Metabolic Dysregulation in Postmenopause: Implications for Knee Joint Health

Background Interleukin 34 (IL-34) is a recently discovered proinflammatory cytokine that can promote inflammation and osteoclastogenesis in arthritic joints. In this study, we tried to assess the serum and synovial fluid (SF) levels of IL-34 in rheumatoid arthritis (RA) patients, and to determine its relationship with disease activity and radiographic damage. Patients and methods ELISA was used to evaluate IL-34 levels in the serum of RA patients (n=50), osteoarthritis (OA) patients (n=28), and healthy control subjects (n=20) and in SF isolated from RA and OA patients. Disease activity in RA patients was assessed using the disease activity score-28 (DAS 28). The extent of radiographic joint damage, narrowing, and erosions was assessed. Results Serum IL-34 level was significantly elevated in RA patients compared to that in OA patients and healthy controls (P<0.0001). Synovial IL-34 level was also significantly elevated in RA patients compared to that in OA patients (P=0.0004). Serum and synovial IL-34 levels were significantly higher in cases that were rheumatoid factor (RF) positive (n=28) compared to the levels in RF-negative RA cases (n=22) (P=0.03 and P=0.04, respectively). Serum and synovial IL-34 levels were positively correlated with RF (r=0.43, P=0.02 and r=0.39, P=0.03, respectively), and with the extent of radiological damage (SENS) (P=0.0002 and P<0.0001, respectively). However, no significant correlation between IL-34 levels and disease activity was found. Conclusion IL-34 appears to play a key role in the pathogenesis of RA and contribute to bone destruction, making it a potential therapeutic target in the management armamentarium of the disease.

Osteoarthritis (OA) is a progressive chronic disease affecting the articular joints, leading to pain and disability. Unlike traditional views that primarily link OA to aging, recent understanding portrays it as a multifactorial degenerative disease of the entire joint. Emerging research highlights metabolic and immune dysregulation in OA pathogenesis, emphasizing the roles of obesity, dyslipidemia, and insulin resistance in altering joint homeostasis. Recent studies have increasingly focused on the complex role of white adipose tissue (WAT) in OA. WAT not only serves metabolic functions but also plays a critical role in systemic inflammation through the release of various adipokines. These adipokines, including leptin and adiponectin, have been implicated in exacerbating cartilage erosion and promoting inflammatory pathways within joint tissues. The overlapping global crises of obesity and metabolic syndrome have significantly impacted joint health. Obesity, now understood to contribute to mechanical joint overload and metabolic dysregulation, heightens the risk of developing OA, particularly in the knee. Metabolic syndrome compounds these risks by inducing chronic inflammation and altering macrophage activity within the joints. The multifaceted effects of obesity and metabolic syndrome extend beyond simple joint loading. These conditions disrupt normal joint function by modifying tissue composition, promoting inflammatory macrophage polarization, and impairing chondrocyte metabolism. These changes contribute to OA progression, highlighting the need for targeted therapeutic strategies that address both the mechanical and biochemical aspects of the disease. Recent advances in understanding the molecular pathways involved in OA suggest potential therapeutic targets. Interventions that modulate macrophage polarization, improve chondrocyte function, or normalize adipokine levels could serve as preventative or disease-modifying therapies. Exploring the role of diet, exercise, and pharmacological interventions in modulating these pathways offers promising avenues for reducing the burden of OA. Furthermore, such methods could prove cost-effective, avoiding the increase in access to healthcare.

To assess the clinical utility of 5 physical therapy (PT) outcome measures in quantifying functional changes in pediatric lower extremity chronic pain treated at a hospital-based interdisciplinary rehabilitation center. This was a cross-sectional study with retrospective review of 173 individuals, 8 to 18 years old, treated from June 2008 to 2013. The measures used were the Timed Up and Go, Timed Up and Down Stairs, Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, 6-minute walk test, and Lower Extremity Functional Scale. Participant performance was correlated with demographic characteristics, the Functional Disability Index, Multidimensional Anxiety Scale for Children, Child Depression Inventory, and Canadian Occupational Performance Measure. Scores from all 5 PT measures showed significant improvement following treatment. Functional Disability Index correlated to every PT measure except the 6-minute walk test. This study supports the clinical use of these PT measures to track functional progress after rehabilitative treatment of lower extremity chronic pain-related disability.

Introduction: The inflammatory process underlies either osteoarthritis (OA) or metabolic syndrome. Systemic inflammation that occurs in the metabolic syndrome will result in the production of inflammatory cytokines and activation of macrophages and chondrocytes. This can affect the entire body including joints and the surrounding tissues, causing OA. Type 2 Diabetes Mellitus (DMT2) and hypertension are the first and second most common metabolic syndrome components found in OA patients. This study aimed to determine the relationship between metabolic syndrome and knee OA in DMT2 patients with hypertension. Methods: By using an analytic observational method and cross-sectional design, this study involved the medical records of patients with DMT2. The sample consisted of 50 medical records selected by using the purposive sampling technique and fulfilling the inclusion and exclusion criteria. Results: This study involved 25 medical records of patients with and without knee (genu) OA. The characteristics of the sample were as follows: 1 medical record of patient aged 36-45 years, 18 medical records of patients aged 46-55 years, 16 medical records of patients aged 56-65 years, 15 medical records of patients aged > 65 years, 21 medical records of male patients, 29 medical records of female patients, 27 medical records with metabolic syndrome, and 23 medical records without metabolic syndrome. The association between metabolic syndrome and knee (genu) OA was analyzed by using the Chi-Square Test using the SPSS application, where the results showed a significance value of p < 0.05 (p = 0.001). Conclusion: This study shows that there is a significant association between metabolic syndrome and knee (genu) OA.

Aims: Asthma is a disease characterized by diffuse and reversible narrowing of the airways, affecting approximately 300 million people worldwide. Metabolic syndrome, on the other hand, is a fatal endocrinopathy that begins with insulin resistance. Numerous studies have investigated the impact of metabolic syndrome on airway inflammation in patients with asthma. In this study, we aimed to investigate the coexistence of metabolic syndrome in patients followed up with a diagnosis of asthma and its impact on asthma control using the asthma control test (ACT). Methods: A total of 50 patients, including 10 men and 40 women aged between 18 and 70 years, who presented to the asthma outpatient clinic of Atatürk Chest Diseases and Thoracic Surgery Training and Research Hospital and were diagnosed with asthma, were included in the study. Participants completed a questionnaire assessing demographic characteristics and medical history. Subsequently, height, weight, waist circumference, and triceps skinfold thickness measurements were taken. Arterial blood pressure was measured, and blood samples were collected after 12 hours of fasting to evaluate serum triglyceride (TG), HDL, and fasting glucose levels, along with a complete blood count. Pulmonary function tests were performed, and participants responded to the short form of the International Physical Activity Questionnaire (IPAQ). Results: Upon evaluation, 30% of the cases were diagnosed with metabolic syndrome. Metabolic syndrome was diagnosed in 40% of male and 27.5% of female patients. Among the 50 participants, 16 (32%) were diagnosed with obesity, 19 (38%) with hypertension, and 1 (2%) with diabetes mellitus. The average duration of asthma follow-up was calculated as 10.8±8.7 years. The prevalence of metabolic syndrome was found to be higher in postmenopausal women compared to premenopausal women, whereas among women using oral contraceptives, the diagnosis of metabolic syndrome was lower than in non-users; however, this was not statistically significant (p>0.05). However, waist circumference measurements were significantly higher in those with metabolic syndrome compared to those without (p<0.05). A significant association was found between serum TG levels and metabolic syndrome diagnosis, while no significant relationship was observed for fasting blood glucose and serum HDL levels. Both systolic and diastolic blood pressure values were found to be higher in individuals with metabolic syndrome, with a statistically significant association between blood pressure values and the diagnosis of metabolic syndrome. According to the ACT results, 4 patente (8%) were under control, 17 (34%) were partially controlled, and 29 (58%) were uncontrolled. Among patients with metabolic syndrome, the forced expiratory volume in 1 second (FEV1) was found to be lower with borderline values. No significant association was found between physical activity levels and metabolic syndrome. Both groups, with and without metabolic syndrome, had low ACT scores, and no significant relationship was found between metabolic syndrome and ACT scores. Conclusion: Nonetheless, based on the findings of this study, we believe that metabolic syndrome should also be considered when planning treatment for asthmatic patients.

Introduction: Osteoarthritis (OA) is the commonest joint disease and is thought to be caused by an imbalance between synthesis and degradation of extracellular cartilage/bone matrix proteins. An overproduction of cartilage-degrading mediators from the inflamed synovial membrane (SM) is now attracting interest. To date, direct in vivo imaging of human SM microcirculation is impossible. The relationship between OA-induced SM microcirculatory disturbances and OA-disease-severity is unknown. Methods: 20 patients with OA of the knee were investigated during total knee arthroplasty by 1)orthogonal polarization spectral (OPS-)imaging of the SM, 2)growth factor synovial fluid (SF) analysis and 3)histological grading of SM inflammation. Disease-specific measure of pain, stiffness and function (WOMAC-Scores) and radiographic stage of disease (Ahlbaeck-score) were assessed in all patients. In vivo OPS-imaging of the SM was performed in 6-10 regions. SF was transcapsularily aspirated for ELISA-analysis of VEGF, MMP1+3, TIMP2, PGE2. SM biopsies were harvested for histolog. graduation of synovialitis. Results: Radiographics in OA-knees revealed 0,3,10,5, and 2 patients for Ahlbaeck-stage 1,2,3,4, and 5. WOMAC score was 5.9 ± 1.4 (pain), 5.6 ± 1.8 (stiffness) and 5.8 ± 1.2 (function). OPS-imaging allowed to visualize human SM microcirculation with funct. capill. density (FCD:190.1 ± 34.0 cm−1), capillary/venular diameters (D: 9.1 ± 2.2/31.5 ± 27.2µm), capillary/ venular RBCV (276 ± 191/190 ± 103µm/s), VBF (17 ± 14/111 ± 105pl/s). Synovialitis score was 2.8 ± 1.1. Synovial levels (pg/ml) were increased with VEGF(1321,3 ± 868,3), MMP-1(20,4 ± 19,3) and -3(1719,8 ± 1646,2), TIMP-2(396,5 ± 86,1), PGE-2(571,3 ± 331,0). Regression of patient age on synovialitis score revealed an association (R = 0.67). There was an inverse correlation between RBCV and VBF in capillaries/venules and the WOMAC-pain score (R = −0.56,R = −0.64). Venular VBF correlated to synovial PGE2-levels. Radiographic Ahlbaeck-stage showed a relation to the VEGF-level (R = 0.76). Elevated TIMP-2-level was associated with increased venular D (R = 0.6) and VBF (R = 0.55). MMP-1-levels significantly correlated to WOMAC-pain score (R = 0.6). Conclusion: This study presents for the first time direct in vivo visualization and quantification of the SM microcirculation in OA patients. The correlations of 1)increased VEGF-levels with radiographic damage, 2)venular D and reduced VBF with pain, 3)synovial blood flow and PGE2 levels and 4) MMP-1 and WOMAC-pain score reflect a causative role of SM microcirculatory disturbances, angiogenic factors in perpetuation of OA-synovitis. These interactions may have therapeutic implications in view of protecting SM microcirculation and targeting expression of destructive mediators in order counteract OA progression.

FRI0320 Radiographic features, better than clinical features, represent actual joint degeneration and inflammation: Considerations for total knee replacement surgery

Objective: This pilot study aimed to determine the correlation of metabolic syndrome (MetS), its components, and increased LDL (low-density lipoprotein) and total cholesterol levels with osteoarthritis (OA). In addition, our goal was to establish the association between MetS and the degree of handicap measured by the Lequesne index of functionality and severity of knee osteoarthritis.Materials and methods: The pilot study included 25 subjects with knee OA and 19 subjects without knee OA. All subjects were menopausal or premenopausal women. MetS was diagnosed according to the National Cholesterol Education Program, Adult Treatment Panel III. OA was diagnosed if Kellgren-Lawrence ≥ 2.Results: MetS was detected in 80% of subjects with OA. In the non-OA group, MetS was detected in 26% of subjects. The difference in MetS prevalence between the two groups was significant (p=0.000). The presence of each MetS component was significant in the OA group, except for central obesity, which presence was marginally significant (p=0.054). Prevalence of increased total (p=0.019) and LDL cholesterol (p=0.000) was also significant in the OA group. A significant difference between OA and the non-OA group was detected in the prevalence of all five MetS components (p=0.016). In the OA group, the Lequesne index of functionality and severity of knee osteoarthritis was not significantly altered between subjects with and without MetS.Conclusion: Metabolic syndrome, its components, increased LDL, and total cholesterol are correlated with osteoarthritis in premenopausal and menopausal women. MetS is not correlated with the degree of handicap in the knee joint measured by the Lequesne index.

Background Osteoarthritis (OA) is a chronic joint disease with complex etiologies characterized by synovial inflammation, subchondral bone remodeling, and the formation of osteophytes, which leads to cartilage deterioration. Periodontitis (PD) is also a chronic inflammatory disease characterized by loss of periodontal ligament and alveolar bone. Recently, the association between OA and metabolic diseases has been proposed, and the association between several systemic diseases such as rheumatoid arthritis, metabolic syndrome and periodontitis has been also revealed. Objectives The aim of this study was to investigate the association between OA and PD in South Korea using data from the Korea National Health and Nutrition Examination Survey (KNHANES) during 2010–2014. Methods Cross-sectional data of 7,969 adults who completed the KHANES, and participated in both a periodontal examination and a knee imaging were analyzed. OA of knee was defined when a participant had knee arthralgia and showed radiographic change of Kellgren-Lawrence (KL) grade over 1. OA patients were grouped into mild (KL grade 1–2) and severe (KL grade 3–4) OA. The periodontal status was assessed by the Community Periodontal Index. Binary logistic regression analysis was performed according to the OA and PD status, severity of OA, and subgroups (age, gender) adjusting for the socio-demographics, oral health behaviors and status, smoking, and drinking. Results Of the 7,969 participants, 1408 (17.7%) had OA and 2987 (37.5%) had PD. OA and PD showed no significant association in overall analysis. However, in subgroup analysis, female patients with severe OA were more likely to have PD (adjusted odd ratio (OR) 1.377, P=0.0316); likewise, OR for severe OA in female patient with PD was 1.367. (P=0.0.54) Conclusions Severe OA and PD were associated with each other especially in female in the Korean population. Further prospective and experimental studies are necessary to identify the impact and mechanisms of association between severe OA and PD in female. References Zhuo Q, Yang W, Chen J, Wang Y. Metabolic syndrome meets osteoarthritis. Nature reviews Rheumatology 2012; 8(12): 729–37. Kwon YE, Ha JE, Paik DI, Jin BH, Bae KH. The relationship between periodontitis and metabolic syndrome among a Korean nationally representative sample of adults. Journal of clinical periodontology 2011; 38(9): 781–6. Disclosure of Interest None declared

Correlation between catastrophizing and Lequesne index in case of osteoarthritis of the knee: A prospective study

BackgroundMetabolic syndrome can be a serious complication of treatment with psychotropic medications, particularly the atypical antipsychotics.MethodAdolescents with bipolar I disorder who were taking at least one mood stabilizer (divalproex sodium...

Background Tissue accumulation of p16INK4A-positive senescent cells is associated with age-related disorders such as osteoarthritis (OA). These senescent cells induce a tissue loss of function through a particular secretory phenotype called SASP (senescence-associated secretory phenotype). Objectives Links between OA onset and cellular senescence remain poorly detailed. We wanted to determine the localization of articular senescent cells in in vivo OA mouse models and study the involvement of mesenchymal stem cells (MSC) senescence in OA pathogenesis. Methods Wild-type mice C57BL/6, SAMP8/R1 (senescence accelerated mouse-prone and resistant), transgenic p16INK4A+/Luc and p16INK4A Luc/Luc were used. Experimental OA was induced by intraarticular injections of collagenase (CIOA). Cartilage, synovial tissue and subchondral bone were analyzed by histology, RT-qPCR and micro-tomography. MSCs come from healthy human donors and primary chondrocytes from OA patients. Results (1) CIOA was induced in senescence-driven luciferase transgenic mice. Under CCD camera, a peak in luminescence was detected at day 24 post-injection revealing the presence of senescent cells in the joint. Remarkably, articular senescence is not only a marker of the pathology but contributes to OA onset: mice deficient in p16INK4a, a main senescence-driving known cell cycle inhibitor, were partially protected against CIOA. These results were confirmed in C57Bl/6 mice after CIOA by showing an increase in gene expression for senescence, catabolic and inflammatory markers in the synovial tissue preceding cartilage degradation. (2) MSCs found in synovial, cartilage, fat pad and bone marrow participate in joint homeostasis. Because MSC are proposed to be at the root of OA development, we hypothesize that cellular senescence onset in these progenitor cells would be a possible etiological factor for OA. We have established an in vitro p16INK4A-induced senescence model on human primary MSC: their intrinsic properties such as self-renewing are altered during senescence onset. Furthermore, in co-culture conditions with chondrocytes from OA patients, senescent MSC lost their extrinsic chondroprotective properties. (3) To in vivo challenge these findings, we rely on the mouse model of accelerated senescence SAMP8, which develop spontaneous OA at the age of 6 months with cartilage degradation, synovial hypertrophy, osteophytosis and subchondral bone remodeling associated to meniscal calcification. Isolated MSC from these mice express senescence but non-inflammatory markers (p16INK4a, p21waf1, MMP13, TGF-β1). Remarkably, intra-articular injection of these isolated SAMP8-derived MSC compared to SAMR1-derived control MSC, in young wid-type C57Bl/6 mice, was suffisant by its own, to induce significant articular cartilage degradation (OA score of 12.2 ± 1.5 vs 6.1 ± 3.5 for SAMP8 and SAMR1 MSC respectively. p Conclusion p16INK4A-induced cellular senescence in MSC played a causative role in cartilage loss of function and OA pathogeny. In vitro, senescent MSC show altered intrinsic and extrinsic supportive tissue functions. In vivo, intra-articular injection of senescent MSC was sufficient to induce cartilage degradation. Specific targeting of such deleterious senescent cells could be an innovating and promising treatment in OA. Acknowledgement We acknowledge FOREUM and AGEMED as supporters of our projects. Disclosure of Interests Olivier Malaise Speakers bureau: Amgen, Yassin Tachikart: None declared, Michael Constantinides: None declared, Marcus Mumme: None declared, Daniele Noel: None declared, Jing Wang: None declared, Christian Jorgensen: None declared, Jean-Marc Brondello: None declared

Severity Grade Assessment Classifications for Both Insulin Resistance Syndrome and Status of Pancreatic Beta Cell Function in Clinical Practice Using Homeostasis Model Assessment Method Indices

Osteoarthritis (OA) is a prevalent degenerative joint disease affecting over 530 million individuals worldwide. Recent studies suggest a potential link between iron overload, a condition characterised by the excessive accumulation of iron in the body, and the onset of OA. Iron is essential for various biological processes, and any disruption in its homeostasis can trigger significant health effects, including OA. This study aimed to elucidate the effects of excess iron on joint tissue and the underlying mechanisms associated with excess iron and OA development. Human articular cartilage (n = 6) and synovium (n = 4) were collected from patients who underwent total knee arthroplasty. Cartilage and synovium explants were incubated with a gradually increasing concentration of ferric ammonium citrate for 3days respectively. The effects of iron homeostasis in tissue explants were analysed using a Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS). To further study the effects of iron excess on OA initiation and development, male 3-week-old Hfe-/- and 5-week-old Tfr2-/- mice, animal models of hereditary haemochromatosis were established. Littermate wild-type mice were fed a high-iron diet to induce dietary overload. All animals were sacrificed at 8weeks of age, and knee joints were harvested for histological analysis. The LA-ICP-MS analysis unveiled changes in the elemental composition related to iron metabolism, which included alterations in FTH1, FPN1, and HAMP within iron(III)-treated cartilage explants. While chondrocyte viability remained stable under different iron concentrations, ex vivo treatment with a high concentration of Fe3+ increased the catabolic gene expression of MMP13. Similar alterations were observed in the synovium, with added increases in GAG content and inflammation markers. In vivo studies further supported the role of iron overload in OA development as evidenced by spontaneous OA symptoms, proteoglycan loss, increased Mankin scores, synovial thickening, and enhanced immunohistochemical expression of MMP13, ADAMTS5, and P21 in Hfe-/-, Tfr2-/-, and diet-induced iron overload mouse models. Our findings elucidate the specific pathways through which excess iron accelerates OA progression and highlights potential targets for therapeutic intervention aimed at modulating iron levels to mitigate OA symptoms. KEY MESSAGES: Iron overload alters joint iron metabolism, increasing OA markers in cartilage and synovium. High iron levels in mice accelerate OA, highlighting genetic and dietary impacts. Excess iron prompts chondrocyte iron storage response, signalling potential OA pathways. Iron dysregulation linked to increased cartilage degradation and synovial inflammation. Our findings support targeted therapies for OA based on iron modulation strategies.

Osteoarthritis (OA) is a chronic degenerative articular disease that leads to physical disability and reduced quality of life. The key pathological events in OA are cartilage degradation and synovial inflammation. Conventional therapies often lead to adverse effects that some patients are unwilling to endure. Traditional Chinese Medicines (TCMs) have long been known for their efficacy in treating OA with minimal side effects. The wingless-type (Wnt) signaling pathway is believed to play a role in OA progression, but there is still a lack of comprehensive understanding on how TCM may treat OA via the Wnt signaling pathway. This study aims to fill this gap by reviewing relevant research on the association between the Wnt signaling pathway and cartilage degradation and synovial inflammation in OA. Meanwhile, we also summarized and categorized TCMs and their active components, such as alkaloids, polysaccharides, flavonoids, sesquiterpene lactones, etc., which have shown varying efficacy in treating OA through modulation of the Wnt/[Formula: see text]-catenin signaling pathway. This work underscores the pivotal role of the Wnt signaling pathway in OA pathogenesis and progression, suggesting that targeting this pathway holds promise as a prospective therapeutic strategy for OA management in the future. TCMs and their active components have the potential to alleviate OA by modulating the Wnt signaling cascade. Harnessing TCMs and their active components to regulate the Wnt signaling pathway presents an encouraging avenue for delivering substantial therapeutic benefits to individuals with OA.