The inflammatory endotype is arguably one of the most well-established endotype in osteoarthritis (OA). While endotyping holds promise for advancing drug development, numerous potential challenges must be considered, addressed and resolved before successful clinical outcomes can be achieved.

Since 2017, the Osteoarthritis Research Society International (OARSI) has hosted the Clinical Trials Symposium (CTS). Each year, OARSI and the CTS steering committee encourage discussions on selected topics among a broad range of stakeholders, including regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists, with the aim of advancing drug development in the OA field.

This report highlights the ongoing tension between academia's "blue ocean" strategy and the feasibility-driven approach of drug developers, all within the context of scientific efforts to find effective solutions. Understanding the needs, goals, constraints, and opportunities of all involved stakeholders is crucial for defining optimal drug development strategies for OA.

A multidisciplinary, collaborative approach is essential for developing effective OA treatments, balancing scientific discovery with regulatory and clinical feasibility.

This study investigated the effects of a high-impact exercise regimen compared with a reference group on systemic cytokine levels in patients with mild knee osteoarthritis (OA). Furthermore, associations between cytokines and magnetic resonance imaging (MRI) transverse relaxation time (T2) mapping and metabolic equivalent task hours (MET-hours) during leisure-time physical activity (LTPA) were assessed.

In this secondary analysis, 73 postmenopausal women aged 50-65 years with mild knee OA were randomized to a 12-month high-impact aerobic/step aerobics training group (n ​= ​35) or a non-training reference group (n ​= ​38). The serum cytokine levels, including interleukin-1 alpha (IL-1α), IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α), were determined via multiplex cytokine assays. The cartilage structure of the medial tibial condyle was assessed by MRI T2 mapping. The primary outcome was between-group differences in cytokine level changes.

After a 12-month follow-up, no significant differences in cytokine level changes were found between the groups. In the intervention group, 12-month changes in TNF-α levels were associated with changes in medial tibial condyle T2. In the reference group, 12-month changes in IL-10 levels were associated with changes in medial tibial condyle T2 and the number of weekly LTPA MET-hours.

A progressive high-impact exercise regimen did not affect systemic cytokine levels compared to the reference group and could therefore offer a possible mode of exercise for postmenopausal women with mild knee OA.

ISRCTN58314639.

Hand osteoarthritis (OA) is a prevalent and disabling condition, yet its pathogenesis remains less studied than OA in large weight-bearing joints. Emerging genetic, epigenetic, and microbiome research suggests that hand OA might be biologically distinct, involving joint-specific pathways not shared by knee or hip OA. This review integrates genome-wide association studies specific to hand OA, highlighting key molecular contributors such as inflammatory cytokines. These genetic insights, together with emerging data on epigenetic alterations and gut microbial dysbiosis, point to broader systemic and regulatory influences on hand OA onset and progression. We also assess pharmacologic interventions tested in randomized controlled trials that have attempted to target these pathways. While agents such as TNF and IL-6 inhibitors, hydroxychloroquine, and corticosteroids have shown limited success, emerging evidence supports the potential of methotrexate in synovitis-positive general hand OA, platelet-rich plasma in thumb carpometacarpal (CMC) OA, and prolotherapy in interphalangeal (IP) OA. These findings illustrate the persistent gap between mechanistic understanding and therapeutic success. Future work must prioritize multifactorial strategies for addressing pain and translational frameworks that link molecular mechanisms to treatment response. In summary, this review offers an update on hand OA and identifies key opportunities for more targeted and effective therapy.

The complex nature of osteoarthritis (OA), driven by the intricate interplay of genetic, environmental, and lifestyle factors, necessitates the development of a single treatment method, which is highly challenging. The long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids often leads to adverse side effects like kidney damage and stomach ulcers. Major health threats like obesity and aging create a milieu of chronic low-grade inflammation and increased mechanical stress on the joints resulting in cartilage deterioration. Additionally, postmenopausal women with lower circulating 17β-estradiol levels experience accelerated joint deterioration due to increased immune activity resulting in the increased production of pro-inflammatory cytokines, with elevated MMP expression and decreased type II collagen synthesis. Polyphenols are nature's gifted magic molecules, which possess diverse biological properties like anti-oxidant, anti-bacterial, anti-inflammatory, estrogenic, and insulin-sensitizing effects, which can manage and treat all the multi-factorial contributing factors of OA effectively. Certain polyphenols can act as phytoestrogens and mimic the effects of natural estrogen by binding to ERα and ERβ and can act as SERMs and prevent degradation of the articular cartilage thereby alleviating osteoarthritic conditions. These molecules downregulate the expression of various pro-inflammatory cytokines, apoptotic genes, and matrix-degrading proteases (MMPs) while upregulating major ECM proteins like type II collagen, aggrecan, and proteoglycans in various osteoarthritic animal models. This review provides a comprehensive overview of the molecular mechanisms involved in OA development and also explores the therapeutic potential of different polyphenols in mitigating joint inflammation and their protective effect in inhibiting the degradation of cartilage extracellular matrix (ECM) and enhancing joint homeostasis.

To investigate the serum and synovial fluid levels of CSF-1 in patients with knee osteoarthritis (KOA) and evaluate its clinical significance.

We selected 143 patients with KOA who received treatment at our hospital from June 2021 to August 2024. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of CSF-1, IL-6, IL-1β, CRP, and HIF-1α in the serum of all study subjects, as well as the levels of these markers in the synovial fluid of all KOA patients. The Kellgren and Lawrence (KL) grading system was used to assess the radiographic severity of all KOA patients. Additionally, we also collected the Visual Analog Scale (VAS) scores and the Western Ontario McMaster University Osteoarthritis Index (WOMAC). Western blot (WB) was used to detect the expression levels of inflammatory factors in macrophages after CSF-1 stimulation.

Compared to healthy volunteers, KOA patients exhibited significantly elevated levels of serum CSF-1, IL-6, IL-1β, CRP, and HIF-1α (p < 0.05). The advanced group of KOA patients had significantly higher levels of serum and synovial fluid CSF-1 compared to the early group. Synovial fluid CSF-1 levels were associated with inflammation and disease severity in KOA patients. CSF-1 stimulation significantly increased the expression of CSF-1R, IL-6, TNF-α, IL-1β, HIF-1α, and MMP-3 in macrophages. Moreover, synovial fluid and serum CSF-1, synovial fluid HIF-1α, and synovial fluid IL-6 were identified as risk factors for advanced KOA.

Our findings indicated that the serum and synovial fluid levels of CSF-1 were significantly increased in KOA patients, even higher in patients with KL grade 3-4. Moreover, CSF-1 was identified as a risk factor associated with advanced stage KOA.

To investigate the relationship between unsaturated fatty acids (UFAs) intake and the risk of all-cause mortality in osteoarthritis (OA) patients.

This cohort study included the data of 3,271 participants with OA using data from the National Health and Nutrition Examination Survey (NHANES). Univariate and multivariable weighted Cox regression models were applied to analyze the relationship between UFAs intake and the risk of mortality in patients with OA. Subgroup analysis was used in age, gender, cardiovascular disease (CVD), hypertension, and diabetes. Hazard ratio (HR), and 95% confidence interval (CI) were calculated.

The median follow-up time was 38.00 (69.00, 104.00) months, with 2,670 participants survived and 601 died. Monounsaturated fatty acids (MUFAs) ≥31.30 was associated with reduced risk of all-cause mortality in OA patients (HR = 0.48, 95% CI: 0.32-0.73). Lowered risk of all-cause mortality in OA patients was observed in patients with octadecenoic acid ≥29.14 (HR = 0.50, 95% CI: 0.34-0.72). Eicosenoic acid of 0.15-0.30 (HR = 0.70, 95% CI: 0.55-0.90) or eicosenoic acid ≥0.30 (HR = 0.62, 95% CI: 0.46-0.84) was related to decreased risk of all-cause mortality in OA patients. Polyunsaturated fatty acids (PUFAs) ≥20.33 was associated with reduced risk of all-cause mortality in OA patients (HR = 0.72, 95% CI: 0.54-0.96). Omega-3 fatty acid ≥1.98 was correlated with decreased risk of all-cause mortality in OA patients (HR = 0.60, 95% CI: 0.45-0.81). Decreased risk of all-cause mortality was found in people with alpha-linolenic acid (ALA) of 1.00-1.83 (HR = 0.75, 95% CI: 0.59-0.96) or ALA ≥1.83 (HR = 0.65, 95% CI: 0.46-0.92) in OA patients. Omega-6 fatty acid ≥18.04 (HR = 0.68, 95% CI: 0.51-0.92) or linoleic acid ≥17.89 (HR = 0.67, 95% CI: 0.50-0.90) were related to decreased risk of all-cause mortality in people with OA.

Total MUFAs and PUFAs, octadecenoic acid, eicosenoic acid, omega-3 fatty acid, ALA, omega-6 fatty acid and linoleic acid were correlated with decreased risk of all-cause mortality in OA patients, which might suggest the importance of specific UFAs supplement in OA patients.

Previous studies have shown that hyaluronic acid can delay the progression of knee osteoarthritis. Existing research has extracted a bright red fluid called cell-free fat extract from human adipose tissue, which may play an important role in delaying the progression of osteoarthritis. By comparing with intra-articular injection of hyaluronic acid, this study aimed to evaluate the effects of intra-articular injection of CEFFE on both clinical efficacy and the reduction of bone marrow edema in patients with early to mid-stage knee osteoarthritis.

A total of 48 patients with KOA (Kellgren-Lawrence grade II-III) symptoms were randomly divided into CEFFE group (24 cases) and HA group (24 cases). The patients in the CEFFE group received five injections of CEFFE (2 ml, 1 time/week), and the patients in the HA group received five injections of HA (2 ml, 1 ml/10 mg, 1 time/week). All the patients underwent clinical assessments using rating scales, including VAS, WOMAC and Lysholm Knee Score. These assessments were conducted at pre-treatment and at 3-week, 6-week, 3-month, and 6-month follow-up timepoints post-treatment. The clinical efficacy was evaluated at the 6-month follow-up after the treatment. The changes in subchondral bone marrow edema before and 6 months after treatment were assessed by grading BME on MRI of the affected knees.

A total of 52 knees from 46 patients were included in the final analysis. Comparison of VAS score, WOMAC score, and Lysholm score between the two groups revealed that the differences between pre-treatment and 3 weeks post-treatment were not statistically significant (P > 0.05). For the VAS score and WOMAC score at 6 weeks, 3 months, and 6 months post-treatment, the CEFFE group was lower than the HA group (P < 0.05). For the Lysholm score, the CEFFE group was higher than the HA group (P < 0.05). Compared with pre-treatment, VAS scores and WOMAC scores were lower and Lysholm scores were higher at all post-treatment time points (P < 0.05). At 6 months post-treatment, the clinical efficacy of the CEFFE group was significantly better than that of the HA group (P < 0.05). At 6 months post-treatment, MRI grading showed that subchondral BME was reduced to different degrees in both groups, with the reduction being more pronounced in the CEFFE group (P < 0.05).

This study demonstrated that intra-articular injection of CEFFE into the knee joint could enhance the durability of tissue-specific cells (especially chondrocytes) and improve cellular metabolic processes, preventing the continued progression of osteoarthritis. Both CEFFE and HA were found to improve clinical symptoms and reduced subchondral bone marrow edema in the treatment of early to mid-stage knee osteoarthritis. However, CEFFE was more effective than HA in achieving these outcomes.

Turmeric extract is a well-known nutraceutical ingredient recognized for its benefits in managing musculoskeletal health. This study evaluated the efficacy and safety of a novel low-dose water-dispersible turmeric extract containing 60% natural curcuminoids (WDTE60N) in participants with mild-to-moderate knee osteoarthritis.

This double-blind, randomized, placebo-controlled trial was conducted at two orthopedic centers in Uttar Pradesh, India (July 2023-November 2023). Participants aged 45-75 years with unilateral or bilateral OA of the knee for >3 months were randomized in 1:1 ratio to receive WDTE60N (250 mg) or placebo capsules once daily for three months. Study endpoints included assessment of changes from baseline to day 90 in pain intensity (visual analog scale [VAS], knee injury and osteoarthritis outcome score [KOOS]), inflammatory biomarkers, and safety profile. Data were analyzed using independent t-test, chi-square test, and analysis of co-variance test.

In total, 139 participants (WDTE60N, n = 70; placebo, n = 69) with mean age and BMI of 56.35 years and 23.89 kg/m2, respectively, were included. The mean reduction (95% CI) in VAS score from baseline to day 90 was significantly higher in the WDTE60N group than in the placebo group (14.41 [13.08, 15.75] vs 6.02 [5.00, 7.05]; p < 0.0001). In the WDTE60N group, the mean change in VAS scores was significantly reduced from as early as day 07 (p = 0.0076), which continued until day 90 (p < 0.0001), compared to the placebo group. Improvement in the mean KOOS scores (baseline-Day 90) was evident, with significantly higher mean scores for each domain (pain, symptoms, activities of daily living, function in sport and recreation, and knee-related quality of life [QoL]) on Day 90 in the WDTE60N group than in the placebo group (p < 0.05). Inflammatory biomarkers (hsCRP, TNF-α, IL-6, and IL-1β) were significantly reduced from baseline to day 90 in the WDTE60N group compared to the placebo group (p < 0.0001). Four mild adverse events were reported during the study period.

Supplementation with the low-dose water-dispersible turmeric extract containing 60% natural curcuminoids for three months was safe and effective in alleviating pain, improving functional status and quality of life and reducing inflammation in participants with mild-to-moderate knee osteoarthritis.

CTRI/2023/07/055411.

Osteoarthritis of the knee joint (OAK) represents a leading cause of pain, functional limitation, and diminished quality of life, particularly among older adults. The association between metabolic syndrome (MetS) and OAK is of growing interest due to the potential impact of MetS components on joint health. While evidence suggests that MetS and its components may influence the development of osteoarthritis (OA), the specific relationship between MetS and the likelihood of progressing to a stage of OAK that requires Total knee replacement (TKA) remains underexplored.

This study aimed to evaluate the association between osteoarthritis of the knee joint (OAK) and metabolic syndrome (MetS) and to know whether the presence of MetS (or its components) increases the risk of OAK requiring Total knee replacement (TKA).

It is a cross-sectional study that includes patients (males and females) above 50. Data collection was done including demographic details, medical history, physical examinations, and laboratory tests. OAK (≥grade 2 Kellgren-Lawrence) and severe OAK (≥grade 3 Kellgren-Lawrence) were evaluated based on radiological findings.

Mean, standard deviation, frequencies, and percentages were calculated for baseline characteristics. To analyze the association between qualitative factors and MetS, the Chi-Square test was used. For comparing quantitative factors, the unpaired t-test was employed. A P value of less than 0.05 was considered statistically significant.

The study involved 107 primary osteoarthritis patients categorized into cases (N = 57), requiring TKA, and controls (N = 50), not requiring TKA. MetS was significantly more prevalent among cases than controls, with 68.4% of cases and 36% of controls testing positive for MetS (P = 0.001). The odds of having MetS were 3.9 times higher in the cases compared to the controls.

The results of our research could shed light on how MetS affects the onset and course of OAK, guiding primary care and prevention measures. It might also emphasize how critical it is to treat MetS symptoms to lessen the severity of OAK. Understanding whether MetS or its components are linked to an increased risk of TKA could provide crucial insights into preventive and therapeutic strategies for managing severe OAK.

Osteoarthritis (OA) is a progressive degenerative disease affected by many factors, and there is currently no effective treatment. In recent years, the latest progress in metabolomics in OA research has revealed several metabolic pathways and new specific metabolites involved in OA. Metabolites play significant roles in the identification and management of OA. This review looks back on the development history of metabolomics and the progress of this technology in OA as well as its potential clinical applications. It summarizes the applications of metabolites in the field of OA and future research directions. This understanding will advance the identification of metabolic treatment goals for OA.

The development of metabolomics offers possibilities for the treatment of OA. This article reviews the relationship between metabolites associated with chondrocytes and OA. Selectively altering these three metabolic pathways and their associated metabolites may hold great potential as new focal points for OA treatment.

Knee osteoarthritis (OA) is a prevalent degenerative joint disease globally, causing pain, stiffness, and disability. Intravascular laser irradiation of blood (ILIB) has been used for chronic pain and musculoskeletal disease. However, evidence on the clinical benefits and serum biomarkers post-ILIB therapy in knee OA is insufficient. We designed a double-blind randomized controlled trial to evaluate the clinical and biological outcomes of ILIB therapy for knee OA. Seventeen patients with knee OA were randomly assigned to the ILIB and control groups. The outcomes included the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Scale, visual analog scale, and biomarker analysis of interleukin (IL)-6, IL-13, IL-1β, epidermal growth factor, macrophage inflammatory protein-1β, and eotaxin. The measurements were performed at baseline and three days, one month, and three months post-intervention. The ILIB group showed a significant improvement in the WOMAC-pain score at one month of follow-up than the control group. IL-1β levels reduced significantly on day three, one month, and three months, and IL-13 levels reduced on day three and three months during follow-up in the ILIB group. ILIB therapy reduced knee OA pain for one month and significantly reduced serum IL-1β and IL-13 levels, suggesting potential for pain management.

Osteoarthritis (OA) is characterised by the failure of normal biological processes to repair following damage. Traditionally, OA was considered a "wear and tear" disorder; however, it is now a recognised inflammatory condition, preceded by molecular modifications. The aim of this study was to evaluate inflammatory markers among individuals with early knee OA (eKOA) and well-matched asymptomatic controls.

Twenty six eKOA (females, n = 13; age = 60.2 ± 5.4 yrs, height = 1.73 ± 0.11 m, body mass = 77.8 ± 12.8 kg, body fat = 33.9 ± 8.5%) and twenty-three asymptomatic individuals (females, n = 14; age = 59.9 ± 5.5yrs, height = 1.71 ± 0.09 m, body mass = 72.6 ± 11.3 kg, body fat = 30.4 ± 8.2%) were recruited. The Timed Up and Go, and the 6 Minute Walk Tests evaluated physical function in addition to pain specific questionnaires (KOOS and ICOAP). Serum levels of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8(CXCL8), IL-10, hsCRP and TNF-α were quantified using a multiplex assay via V-plex®Sector Imager 2400.

As hypothesised, only KOOS and EQ-5D-5L metrics differed between the groups for non-blood derived measures (p < 0.04). Only IL-6 was higher in eKOA (P = 0.02; 95% CI = 0.202; by 0.197 pg/mL; 34.5%). Among eKOA, IL-6 did not relate to severity of KOOS pain (P = 0.696, r = -0.088), but had a positive relationship with ICOAP consistent (r = 0.469, P = 0.045) rather than intermittent pain. There was a moderate correlation between 6MWD and IL-8 (r = 0.471, P = 0.012).

Our results illustrate the potential for IL-6 as a biomarker for eKOA, and introduce the proposition for particular consideration in those with consistent pain. Further, for the first time the present data showed greater walking distance in eKOA with lower circulating IL-8. Future work should seek to verify these results and further investigate IL-6 and IL-8 related molecular pathways in eKOA, and their potential relationships with consistent knee pain and physical function.

Osteoarthritis (OA), a common degenerative joint disease, is characterized by the apoptosis of chondrocytes as a primary pathophysiological change, with endoplasmic reticulum stress (ERS) playing a crucial role. It has been demonstrated that an imbalance in endoplasmic reticulum (ER) homeostasis can lead to ERS, activating three cellular adaptive response pathways through the unfolded protein response to restore ER homeostasis. Mild ERS exerts a protective effect on cells, while prolonged ERS that disrupts the self-regulatory balance of the ER activates apoptotic signaling pathways, leading to chondrocyte apoptosis and hastening OA progression. Hence, controlling the ERS signaling pathway and its apoptotic factors has become a critical focus for preventing and treating OA. This review aims to elucidate the key mechanisms of ERS pathway-induced apoptosis, associated targets, and regulatory pathways, offering valuable insights to enhance the mechanistic understanding of OA. It also reviews the mechanisms studied for ERS-related drugs or compounds for the treatment of OA.

To identify key molecular components within the femoroacetabular impingement hip and compare the findings between male and female patients across varying age groups.

All patients undergoing hip arthroscopy for femoroacetabular impingement syndrome (FAIS) without hip dysplasia were included. During hip arthroscopy, performed at University of Wisconsin Health, loose articular cartilage, excess synovium, damaged labral tissue, and minimal adipose tissue were debrided only as needed for visualization and tissue repair purposes and collected. Tissue was processed and used for quantitative polymerase chain reaction (qPCR). Genes were selected for qPCR on the basis of their associated function in inflammation and/or extracellular matrix remodeling during the progression of osteoarthritis.

A total of 91 male (M) and female (F) patients 15 to 58 years old were included in the study. qPCR results indicated that Interleukin-6 (P < .05, 95% confidence interval [CI] 0.047-0.083 F, 0.070-0.12 M) and Interleukin-8 (P = .04, 95% CI 0.059-0.10 F, 0.082-0.18 M) were significantly greater in male patients compared with female patients regardless of age, and IL6 (P = .02, 95% CI [0.026-0.070] F, [0.067-0.17] M), Interleukin-1ß (P < .01 95% CI [0.013-0.063] F, [0.073-0.25] M), and Matrix metalloproteinase-13 (P = .047, 95% CI [0.0051-0.017] F, [0.0084-0.052] M) were significantly greater in male patients younger than 20 years old compared with female patients younger than 20 years old.

In patients with FAIS, there are significant differences between male and female patients in the biomarkers present in the affected hip at the time of surgery. Male patients have greater levels of IL6 and IL8 and male patients younger than 20 years of age have greater levels of IL1β, IL6, and MMP13 compared with age-matched female patients.

A better understanding of the molecular markers present during varying stages of FAIS and in patients of different ages will help characterize the pathologic process behind FAIS. This may also help define future methods of targeted treatment and prevention of disease progression.

Although various joint injuries result in post-traumatic osteoarthritis (PTOA), differences in chondrocyte response to specific injuries, such as blunt compression or fracture, are unclear. Furthermore, the role of underlying joint inflammation, or synovitis, is often not considered. We investigated how injury mechanisms and underlying synovitis affect chondrocyte gene expression using osteochondral injury models with synovial co-culture. We hypothesized that the state of synovitis as well as the mechanism of biomechanical cartilage injury differentially alter the gene expression of chondrocytes and that these responses are regulated by the pro-inflammatory cytokine interleukin 1 (IL-1). The mechanism of injury and level of synovial inflammation both significantly regulated chondrocyte gene expression and associated pathways, uncovering distinct characteristics of fracture and compression injury mechanisms. Targeting IL-1 following injury reduced the inflammatory response and could have clinical implications. The results from this study show that crosstalk between biomechanics and inflammation in the context of synovitis and cartilage injury mechanism is an important consideration for PTOA.

Osteoarthritis (OA) is a chronic inflammatory joint disorder characterized by cartilage degradation and bone remodeling. This study investigated the regulatory role of metallothionein 1 (MT1) in modulating immune responses and the balance between regulatory T cells (Treg) and T helper 17 cells (Th17) in OA. Peripheral blood mononuclear cells (PBMCs) from healthy individuals and OA patients were assessed for cytokine expression linked to Treg/Th17 homeostasis. OA was induced in wild-type (WT) and Mt1 knockout (MT1KO) mice via surgical destabilization of the medial meniscus. Clinical scores, pathological features, inflammatory cytokines, and Treg/Th17 balance were evaluated. MT1KO mice showed significantly elevated Mt1, pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and exacerbated OA progression, characterized by increased knee joint diameter, inflammatory infiltration, and cartilage destruction. Mechanistically, disrupted Treg/Th17 balance played a pivotal role in OA exacerbation, with MT1KO promoting Th17 differentiation and reducing Treg populations. Additionally, the compensatory elevation of anti-inflammatory interleukin-10 (IL-10) in OA patients hinted at a nuanced immune regulatory mechanism. The study illuminates intricate interactions involving MT1, Treg/Th17 cells, and pro-inflammatory cytokines in OA pathogenesis, suggesting MT1's potential as a pivotal regulatory factor and a therapeutic target for mitigating immune dysregulation in OA.

Osteoarthritis (OA) is a common chronic joint disease characterized by articular cartilage degeneration, subchondral sclerosis, synovitis, and osteophyte formation. OA is associated with disability and impaired quality of life, particularly among the elderly. Leptin, a 16-kD non-glycosylated protein encoded by the obese gene, is produced on a systemic and local basis in adipose tissue and the infrapatellar fat pad located in the knee. The metabolic mechanisms employed by leptin in OA development have been widely studied, with attention being paid to aging as a corroborative risk factor for OA. Hence, in this review, we have attempted to establish a potential link between leptin and OA, by focusing on aging-associated mechanisms and proposing leptin as a potential diagnostic and therapeutic target in aging-related mechanisms of OA that may provide fruitful guidance and emphasis for future research.

Numerous studies have shown that vitamin D may play an important role in modulating the inflammatory process. This study aimed to evaluate the effect of vitamin D supplementation on inflammatory markers in patients with orthopedic disorders and obesity. Thirty-three obese subjects were included in the study and were divided into two groups based on their medical condition: acute orthopedic diseases and chronic orthopedic diseases. Inclusion criteria for the research included age 18-75 years, BMI > 30 kg/m2, vitamin D deficiency, and no previous vitamin D supplementation. Samples were collected before and after 3 months of 4000 IU/day vitamin D supplementation. The study used enzyme-linked immunosorbent assay (ELISA) and measured serum levels of markers such as chitinase-3-like protein 1 (YKL-40), interleukin 6 (IL-6), interleukin 17 (IL-17), tumor necrosis factor (TNF-α), and adiponectin. After 3 months of vitamin D supplementation, a statistically significant increase in vitamin D and IL-17 levels was observed in the group with acute orthopedic diseases. Similarly, after supplementation, a statistically significant increase in vitamin D, IL-6 and TNF-α levels was observed in the group with chronic orthopedic diseases. Moreover, after vitamin D supplementation, statistically significantly higher adiponectin levels were observed in the chronic orthopedic group than in the acute orthopedic group. Despite high-dose vitamin D supplementation, inflammatory markers increased in acute and chronic orthopedic conditions. Based on our study, vitamin D does not reduce inflammation in patients with orthopedic conditions and obesity.

Osteoarthritis (OA) is regarded as one of the most prevealent irreversible joint degenerative disorder worldwide. Recently, considerable interest in utilizing intra-articular (IA) injections for managing OA has been raised.

In this study, IA injectable surface modified iron oxide microparticles (SMIOMPs) loaded with Diacerein (DCN) were developed. The effects of formulation parameters on particle size, entrapment efficiency, and zeta potential were explored using factorial design. The optimized formulation was characterized regarding morphology and in vitro release. Differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR) were done to assess interactions. Further, sterilization and in vivo performance in rats with induced arthritis has been performed for the optimized formulation.

The selected optimized system included 2M FeCL3 and 1% chitosan as a surface modifier achieved high drug entrapment of 85.25% with a PS of 1.54 µm and sustained DCN release. Morphological examination of the optimized formulation revealed spherical particles with chitosan coat. DSC and FTIR results indicated the absence of undesired interactions between DCN and the used components. No significant change in the measured parameters was observed following sterilization using gamma radiation. In vivo assessment revealed superior performance for the optimized formulation in reducing cartilage inflammation and degradation. Plasma levels of tumor necrosis factor α and Interleukin-1 beta, as well as knee diameter, were significantly reduced in the treated groups compared to the untreated ones.

Overall, the results suggest that the proposed DCN-loaded SMIOMPs represent a promising advancement in the arena of cartilage regeneration.

Knee osteoarthritis (KOA) is a common chronic joint disease globally. Synovial inflammation plays a pivotal role in its pathogenesis, preceding cartilage damage. Identifying biomarkers in osteoarthritic synovial tissues holds promise for early diagnosis and targeted interventions. Gene expression profiles were obtained from the Gene Expression Omnibus database. Subsequent analyses included differential expression gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) on the combined datasets. We performed functional enrichment analysis on the overlapping genes between DEGs and module genes and constructed a protein-protein interaction network. Using Cytoscape software, we identified hub genes related to the disease and conducted gene set enrichment analysis on these hub genes. The CIBERSORT algorithm was employed to evaluate the correlation between hub genes and the abundance of immune cells within tissues. Finally, Mendelian randomization analysis was utilized to assess the potential of these hub genes as biomarkers. We identified 46 differentially expressed genes (DEGs), comprising 20 upregulated and 26 downregulated genes. Using WGCNA, we constructed a gene co-expression network and selected the most relevant modules, resulting in 24 intersecting genes with the DEGs. KEGG enrichment analysis of the intersecting genes identified the IL-17 signaling pathway, associated with inflammation, as the most significant pathway. Cytoscape software was utilized to rank the candidate genes, with JUN, ATF3, FOSB, NR4A2, and IL6 emerging as the top five based on the Degree algorithm. A nomogram model incorporating these five genes, supported by ROC curve analysis, validated their diagnostic efficacy. Immune infiltration and correlation analysis revealed that macrophages were significantly associated with JUN (p < 0.01), FOSB (p < 0.01), and NR4A2 (p < 0.05). Additionally, T follicular helper cells showed significant associations with ATF3 (p < 0.05), FOSB (p < 0.05), and JUN (p < 0.05). Mendelian randomization analysis provided strong evidence linking JUN (IVW: OR = 0.910, p = 0.005) and IL6 (IVW: OR = 1.024, p = 0.026) with KOA. Through the utilization of various bioinformatics analysis methods, we have pinpointed key hub genes relevant to knee osteoarthritis. These findings hold promise for advancing pre-symptomatic diagnostic strategies and enhancing our understanding of the biological underpinnings behind knee osteoarthritis susceptibility genes.

Background: Arthritis, a debilitating joint disease, remains a significant global health burden. This study uncovers the therapeutic potential of the medicinal plant Smilax glabra Roxb. (SGR) in attenuating progression of disease by modulating immune responses. Methods: Through computational approaches, key bioactive compounds in SGR were identified by using freely available databases: TCMSP, TCMID, HIT2.0, HERB, and INPUT in order to elucidate their underlying mechanisms of action. Therapeutic targets for the disease have been retrieved by TTD, GeneCard, and OMIM databases. The STRING database was used to analyze the protein-protein interactions (PPI) of intersecting genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to reveal the functional roles of genes. Mcule was used for molecular docking and binding affinity of compounds and targets were evaluated by DeepPurpose model. ALP activity, cell viability assay, TRAP staining were also performed. Results: A total of 14 active SGR compounds with 59 common targets for arthritis have been identified. These targets have a major role in controlling biological processes such as wound healing, oxygen responses, and chemical stimuli. Molecular docking by Mcule platform demonstrated that quercetin and β-sitosterol showed higher binding energy affinities with TNF, TP53, PTGS2, and JUN as compared to other targets. To explore the complex relationship between compounds and targets, pre-trained Davis and KIBA models were used to predict the affinity values of selected compounds. In MC3T3-E1 cells, ALP activity was significantly increased and bone marrow macrophages (BMM) showed a low number of TRAP-positive cells in SGR-treated cells. Conclusions: Our findings demonstrate that SGR effectively inhibits/regulates inflammatory responses, prevents cartilage degradation, promotes bone regeneration, and can be used as a promising candidate for the development of novel arthritis treatment.

The study aimed to assess Sirt6 levels in serum of knee osteoarthritis (OA) patients compared to healthy individuals to evaluate its correlation with OA and to understand how Sirt6 is linked with the change in IL-6 levels.

The cross-sectional study involved 50 knee OA patients clinically diagnosed as per the American College of Rheumatology guidelines and 50 healthy controls. Radiological examination as per Kellgren-Lawrence (KL) criteria was done to determine the disease severity. Peripheral blood samples were collected from each participant, and serum Sirt6 and IL-6 levels were measured using ELISA.

The serum Sirt6 levels in knee OA patients were significantly lower as compared to healthy controls (p = 0.023). Patients with knee OA of KL grade 4 had significantly lower Sirt6 levels as compared to those with KL grade 2 OA (p = 0.031). Individuals of younger age group had higher Sirt6 levels compared to older age group. IL-6 levels in knee OA patients were significantly higher as compared to controls (p = 0.007). A negative correlation was observed between serum Sirt6 and IL-6 levels (r = - 0.407; p = 0.035).

The study concludes that serum Sirt6 levels are inversely associated with knee OA and may serve as a potential biomarker for the disease. Moreover, a negative correlation between Sirt6 and IL-6 levels was observed in this study. Further investigations are necessary to confirm these findings and to explore the mechanisms by which Sirt6 and IL-6 are involved in OA.

Background and Objectives: Total knee arthroplasty (TKA) improves balance performance in patients with osteoarthritis; however, balance deficit and fall incidence after TKA have been reported. This study aimed to determine the effects of combined balance exercises on knee range of motion (ROM), balance, gait, and functional outcomes during the acute phase after TKA. Materials and Methods: A total of 42 participants were randomly assigned to either the combined balance group (n = 21) or the general physical therapy (control) group (n = 21). The combined balance exercise group performed exercise programs for 30 min per session, five times a week for 4 weeks (20 sessions), and the control group completed general physical therapy, which included active simple exercise. Measurements were performed before and after the 4 weeks of training to assess changes in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), knee joint ROM, static balance, timed up-and-go (TUG), and 10 m walk test (10 MWT). Results: The combined balance exercise group demonstrated significant improvements post intervention (p < 0.05) for all outcomes. The time × group interaction effect for the WOMAC scores showed statistically significant interaction effects for pain, stiffness, and physical function; the static and dynamic balance values showed statistically significant interaction effects for CEA, PL, AV, and TUG; and gait ability showed a significant interaction effect for the 10 m walk test (p < 0.05). Conclusions: This study confirmed that combined balance training with general physical therapy has a positive effect on ROM, static and dynamic balance, gait, and functional outcomes in the acute phase post TKA and that combined balance exercise can be proposed as a rapid rehabilitation intervention with general physical therapy following TKA.

Posttraumatic osteoarthritis (PTOA) is closely related to the inflammatory response caused by mechanical injury and leads to joint degeneration. Herein, we aimed to evaluate the role and underlying mechanism of NUMB in PTOA progression. Anterior cruciate ligament transection (ACLT)-induced rats and interleukin (IL)-1β-treated chondrocytes were used as in vivo and in vitro models of PTOA, respectively. The NUMB overexpression plasmid (pcDNA-NUMB) was administered by intra-articular injection to PTOA model rats, and safranin O-fast green staining, the Osteoarthritis Research Society International (OARSI) scoring system, and HE staining were used to evaluate the severity of cartilage damage. The secretion of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and chondrocyte-specific markers (MMP13 and COL2A1) was detected via ELISA. Cell viability and apoptosis were evaluated by MTT and TUNEL assays. NUMB was expressed at lower levels in ACLT-induced PTOA rats and in IL-1β-treated chondrocytes than in control rats and cells. NUMB overexpression enhanced cell viability and reduced cell apoptosis, inflammation and cartilage degradation in chondrocytes stimulated by IL-1β. NUMB bound to BTRC to promote p-IκBα expression, resulting in NF-κB pathway inactivation. BTRC overexpression reversed the promoting effect of NUMB overexpression on cell viability and the inhibitory effects of NUMB overexpression on apoptosis, inflammation and cartilage degradation in IL-1β-induced chondrocytes. In addition, overexpression of NUMB alleviated articular cartilage damage by repressing inflammation and cartilage degradation in ACLT-induced PTOA rats. Our data indicated that NUMB regulated PTOA progression through the BTRC/NF-κB pathway, which may be a viable therapeutic target in PTOA.

Osteoarthritis (OA) is one of the most common causes of disability around the globe, especially in aging populations. The main symptoms of OA are pain and loss of motion and function of the affected joint. Hyaline cartilage has limited ability for regeneration due to its avascularity, lack of nerve endings, and very slow metabolism. Total joint replacement (TJR) has to date been used as the treatment of end-stage disease. Various joint-sparing alternatives, including conservative and surgical treatment, have been proposed in the literature; however, no treatment to date has been fully successful in restoring hyaline cartilage. The mechanical and frictional properties of the cartilage are of paramount importance in terms of cartilage resistance to continuous loading. OA causes numerous changes in the macro- and microstructure of cartilage, affecting its mechanical properties. Increased friction and reduced load-bearing capability of the cartilage accelerate further degradation of tissue by exerting increased loads on the healthy surrounding tissues. Cartilage repair techniques aim to restore function and reduce pain in the affected joint. Numerous studies have investigated the biological aspects of OA progression and cartilage repair techniques. However, the mechanical properties of cartilage repair techniques are of vital importance and must be addressed too. This review, therefore, addresses the mechanical and frictional properties of articular cartilage and its changes during OA, and it summarizes the mechanical outcomes of cartilage repair techniques.

Knee osteoarthritis (KOA) presents a prevalent orthopedic condition causing substantial impairment in the quality of life and imposing a significant societal and economic burden. Mesenchymal stromal/stem cells (MSCs), known for their regenerative properties and immunomodulatory effects, have emerged as a promising therapeutic avenue in regenerative medicine. Despite MSCs' therapeutic potential, their precise mechanisms of action in KOA remain underexplored.

Conducted as a randomized, open-label clinical trial, 20 patients will be enrolled, with 10 in the intervention group and 10 in the control group. The primary focus will be to explore the molecular mechanisms associated with MSC therapy. Biomarkers and gene expressions related to cartilage metabolism, inflammation, immune modulation, and pain in the synovial fluid, blood, and tissue samples will be analyzed. Patients will undergo pre- and post-treatment evaluations using patient-reported outcome measures (PROMs) and comprehensive clinical assessments.

This is an exploratory study with the goal to provide comprehensive insights into the therapeutic effects of MSCs on a molecular level, potentially paving the way for optimized and more effective MSC-based therapies in the management of KOA, as well as furthering the development of novel treatment strategies.

ClinicalTrials.gov, NCT06078059. Registered on 5 October 2023.

Hyaluronic acid injection is commonly used clinically to slow down the development of osteoarthritis (OA). A newly developed therapeutic method is to implant chondrocytes/stem cells to regenerate cartilage in the body. The curative effect of stem cell therapy has been proven to come from the paracrine of stem cells. In this study, exosomes secreted by stem cells from human exfoliated deciduous teeth (SHED) and hyaluronic acid were used individually to evaluate the therapeutic effect in slowing down OA. SHED was cultured in a serum-free medium for three days, and the supernatant was collected and then centrifuged with a speed difference to obtain exosomes containing CD9 and CD63 markers, with an average particle size of 154.1 nm. SW1353 cells were stimulated with IL-1β to produce the inflammatory characteristics of OA and then treated with 40 μg/mL exosomes and hyaluronic acid individually. The results showed that the exosomes successfully inhibited the pro-inflammatory factors, including TNF-α, IL-6, iNOS, NO, COX-2 and PGE2, induced by IL-1β and the degrading enzyme of the extrachondral matrix (MMP-13). Collagen II and ACAN, the main components of the extrachondral matrix, were also increased by 1.76-fold and 2.98-fold, respectively, after treatment, which were similar to that of the normal joints. The effect can be attributed to the partial mediation of SHED exosomes to the NF-κB pathway, and the ability of exosomes to inhibit OA is found not inferior to that of hyaluronic acid.

Osteoarthritis (OA) is a degenerative joint disease characterised by the breakdown of cartilage, causing pain, stiffness, and limited movement. Early diagnosis is crucial for effective management but remains challenging due to non-specific early symptoms. This study explores the application of Discriminant Function Analysis (DFA) to classify OA patients and healthy volunteers based on biomarker concentrations of Interleukin-6 (IL-6), Tumour necrosis factor-alpha (TNF-α), and Myeloperoxidase (MPO). DFA was employed to analyse biomarker data from 86 participants (58 patients, 28 volunteers) to evaluate the discriminatory power of these biomarkers in predicting OA. Significant differences were observed in MPO and TNF-α levels between groups, while IL-6 did not show a significant distinction. The iterative classification process improved model assumptions and classification accuracy, achieving a pre-classification accuracy of 71.8%, which adjusted to 57.1% post-classification. The results highlight DFA's potential in OA diagnosis, suggesting its utility in managing complex data and aiding personalised treatment strategies. The study underscores the need for larger sample sizes and additional biomarkers to enhance diagnostic robustness and provides a foundation for integrating DFA into clinical practice for early OA detection.

Carpal tunnel syndrome (CTS), an entrapment neuropathy caused by pressure of the median nerve, is a progressive condition that can lead to a decreased quality of life. Studies suggest an association between CTS and arthritis; however, previous studies examining osteoarthritis (OA) and CTS are limited in number, scope and study design. This study estimated the incidence and risk of CTS among patients with OA, both overall and by specific joints, in a large population-based cohort in the United States.

Patients from the Optum claims database aged ≥ 45 years and diagnosed with OA between January 1, 2018, and December 31, 2022, were eligible for the OA cohort. The non-OA cohort included those without a diagnosis of OA at the index date and no history of OA for 12 months pre-index. Baseline characteristics were balanced using propensity score matching. The risk of CTS in the OA and non-OA cohort were evaluated using incidence rates and adjusted hazard ratios that were estimated using Cox regression.

After applying the inclusion/exclusion criteria, 3,610,240 of the 6,023,384 adults with a diagnosis of OA remained in the OA cohort. After propensity-score matching, each cohort included 1,033,439 individuals. The incidence rates for CTS per 1000 person-years were 7.35 (95% confidence interval [CI] 7.21-7.49) in the OA cohort and 1.44 (95% CI 1.38-1.50) in the non-OA cohort. The risk of developing CTS in patients with OA was ~ 4 times that of patients without (hazard ratio = 3.80; 95% CI 3.54-4.07). This increased risk was found across all OA joint types, with OA of the hand/wrist having the highest risk for CTS. Additionally, multiple OA joints presented a higher risk compared with a single affected joint.

OA increases the risk of CTS, but this is not limited to patients with hand/wrist OA, suggesting a systemic impact of OA on CTS. While the risk appears highest for patients with hand/wrist OA, patients with more distant affected joints like knee or hip also have an increased risk of CTS.

Worldwide, osteoarthritis (OA) is the most common cause of joint pain in older people. Many factors contribute to osteoarthritis' development and progression, including secondary osteoarthritis' underlying causes. It is important to note that osteoarthritis affects all four tissues: cartilage, bone, joint capsule, and articular apparatus. An increasingly prominent area of research in osteoarthritis regulation is microRNAs (miRNAs), a small, single-stranded RNA molecule that controls gene expression in eukaryotes. We aimed to assess and summarize current knowledge about the mechanisms of the action of miRNAs and their clinical significance. Osteoarthritis (OA) is affected by the interaction between miRNAs and inflammatory processes, as well as cartilage metabolism. MiRNAs also influence cartilage cell apoptosis, contributing to the degradation of the cartilage in OA. Studies have shown that miRNAs may have both an inhibitory and promoting effect on osteoporosis progression through their influence on molecular mechanisms. By identifying these regulators, targeted treatments for osteoarthritis may be developed. In addition, microRNA may also serve as a biomarker for osteoarthritis. By using these biomarkers, the disease could be detected faster, and early intervention can be instituted to prevent mobility loss and slow deterioration.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to joint destruction. Numerous pro-inflammatory mediators, including adipokines, play an important role in the pathogenesis of RA.

The aim of the study was to investigate the relationships between selected plasma cytokines and expression of adiponectin and its receptors in the synovium and the infrapatellar fat pad in patients with RA and osteoarthritis (OA).

Blood, synovium and fat pad samples from 18 patients with RA and 18 with OA were collected during joint replacement surgery. Spearman rank correlations between plasma concentrations of selected cytokines (IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 p40, IL-13, IL-17, G-CSF and GM-CSF) and the expression of adiponectin and its receptors were determined. Plasma levels of cytokines were determined using a magnetic bead-based multiplex assay, mRNA expression of adiponectin and its receptors were determined by real-time PCR.

In OA patients, there were significant positive correlations between adiponectin expression in the synovial membrane and plasma levels of IL-1β, IL-4, G-CSF and GM-CSF, as well as a significant positive correlation between adiponectin expression in the fat pad and plasma levels of GM-CSF. In addition, OA patients showed significant negative correlations between AdipoR1 and AdipoR2 expression in the synovial membrane and plasma IL-6 levels, as well as between AdipoR2 expression in the synovial membrane and plasma MCP-1 and TNF-α levels. In patients with RA, there were no significant correlations between adiponectin expression in the synovial membrane and infrapatellar fat pad and plasma levels of the cytokines studied. In addition, RA patients showed a statistically significant negative correlation between AdipoR1 expression in the synovial membrane and plasma levels of TNF-α, IL-7, IL-12 and IL-13, and a significant negative correlation between AdipoR1 expression in the infrapatellar fat pad and plasma levels of IL-1β.

Adiponectin and its receptors showed the correlations with several plasma cytokines, however, a thorough understanding of the role of adiponectin in RA and OA requires further investigation.

Osteoarthritis (OA) is a typical joint degenerative disease that is prevalent worldwide and significantly affects the normal activities of patients. Traditional treatments using diclofenac (DCF) as an anti-inflammatory drug by oral administration and transdermal delivery have many inherent deficiencies. In this study, a lubricating microneedles (MNs) system for the treatment of osteoarthritis with multistage sustained drug delivery and great reduction in skin damage during MNs penetration is developed. The bilayer dissolvable MNs system, namely HA-DCF@PDMPC, is prepared by designating the composite material of hyaluronic acid (HA) and covalently conjugated drug compound (HA-DCF) as the MNs tips and then modifying the surface of MNs tips with a self-adhesive lubricating copolymer (PDMPC). The MNs system is designed to achieve sustained drug release of DCF via ester bond hydrolysis, physical diffusion from MNs tips, and breakthrough of lubrication coating. Additionally, skin damage is reduced due to the presence of the lubrication coating on the superficial surface. Therefore, the lubricating MNs with multistage sustained drug delivery show good compliance as a transdermal patch for OA treatment, which is validated from anti-inflammatory cell tests and therapeutic animal experiments, down-regulating the expression levels of pro-inflammatory factors and alleviating articular cartilage destruction.

Modified Jiawei Juanbi decoction (MJD) is used for the treatment of early-stage knee osteoarthritis (KOA). Here, modified Jiawei Juanbi decoction (MJD) was employed for the treatment of early-stage knee osteoarthritis (KOA) and its mechanisms were assessed via metabonomics and network pharmacology. A total of 24 male Sprague-Dawley rats were randomly allocated into a normal control group, a model group, and an MJD group (n = 8 rats per group). Each rat group was further equally divided into two subgroups for investigation for either 14 or 28 days. A rat model of early-stage KOA was constructed and rats were treated with MJD. Effects were evaluated based on changes in knee circumference, mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). We also analyzed histopathological changes in articular cartilage. High-resolution mass spectrometry was used to analyze the chemical profile of MJD, identifying 228 components. Using an LC-Q-TOF-MS metabonomics approach, 33 differential metabolites were identified. The relevant pathways significantly associated with MJD include arginine and proline metabolism, vitamin B6 metabolism, as well as the biosynthesis of phenylalanine, tyrosine and tryptophan. The system pharmacology paradigm revealed that MJD contains 1027 components and associates with 1637 genes, of which 862 disease genes are related to osteoarthritis. The construction of the MJD composition-target-KOA network revealed a total of 140 intersection genes. A total of 39 hub genes were identified via integration of betweenness centrality values greater than 100 using CytoHubba. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed several significantly affected signaling pathways including the HIF-1, AGE-RAGE (in diabetic complications), IL-17, rheumatoid arthritis and TNF pathways. Integrated-omics and network pharmacology approaches revealed a necessity for further detailed investigation focusing on two major targets, namely NOS2 and NOS3, along with their essential metabolite (arginine) and associated pathways (HIF-1 signaling and arginine and proline metabolism). Real-time PCR validated significantly greater downregulation of NOS2 and HIF-1ɑ in the MJD as compared to the model group. Molecular docking analysis further confirmed the binding of active MJD with key active components. Our findings elucidate the impact of MJD on relevant pathophysiological and metabolic networks relevant to KOA and assess the drug efficacy of MJD and its underlying mechanisms of action.

Sleep apnea syndrome(SAS) and osteoarthritis (OA) are two prevalent diseases that often coexist, but the causal relationship between them remains unclear. In light of this, our team utilizes Mendelian Randomization and bioinformatics analysis methods to investigate the potential association between the two diseases.

In this study, we utilized GWAS data pertaining to SAS and OA to assess the causal relationship between the two diseases through Mendelian randomization (MR) analysis. We then employed transcriptomic data to perform differential gene identification, WGCNA, shared gene determination, functional enrichment analysis, and colocalization analysis, all designed to further elucidate the mechanisms underlying the association between the two diseases. In the end, we utilized Mendelian randomization (MR) analysis again to delve deeper into the relationship between the two diseases and immune cells.

Our research findings indicate that SAS is a risk factor for OA (p = 0.000004), knee OA (p = 0.0000001) and hip OA(p = 0.001). Furthermore, OA (p = 0.000195), knee OA (p = 0.001) are significant risk factors for SAS. However, there is no clear evidence that hip OA (p = 0.892) is a risk factor for SAS. Interestingly, the genes shared between OA and SAS are significantly enriched in leukocyte migration, leukocyte chemotaxis. Moreover, colocalization analysis suggests that the genes JUNB, COL8A1, FOSB, and IER2 may be key genes associated with both diseases. Furthermore, 57 immune cell phenotypes are associated with SAS, 95 with OA, and 6 shared between both diseases.

This research confirmed the bidirectional causal relationship between SAS and OA. Notably, the 4 genes (JUNB, COL8A1, FOSB, IER2) and 6 immune phenotypes are crucial for both diseases, these provide hopeful targets for future interventions against these two diseases.

Neutralization of Interleukin (IL)-6-signaling by antibodies is considered a promising tool for the treatment of osteoarthritis (OA). To gain further insight into this potential treatment, this study investigated the effects of IL-6-signaling and IL-6 neutralization on chondrocyte metabolism and the release of IL-6-signaling-related mediators by human chondrocytes.

Chondrocytes were collected from 49 patients with advanced knee/hip OA or femoral neck fracture. Isolated chondrocytes were stimulated with different mediators to analyze the release of IL-6, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130). The effect of IL-6 and IL-6/sIL-6R complex as well as neutralization of IL-6-signaling on the metabolism was analyzed.

OA chondrocytes showed high basal IL-6 production and release, which was strongly negatively correlated with the production of cartilage-matrix-proteins. Chondrocytes produced and released sIL-6R and sgp130. The IL-6/sIL-6R complex significantly increased nitric oxide, prostaglandin E2 and matrix metalloproteinase 1 production, decreased Pro-Collagen Type II and mitochondrial ATP production, and increased glycolysis in OA chondrocytes. Neutralization of IL-6-signaling by antibodies did not significantly affect the metabolism of OA chondrocytes, but blocking of glycoprotein 130 (gp130)-signaling by SC144 significantly reduced the basal IL-6 release.

Although IL-6 trans-signaling induced by IL-6/sIL-6R complex negatively affects OA chondrocytes, antibodies against IL-6 or IL-6R did not affect chondrocyte metabolism. Since inhibition of gp130-signaling reduced the enhanced basal release of IL-6, interfering with gp130-signaling may ameliorate OA progression because high cellular release of IL-6 correlates with reduced production of cartilage-matrix-proteins.

Systemic inflammation, particularly the elevation of interleukin-6 (IL-6), plays an important role in the maintenance and progression of knee osteoarthritis. Insomnia, being highly prevalent in knee osteoarthritis, is understood to be a risk factor for systemic inflammation. The present study examined if cognitive behavioral therapy for insomnia (CBT-I) would reduce circulating IL-6 levels to a larger extent than the active control condition via greater improvement in sleep maintenance disturbance at mid-treatment, among individuals with knee osteoarthritis and insomnia disorder.

This is an ancillary study (N = 64) from a larger double-blind, randomized, active controlled clinical trial. Serum IL-6 was measured at baseline, post-treatment, and 3- and 6-month follow-ups. Sleep was measured by daily sleep diaries.

Overall, there was no significant IL-6 trajectory differences between CBT-I and the active control (p = .64). Compared to the active control, CBT-I demonstrated greater improvement in sleep maintenance disturbance at mid-treatment (p = .01), which, in turn, was significantly associated with lower levels of IL-6 at 3-month follow-up (p < .05). Sleep maintenance disturbance at mid-treatment did not significantly predict changes in IL-6 levels at post-treatment (p = .43) and 6-month follow-up (p = .90).

Our study demonstrates that CBT-I can be efficacious in improving sleep maintenance disturbance among individuals with knee osteoarthritis and insomnia disorder. However, no convincing evidence was found that CBT-I can substantially reduce IL-6 levels via improvement in sleep. CBT-I alone may not be effective in reducing systematic inflammation in this clinical population.

NCT00592449.

Obesity-related joint pain is a common and debilitating condition that significantly impacts the quality of life, primarily due to the excess weight straining the joints. This results in inflammation and degeneration, which can cause pain, stiffness, and difficulty moving. We aimed to comprehensively review the literature discussing surgical interventions for obesity-related joint pain. We searched across databases (PubMed, Scopus, and Cochrane Library) to identify studies published between 2000 and 2023 that assessed surgical interventions for obesity-related joint pain. This review highlights the complex interplay of mechanical, inflammatory, and metabolic factors contributing to joint pain in obese individuals, highlighting both surgical and non-surgical interventions. Non-surgical interventions include weight loss, exercise, physical therapy, and medications. Surgical interventions include bariatric surgery and joint replacement surgery. Bariatric surgery significantly reduces body weight and improves the quality of life outcomes; however, multiple studies have found no improvement or worsening of joint pain post-surgery. Total joint arthroplasty has demonstrated good improvement in pain and function outcomes based on recent meta-analyses, although risks of complications are higher in obese patients. The treatment choice for obesity-related joint pain depends on the individual patient's circumstances. Non-surgical interventions are usually the first line of treatment. However, if these interventions are not effective, surgical interventions may be an option.

Background and Objectives: Knee osteoarthritis (KOA) is a degenerative disease that is continuously targeting people of different ages, but especially the elderly population, the number of which tends to increase continuously at the global level. Apart from age, excess weight can influence the evolution of the disease, with obesity being associated with a weak inflammation stage and an imbalance between pro-inflammatory and anti-inflammatory cytokines. The present work aimed to analyze specific biomarkers, namely ACRP-30, IL-10, TNF-α, and IL-6, in knee synovial fluid, and correlate them with KOA patients' clinical data, radiographic changes, and functional and pain scores. Materials and Methods: 24 subjects with KOA and over 50 years of age participate in the present study. Synovial fluid was harvested using ultrasound guidance from the target knees of the enrolled KOA patients, and the levels of ACRP-30, IL-10, TNF-α, and IL-6 were measured using enzyme-linked immunosorbent assays (ELISA). All patients underwent a supine X-ray at the target knee and were classified using Kellgren-Lawrence (K-L) grading. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) was used to assess self-reported physical function, pain, and stiffness. Results: The obtained results highlighted a significant correlation between age and adiponectin level (p = 0.0451, r = -0.412). Also, the IL-10 values are lower in cases where the intensity of the pain is more pronounced (p = 0.0405, r = -0.421). In addition, analyzing the data by gender, it was observed that in the case of males, stiffness is more related to age (p = 0.0079, r = 0.7993), compared to women (p = 0.0203, r = 0.6223). In the case of women, the progression of the disease tends to increase more intensively the WOMAC score's total values (p = 0.00031, r = 0.8342), compared with men (p = 0.0289, r = 7013). Regarding interleukins and BMI, significant correlations were observed only in the case of men. Conclusions: A significant correlation between age and adiponectin, and adiponectin and IL-6, suggests that advanced age may contribute to adiponectin reduction. Comparing men with women, it was observed that men's age is more related to rigidity, and IL-6 and IL-10 are directly correlated to BMI; in addition, women seem to be more sensitive to pain and stiffness.

Osteoarthritis (OA) is a multifactorial disease depending on molecular, genetic, and environmental factors like mechanical strain. Next to the cartilage and the subchondral bone, OA also affects the synovium, which is critically involved in the maintenance of joint homeostasis. As there is a correlation between the extracellular sodium content in the knee joint and OA, this study investigates the impact of sodium on OA-associated processes like inflammation and bone remodeling without and with mechanical loading in synovial fibroblasts. For that purpose, murine synovial fibroblasts from the knee joint were exposed to three different extracellular sodium chloride concentrations (-20 mM, ±0 mM and +50 mM NaCl) in the absence or presence of compressive or intermittent tensile strain. In addition to the intracellular Na+ content and gene expression of the osmoprotective transcription factor nuclear factor of activated T cells 5 (Nfat5), the gene and protein expression of inflammatory mediators (interleukin-6 (IL6), prostaglandin endoperoxide synthase-2 (Ptgs2)/prostaglandin E2 (PGE2)), and factors involved in bone metabolism (receptor activator of NF-κB ligand (RANKL), osteoprotegerin (OPG)) were analyzed by qPCR and ELISA. Mechanical strain already increased intracellular Na+ and Nfat5 gene expression at standard salt conditions to levels obtained by exposure to increased extracellular Na+ content. Both high salt and compressive strain resulted in elevated IL6 and PGE2 release. Intermittent tensile strain did not increase Il6 mRNA expression or IL6 protein secretion but triggered Ptgs2 expression and PGE2 production. Increased extracellular Na+ levels and compressive strain increased RANKL expression. In contrast, intermittent tension suppressed RANKL expression without this response being subject to modification by extracellular sodium availability. OPG expression was only induced by compressive strain. Changes in extracellular Na+ levels modified the inflammatory response and altered the expression of mediators involved in bone metabolism in cells exposed to mechanical strain. These findings indicate that Na+ balance and Nfat5 are important players in synovial fibroblast responses to mechanical stress. The integration of Na+ and Na+-dependent signaling will help to improve the understanding of the pathogenesis of osteoarthritis and could lead to the establishment of new therapeutic targets.