes in periarticular and subchondral bone. Recent studies have reported that Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) have significant effects on the proliferation, migration, and survival of chondrocytes and fibroblast-like synovial cells (FLSs). YAP/TAZ signaling pathway, as well as the related Hippo-YAP signaling pathway, are responsible for the condition of cells and articular cartilage in joints. They are tightly regulated to maintain metabolism in chondrocytes and FLSs because abnormal expression may result in cartilage damage. However, the roles and mechanisms of the Hippo-YAP pathway in arthritis remain largely unknown. This review summarizes the roles and key functions of YAP/TAZ and the Hippo-YAP signaling pathway in FLSs and chondrocytes for the induction of proliferation, migration, survival, and differentiation in rheumatoid arthritis (RA) and osteoarthritis (OA) research. We also discuss the therapeutic strategies involving YAP/TAZ and the related Hippo-YAP signaling pathway involved in OA.

Osteoarthritis (OA) is a chronic disease characterized by the progressive loss of cartilage and failure of the diarrheal joint. Quercetin has been reported to attenuate the development of OA. Bone marrow derived mesenchymal stem cell (BMSC)-derived exosomes are involved in OA progression. However, the role of BMSC-derived exosomes in quercetin-mediated progression of OA remains unclear. Western blotting and RT-qPCR were used to assess protein and mRNA levels, respectively. CCK8 assay was performed to assess cell viability, and cell apoptosis was assessed using flow cytometry. A dual-luciferase assay was performed to assess the relationship between miR-124-3p and TRAF6 expression. Furthermore, in vivo experiments were performed to test the function of exosomes derived from Quercetin-treated BMSCs in OA patients. IL-1β significantly inhibited the viability of chondrocytes, whereas the conditioned medium of Quercetin-treated BMSCs (BMSCsQUE-CM) reversed this phenomenon through exosomes. IL-1β notably upregulated MMP13 and ADAMT5 and reduced the expression of COL2A1 in chondrocytes, which were rescued by BMSCsQUE-CM. The effects of BMSCsQUE-CM on these three proteins were reversed in the absence of exosomes. Exosomes can be transferred from BMSCs to chondrocytes, and exosomes derived from Quercetin-treated BMSCs (BMSCsQue-Exo) can reverse the apoptotic effects of IL-1β on chondrocytes. The level of miR-124-3p in BMSCs was significantly upregulated by quercetin, and miR-124-3p was enriched in BMSCsQue-Exo. TRAF6 was identified as a direct target of miR-124-3p, and BMSCsQue-Exo abolished the IL-1β-induced activation of MAPK/p38 and NF-κB signaling. Furthermore, BMSCsQue-Exo significantly attenuated OA progression in vivo. Exosomes derived from Quercetin-treated BMSCs inhibited OA progression through the upregulation of miR-124-3p.

Circular RNAs (circRNAs) have been extensively implicated in osteoarthritis (OA) progression. Therefore, this study explores the impact of hsa_circ_0004662 on OA progression and the related molecular mechanism.

Human articular chondrocyte injury was induced by IL-1β to construct the OA model in vitro. Hsa_circ_0004662 and microRNA (miR)-424-5p expression in chondrocytes was evaluated with qRT-PCR. Vascular endothelial growth factors A (VEGFA) expression was examined with qRT-PCR and western blot after hsa_circ_0004662 knockdown or miR-424-5p overexpression in chondrocytes. Subsequent to loss- and gain-of-function assays in IL-1β-induced chondrocytes, the proliferation and apoptosis of chondrocytes were assessed with CCK-8 assay and flow cytometry, respectively. The expression of MMP13, Aggrecan, and apoptosis-related proteins Bax and Bcl-2 was measured with western blot. The binding of miR-424-5p to hsa_circ_0004662 and VEGFA was assessed with a dual-luciferase reporter gene assay.

Hsa_circ_0004662 was up-regulated, but miR-424-5p was down-regulated in IL-1β-induced chondrocytes. Mechanistically, both hsa_circ_0004662 and VEGFA bound to miR-424-5p, and hsa_circ_0004662 enhanced VEGFA expression by downregulating miR-424-5p. Hsa_circ_0004662 knockdown elevated cell proliferation, decreased apoptosis and MMP13 and Bax expression, and increased Aggrecan and Bcl- 2 expression in IL-1β-induced chondrocytes, which was counteracted by further miR- 424-5p down-regulation or VEGFA overexpression.

Hsa_circ_0004662 facilitates OA progression via the miR-424-5p/ VEGFA axis.

Osteoarthritis (OA) is a degenerative joint disease commonly found in middle-aged and older people. Chondrocytes are the only cells in joint cartilage that are difficult to heal after pyroptosis, and they will aggravate the wear and tear of joint cartilage and affect the progression of OA. Pyroptosis is a novel form of programmed cell death, and the classical pyroptosis pathway is a programmed cell death pattern mediated by inflammatory cysteine protease-1. Activation of NLRP3 leads to activation and cleavage of caspase-1 precursors, which in turn leads to activation and cleavage of GSDMD proteins and the release of proinflammatory factors. Resolvin D1 (RvD1) is a specialized pro-resolving mediator (SPM) derived from omega-3 unsaturated fatty acids that reduces inflammation and catabolic responses in OA chondrocytes. However, it is unclear whether RvD1 promotes OA chondrocyte proliferation and thus joint cartilage repair. Our results show that RvD1 regulates the NLRP3/caspase-1 signaling pathway by inhibiting the expression of caspase-1, promoting the proliferation of OA chondrocytes, promoting the repair of articular cartilage in rats and delaying the progression of osteoarthritis.

The histone deacetylase inhibitor (HDACi) was a milestone in the treatment of refractory T-cell lymphoma. However, the beneficial effects of HDACi have not been appreciated in osteoarthritis (OA). Herein, we implemented a microcarrier system because of the outstanding advantages of controlled and sustained release, biodegradability, and biocompatibility. The poly(d,l-lactide-co-glycolide) (PLGA) microcapsules have a regulated and sustained release profile with a reduced initial burst release, which can improve the encapsulation efficiency of the Chidamide. The emulsion solvent evaporation strategy was used to encapsulate Chidamide in PLGA microcapsules. The encapsulation of Chidamide was established by UV-vis spectra and scanning electron microscopy. Additionally, the inhibition of Tnnt3 and immune stimulation by Chidamide helped to inhibit cartilage destruction and prevent articular cartilage degeneration. Based on the results, the Chidamide in PLGA microcapsules provides a transformative therapeutic strategy for the treatment of osteoarthritis patients to relieve symptoms and protect against cartilage degeneration.

Osteoarthritis (OA) is a joint degenerative disease commonly observed in the old population, lacks effective therapeutic methods, and markedly impacts the normal lives of patients. Degradation of extracellular matrix (ECM) is reported to participate in OA development, which is a potential target for treating OA. Cabozantinib is an inhibitor of tyrosine kinases and is recently claimed with suppressive properties against inflammation. Herein, the protective function of Cabozantinib on advanced glycation end products (AGEs)-induced damages to chondrocytes was tested. SW1353 chondrocytes were stimulated with 100 μg/ml AGEs with or without 10 and 20 μM Cabozantinib for 24 h. Signally increased reactive oxygen species (ROS) levels, declined reduced glutathione (GSH) levels, and elevated release of inflammatory cytokines were observed in AGEs-stimulated SW1353 chondrocytes, which were markedly reversed by Cabozantinib. Moreover, the notably reduced type II collagen and aggrecan levels, and increased matrix metalloproteinase-13 (MMP-13) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs-5 (ADAMTS-5) levels in AGEs-stimulated SW1353 chondrocytes were largely rescued by Cabozantinib. The downregulated Sry-type high-mobility-group box 9 (SOX-9) observed in AGEs-stimulated SW1353 chondrocytes was abolished by Cabozantinib. Furthermore, the impact of Cabozantinib on type II collagen and aggrecan levels in AGEs-treated SW1353 chondrocytes was abrogated by silencing SOX-9. Collectively, Cabozantinib prevented AGEs-induced degradation of type 2 collagen and aggrecan in human chondrocytes by mediating SOX-9.

Introduction: Osteoarthritis (OA) is disabling and degenerative disease of the joints that is clinically characterized by pain and loss of function. With no disease-modifying treatment available, current therapies aim at pain management but are of limited efficacy. Cannabis products, specifically cannabinoids, are widely used to control pain and inflammation in many diseases with no scientific evidence demonstrating their efficacy in OA. Objective: We investigated the effects of non-euphorigenic cannabis extracts, CBD oil and cannabigerol oil (CBG oil), on pain and disease progression in OA mice. Methods and Results: Twelve-week-old male C57BL/6J mice received either sham or destabilization of the medial meniscus (DMM) surgery. DMM mice were treated with vehicle, CBD oil, or CBG oil. The gait of DMM mice was impaired as early as 2 weeks following surgery and continued deteriorating until week 8, which was restored by CBD oil and CBG oil treatments throughout the disease course. Mechanical allodynia developed in DMM mice, however, was not ameliorated by any of the treatments. On the other hand, both CBD oil and CBG oil ameliorated cold allodynia. In open field test, both oil treatments normalized changes in the locomotor activity of DMM mice. CBD oil and CBG oil treatments significantly reduced synovitis in DMM mice. Only CBG oil reduced cartilage degeneration, chondrocyte loss, and matrix metalloproteinase 13 expression, with a significant increase in the number of anabolic chondrocytes. Subchondral bone remodeling found in vehicle-treated DMM mice was not ameliorated by either CBD or CBG oil. Conclusions: Our results show evidence for the therapeutic efficacy of CBD oil and CBG oil, where both oils ameliorate pain and inflammation, and improve gait and locomotor activity in OA mice, representing clinical pain and function. Importantly, only CBG oil is chondroprotective, which may provide superior efficacy in future studies in OA patients.

Osteoarthritis (OA) is a widespread joint condition affecting millions globally, presenting a growing socioeconomic burden thus making the development of more effective therapeutic strategies crucial. This review emphasizes recent advancements in lipid-based drug delivery systems (DDSs) for intra-articular administration of OA therapeutics, encompassing non-steroidal anti-inflammatory drugs, corticosteroids, small molecule disease-modifying OA drugs, and RNA therapeutics. Liposomes, lipid nanoparticles, lipidic mesophases, extracellular vesicles and composite systems exhibit enhanced stability, targeted delivery, and extended joint retention, which contribute to improved therapeutic outcomes and minimized systemic drug exposure. Although active targeting strategies hold promise, further research is needed to assess their targeting efficiency in physiologically relevant conditions. Simultaneously, multifunctional DDSs capable of delivering combinations of distinct therapeutic classes offer synergistic effects and superior OA treatment outcomes. The development of such long-acting systems that resist rapid clearance from the joint space is crucial, where particle size and targeting capabilities emerge as vital factors. Additionally, combining cartilage lubrication properties with sustained drug delivery has demonstrated potential in animal models, meriting further investigation in human clinical trials. This review highlights the crucial need for direct, head-to-head comparisons of novel DDSs with standard treatments, particularly within the same drug class. These comparisons are essential in accurately evaluating their effectiveness, safety, and clinical applicability, and are set to significantly shape the future of OA therapy.

Osteoarthritis (OA) is the most common irreversible chronic joint dysfunction disease, which is pathologically characterized by disturbance of articular cartilage homeostasis leading to subsequent inflammatory response and cartilage extracellular matrix (ECM) degradation. Increasing evidence has demonstrated the dysregulation of transcription factors play crucial roles in the occurrence and development of osteoarthritis (OA), but the potential functions and mechanism of most transcription factors in OA has not been completely illuminated. In this study, we identified that transcription factor V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) was significantly down-regulated in OA cartilage and IL-1β-induced OA chondrocytes. Functional experiments in vitro demonstrated that the overexpressed ETS2 strikingly enhanced proliferation, outstandingly suppressed apoptosis, and dramatically reduced inflammation and ECM degradation in IL-1β-induced OA chondrocytes, whereas the knockdown of ETS2 led to the opposite effects. Further in vivo studies have shown that up-regulated ETS2 dramatically ameliorates cartilage injury in DMM-induced OA mice. Mechanical studies have disclosed that DNMT1-mediated downregulation of ETS2 dramatically promotes STAT1 by inhibiting miR-155 transcription, and increased STAT1 initiates a feedback loop that may enhance DNMT1-mediated hypermethylation of ETS2 to inhibit ETS2 expression, thus forming a DNMT1/ETS2/miR-155/STAT1 feedback loop that inhibits MAPK signaling pathways and aggravates OA cartilage injury. In all, our results revealed that overexpression of ETS2 markedly ameliorated OA cartilage injury through the ETS2/miR-155/STAT1/DNMT1 feedback loop, providing a new perspective on the pathogenesis and therapeutic strategies for OA.