Integrated Network Pharmacology and Experimental Validation Approach to Investigate the Mechanisms of Radix Rehmanniae Praeparata - Angelica Sinensis - Radix Achyranthis Bidentatae in Treating Knee Osteoarthritis.

Background: Knee osteoarthritis (KOA) is a persistent degenerative condition characterized by the deterioration of cartilage. The Chinese herbal formula Radix Rehmanniae Praeparata- Angelica Sinensis-Radix Achyranthis Bidentatae (RAR) has often been used in effective prescriptions for KOA as the main functional drug, but its underlying mechanism remains unclear. Therefore, network pharmacology and verification experiments were employed to investigate the impact and mode of action of RAR in the treatment of KOA. Methods: The destabilization of the medial meniscus model (DMM) was utilized to assess the anti-KOA effect of RAR by using gait analysis, micro-computed tomography (Micro-CT), and histology. Primary chondrocytes were extracted from the rib cartilage of a newborn mouse. The protective effects of RAR on OA cells were evaluated using a CCK-8 assay. The antioxidative effect of RAR was determined by measuring reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione (GSH) production. Furthermore, network pharmacology and molecular docking were utilized to propose possible RAR targets for KOA, which were further verified through experiments. Results: In vivo, RAR significantly ameliorated DMM-induced KOA characteristics, such as subchondral bone sclerosis, cartilage deterioration, gait abnormalities, and the degree of knee swelling. In vitro, RAR stimulated chondrocyte proliferation and the expression of Col2a1, Comp, and Acan. Moreover, RAR treatment significantly reduced ROS accumulation in an OA cell model induced by IL-1ß and increased the activity of antioxidant enzymes (SOD and GSH). Network pharmacology analysis combined with molecular docking showed that Mapk1 might be a key therapeutic target. Subsequent research showed that RAR could downregulate Mapk1 mRNA levels in IL-1ß-induced chondrocytes and DMM-induced rats. Conclusion: RAR inhibited extracellular matrix (ECM) degradation and oxidative stress response via the MAPK signaling pathway in KOA, and Mapk1 may be a core target.

Demonstrating antibiotic stewardship while diagnosing and treating bilateral pseudoseptic arthritis: a case report.

INTRODUCTION: Although viscosupplementation is a commonly used treatment for osteoarthritis and is widely regarded as a safe treatment option, it is associated with the rare complication of pseudoseptic arthritis. Most existing case reports that cite this rare complication employed the use of early broad-spectrum antibiotics. CASE PRESENTATION: In this case report, we present a 61-year-old African American female patient who presented with bilateral knee pseudoseptic arthritis in the setting of viscosupplementation. She presented 3 days after bilateral viscosupplementation injections with bilateral knee swelling, discomfort, and pain with micromotion. Her white blood cell count (WBC) was 12.83 (4.5-11 normal), her C-reactive protein (CRP) level was 159 mg/L (0-10 normal), and her erythrocyte sedimentation rate (ESR) was 79 mm/hour (0-40 normal). Her left knee aspirate yielded 38,580 WBC with a negative gram stain and negative cultures. Her right knee aspirate yielded 29,670 WBC with a negative gram stain and negative cultures. Through the utilization of careful clinical monitoring, ice therapy, and non-steroidal inflammatory medication, we were able to successfully treat this patient while maintaining proper antibiotic stewardship. CONCLUSION: Pseudoseptic arthritis in the setting of viscosupplementation can be adequately treated and monitored without the use of antibiotics.

Demonstrating the effectiveness of intra-articular prolotherapy combined with peri-articular perineural injection in knee osteoarthritis: a randomized controlled trial.

BACKGROUND: This study aimed to compare the efficacy of intra-articular prolotherapy (IG) combined with peri-articular perineural injection (PG) in the management of knee osteoarthritis (KOA). METHODS: A total of 60 patients with the diagnosis of KOA were included in this double-blinded randomized controlled clinical trials. The inclusion criteria were as follow: (1) 48-80 years old; (2) the diagnose of KOA; (3) the grade 2 and 3 of the Kellgern-Lawrence grading scale; (4) the pain, crepitation, and knee joint stiffness continuing for 3 months at least. The main exclusion criteria were as follow: (1) any infection involving the knee skin; (2) history of any Influencing factors of disease. All patients were divided into three groups and received either IG, PG and I + PG under the ultrasound guidance and the 2, 4 and 8 weeks follow-up data of patients were available. (IG n = 20 or PG n = 20, I + PG n = 20). Visual Analogue Scale (VAS), The Western Ontario McMaster University Osteoarthritis Index (WOMAC) and the pressure pain threshold (PPT) were used as outcome measures at baseline, 2, 4 and 8 weeks. RESULTS: There were no statistically significant differences in terms of age, sex, BMI, duration of current condition and baseline assessments of pain intensity, WOMAC scores and PPT. After treatment, the improvement of VAS activity, WOMAC and PPT values was showed compared with pre-treatment in all groups (p < 0.05). At 4 and 8 weeks after treatment, the VAS and WOMAC scores of the I + PG were significantly lower than those of the PG or IG, and the difference was statistically significant (p < 0.05). The PPT values of PG and I + PG were significantly improved compared to IG at 2, 4, and 8 weeks after treatment. CONCLUSION: The ultrasound guided I + PG of 5% glucose seem to be more effective to alleviate pain and improve knee joint function than single therapy in short term. Clinical rehabilitators could clinically try this combination of I + PG to improve clinical symptoms in patients with KOA.

Exploring the pharmacological mechanism of Glycyrrhiza uralensis against KOA through integrating network pharmacology and experimental assessment.

Knee osteoarthritis (KOA), a major health and economic problem facing older adults worldwide, is a degenerative joint disease. Glycyrrhiza uralensis Fisch. (GC) plays an integral role in many classic Chinese medicine prescriptions for treating knee osteoarthritis. Still, the role of GC in treating KOA is unclear. To explore the pharmacological mechanism of GC against KOA, UPLC-Q-TOF/MS was conducted to detect the main compounds in GC. The therapeutic effect of GC on DMM-induced osteoarthritic mice was assessed by histomorphology, µCT, behavioural tests, and immunohistochemical staining. Network pharmacology and molecular docking were used to predict the potential targets of GC against KOA. The predicted results were verified by immunohistochemical staining Animal experiments showed that GC had a protective effect on DMM-induced KOA, mainly in the improvement of movement disorders, subchondral bone sclerosis and cartilage damage. A variety of flavonoids and triterpenoids were detected in GC via UPLC-Q-TOF/MS, such as Naringenin. Seven core targets (JUN, MAPK3, MAPK1, AKT1, TP53, RELA and STAT3) and three main pathways (IL-17, NF-κB and TNF signalling pathways) were discovered through network pharmacology analysis that closely related to inflammatory response. Interestingly, molecular docking results showed that the active ingredient Naringenin had a good binding effect on anti-inflammatory-related proteins. In the verification experiment, after the intervention of GC, the expression levels of pp65 and F4/80 inflammatory indicators in the knee joint of KOA model mice were significantly downregulated. GC could improve the inflammatory environment in DMM-induced osteoarthritic mice thus alleviating the physiological structure and dysfunction of the knee joint. GC might play an important role in the treatment of knee osteoarthritis.

The efficacy and safety of leucine-enriched essential amino acids in knee osteoarthritis patients: A randomized controlled trial.

BACKGROUND: Supplementation with leucine-enriched essential amino acids (LEAAs) has shown efficacy in the recovery of muscle injury and activation of muscle synthesis. Muscle function in knee osteoarthritis is a crucial factor for managing pain and preserving ambulatory function. However, the efficacy and safety of LEAAs supplementation in patients with knee osteoarthritis have not been evaluated. METHODS: In this prospective analysis, we evaluated the efficacy and safety of supplementation with 12 g of LEAAs daily for 8 weeks in knee-symptomatic osteoarthritis patients. For assessing the efficacy, clinical pain, calf circumference, and disability were assessed using questionnaires (visual analog scale, Knee Society Score, and 36-item short form survey [SF-36]), laboratory analyses (total protein and albumin), and radiologic study (dual-energy X-ray absorptiometry [DEXA]) for muscle and bone density. To evaluate safety, generalized or localized protein allergic reactions, complete blood count, liver and kidney function, and serum glucose were measured. RESULTS: Sixty-five participants, categorized into the experimental (n = 32) and control (n = 33) groups, were included in this 8-week trial from March 2022 to July 2022. A significantly higher efficacy was observed in the experimental group than in the control group, as indicated by muscle density in the DEXA scan (P = .001) and SF-36 (P < .001). The safety evaluation revealed no related generalized or local protein allergy. Hematological findings, serum glucose, and kidney and liver toxicity were not significantly different between the groups. CONCLUSION: Supplementation with leucine-enriched proteins is safe and efficacious in the improvement of muscle density and quality of life.

Effectiveness and safety of polyacrylamide hydrogel injection for knee osteoarthritis: results from a 12-month follow up of an open-label study.

OBJECTIVE: There are few effective osteoarthritis (OA) therapies. A novel injectable polyacrylamide hydrogel (iPAAG) previously demonstrated efficacy and safety up to week 26 in an open-label study of knee OA. Here we report longer-term effectiveness and safety data. METHODS: This multi-centre, open-label study included patients with symptomatic and radiographic knee OA. Primary outcome was WOMAC pain (0-100 scale) at 13 weeks, and patients continued to 26 weeks before entering a further 26-week extension phase. Secondary efficacy outcomes included WOMAC stiffness and function subscales, Patient Global Assessment (PGA) and proportion of OMERACT-OARSI responders. Safety outcomes were adverse events (AEs). RESULTS: 49 participants (31 women, mean age 70) received an ultrasound-guided, intra-articular injection of 6 ml iPAAG; 46 completed the extension phase to 52 weeks. There was a significant reduction in the WOMAC pain score from baseline to 52 weeks (- 17.7 points (95% CI - 23.1; - 12.4); p < 0.0001). Similar sustained improvements were observed for WOMAC stiffness (11.0 points; 95% CI - 17.0; - 4.9), physical function (18.0 points; 95% CI - 19.1; - 10.6), and PGA (16.3 points; 95% CI - 23.1; - 9.4). At 52 weeks 62.2% of patients were OMERACT-OARSI responders. From 26 to 52 weeks, 8 adverse effects (AE), including 1 serious AE (cerebrovascular accident) were reported in 5 subjects. None of the new adverse events were thought to be device related. CONCLUSION: This open-label study suggests persistent benefits and safety of iPAAG through 52 weeks after a single injection. TRIAL REGISTRATION: Clinicaltrials.gov NCT04179552.

Revolutionizing Knee Osteoarthritis Treatment: Innovative Self-Nano-Emulsifying Polyethylene Glycol Organogel of Curcumin for Effective Topical Delivery.

In the current study, self-nano-emulsifying (SNE) physically cross-linked polyethylene glycol (PEG) organogel (SNE-POG) as an innovative hybrid system was fabricated for topical delivery of water-insoluble and unstable bioactive compound curcumin (CUR). Response surface methodology (RSM) based on Optimal Design was utilized to evaluate the formulation factors. Solid fiber mechanism with homogenization was used to prepare formulations. Pharmaceutical evaluation including rheological and texture analysis, their mathematical correlations besides physical and chemical stability experiments, DSC study, in vitro release, skin permeation behavior, and clinical evaluation were carried out to characterize and optimize the SNE-OGs. PEG 4000 as the main organogelator, Poloxamer 188 (Plx188) and Ethyl Cellulose (EC) as co-gelator/nanoemulsifier agents, and PEG 400 and glycerin as solvent/co-emulsifier agents could generate SNE-POGs in PS range of 356 to 1410 nm that indicated organic base percentage and PEG 4000 were the most detrimental variables. The optimized OG maintained CUR stable in room and accelerated temperatures and could release CUR sustainably up to 72 h achieving high flux of CUR through guinea pig skin. A double-blind clinical trial confirmed that pain scores, stiffness, and difficulty with physical function were remarkably diminished at the end of 8 weeks compared to the placebo (71.68% vs. 7.03%, 62.40% vs. 21.44%, and 45.54% vs. 8.66%, respectively) indicating very high efficiency of system for treating knee osteoarthritis. SNE-POGs show great potential as a new topical drug delivery system for water-insoluble and unstable drugs like CUR that could offer a safe and effective alternative to conventional topical drug delivery system.

Association of Pharmacologic Treatment of Depression/Anxiety With Initial Patient-Reported Outcome Measures in Patients With Hip and Knee Osteoarthritis.

INTRODUCTION: Depression and anxiety are common comorbidities that may exacerbate osteoarthritis (OA)-related pain. We aim to evaluate the effect of pharmacologic treatment of depression/anxiety on hip and knee patient-reported outcome measures (PROMs). METHODS: A multi-institutional PROMs database was queried for patients with depression or anxiety and hip or knee OA who completed a PROMs questionnaire at an initial orthopaedic visit between January 2015 and March 2023. Data on demographics, comorbidities, and duration of pharmacologic treatment of depression/anxiety were obtained. Patients were stratified into three cohorts based on treatment duration. PROMs were compared across cohorts. RESULTS: Two thousand nine hundred sixty patients who completed PROMs at their initial orthopaedic visit had both OA and depression/anxiety. One hundred thirty-four (4.5%) received pharmacologic treatment of depression/anxiety for < 1 year, versus 196 (6.6%) for more than 1 year. In unadjusted analyses, patients with pharmacologic treatment had significantly lower Patient-Reported Outcomes Measurement Information System (PROMIS)-Physical (39.8 [IQR 34.9, 44.9] vs 42.3 [37.4, 47.7], P < 0.001) and PROMIS-Mental (43.5 [36.3, 50.8] vs 48.3 [41.1, 53.3], P < 0.001) scores than those without treatment. After adjusting for demographics and comorbidities, only differences in PROMIS-Mental scores remained statistically significant, with pharmacologic treatment associated with lower scores (ß = -2.26, 95% CI, [-3.29, -1.24], P < 0.001). On secondary analysis including duration of pharmacologic treatment, < 1 year of treatment was associated with significantly lower PROMIS-Mental scores than those not treated (ß = -4.20, 95% CI [-5.77, -2.62], P < 0.001) while scores of patients with more than 1 year of treatment did not differ significantly from those without treatment. CONCLUSION: :Our results indicate that pharmacologic treatment of depression/anxiety is associated with improved psychological health but not with improved physical symptoms related to OA. We observed a nonsignificant trend that patients with depression/anxiety who warrant pharmacologic treatment tend to have worse physical symptoms than those who do not; however, unadjusted analyses suggest this is a complex relationship beyond the isolated effect of pharmacologic treatment.

[Status of outcome measures in randomized controlled trials of kidney-tonifying and blood-activating method in treatment of knee osteoarthritis].

This study assesses the status of outcome measures in the randomized controlled trial(RCT) involving the kidney-tonif-ying and blood-activating method for treating knee osteoarthritis(KOA), aiming to establish a theoretical foundation for the development of a core set of outcome measures in traditional Chinese medicine(TCM) treatment of KOA. The relevant articles were retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, and Web of Science, in addition to ClinicalTrials.gov and the China Clinical Trial Registration Center, with the time interval from inception to August 2023. The RCT of treating KOA with the kidney-tonifying and blood-activating method was included. Two assessors independently conducted literature screening, data collection, and qualitative analysis to compile the outcome measure results. A total of 350 RCTs were included, involving 165 outcome measures with the total frequency of 1 462. These outcome measures were categorized into six domains: symptom and sign measures(23) with the frequency of 718(49.1%), TCM symptom and syndrome measures(3) with the frequency of 53(3.6%), physical examination measures(130) with the frequency of 506(34.6%), quality of life measures(4) with the frequency of 20(1.3%), long-term efficacy measures(2) with the frequency of 6(0.4%), and safety measures(3) with the frequency of 159(10.9%). Additionally, 53 studies used TCM syndrome and symptom scores as indicators of efficacy, employing eight distinct measurement tools. The RCTs involving the kidney-tonifying and blood-activating method for treating KOA had a variety of problems, such as unclear prio-ritization of outcome measures, diversity in measurement tools, absence of standardized assessment criteria for specific measures, and non-standardized usage. These problems affected the research quality and reliability. Hence, it is advisable to draw upon international expertise, improve research design, and merge TCM efficacy characteristics with clinical research to establish a core set of KOA outcome measures aligned with TCM principles.

Network pharmacology combined with experimental validation to investigate the effect of Rongjin Niantong Fang on chondrocyte apoptosis in knee osteoarthritis.

Knee osteoarthritis (KOA) is a chronic degenerative disease that affects the quality of life of middle­aged and elderly individuals, and is one of the major factors leading to disability. Rongjin Niantong Fang (RJNTF) can alleviate the clinical symptoms of patients with KOA, but the molecular mechanism underlying its beneficial effects on KOA remains unknown. Using pharmacological analysis and in vitro experiments, the active components of RJNTF were analyzed to explore their potential therapeutic targets and mechanisms in KOA. The potential targets and core signaling pathways by which RJNTF exerts its effects on KOA were obtained from databases such as Gene Expression Omnibus, Traditional Chinese Medicine Systems Pharmacology and Analysis Platform. Subsequently, chondrocyte apoptosis was modeled using hydrogen peroxide (H2O2). Cell Counting Kit­8 assay involving a poly [ADP­ribose] polymerase­1 (PARP1) inhibitor, DAPI staining, reverse transcription­quantitative PCR, Annexin V­FITC/PI staining and flow cytometry, western blotting and co­immunoprecipitation analysis were used to determine the therapeutic efficacy of RJNTF on KOA and to uncover the molecular mechanism. It was found that PARP1­knockdown lentivirus, incubation with PARP1 inhibitor PJ34, medium and high doses of RJNTF significantly reduced H2O2­induced chondrocyte apoptosis. Medium and high doses of RJNTF downregulated the expression of cleaved caspase­3, cleaved PARP1 and PAR total proteins, as well as nucleus proteins of apoptosis­inducing factor (AIF) and migration inhibitory factor (MIF), and upregulated the expression of caspase­3, PARP1 total protein, as well as the cytoplasmic expression of AIF and MIF, suggesting that RJNTF may inhibit chondrocyte apoptosis through the PARP1/AIF signaling pathway.

Modified Mesenchymal stem cell, platelet-rich plasma, and hyaluronic acid intervention in early stage osteoarthritis: A systematic review, meta-analysis, and meta-regression of arthroscopic-guided intra-articular approaches.

BACKGROUND: Mesenchymal stem cells (MSCs) hold promise for osteoarthritis (OA) treatment, potentially enhanced by combining them with platelet-rich plasma (PRP) and hyaluronic acid (HA). This study aimed to assess the synergy of MSCs, PRP, and varying HA doses, and determine optimal MSC sources to treat early-stage OA in the perspective of Lysholm score, VAS Score, KSS score, and WOMAC score. METHOD: Original articles from 2013 to 2023 were screened from four databases, focusing on clinical trials and randomized controlled trials. The Risk of Bias in Non-randomized Studies-of Interventions (ROB-2) tool evaluated bias, and a PICOS criteria table guided result construction. Revman 5.4 analyzed outcomes such as Lysholm score, VAS score, KSS, WOMAC score, cartilage volume, and defect size using MRI. This systematic review adhered to PRISMA guidelines. RESULT: Nine studies met the final inclusion criteria. Meta-analysis revealed a significant improvement in Lysholm score (MD: 17.89; 95% CI: 16.01, 19.77; I2 = 0%, P = 0.56), a notable reduction in VAS score (MD: -2.62; 95% CI: -2.83, -2.41; I2 = 99%, P < 0.00001), elevated KSS (MD: 29.59; 95% CI: 27.66, 31.52; I2 = 95%, P < 0.0001), and reduced WOMAC score (MD: -12.38; 95% CI: -13.75, -11.01; I2 = 99%, P < 0.0001). CONCLUSIONS: Arthroscopic guided high-dose subchondral application of primary cultured synovial MSCs in popliteal PRP media with HA effectively regenerates cartilage defects and improves clinical outcomes in early-stage osteoarthritis. Clarification of MSC sources and quantities enhances the understanding of this promising treatment modality.

Efficacy and safety of extracorporeal shock wave therapy combined with sodium hyaluronate in treatment of knee osteoarthritis: a systematic review and Meta-analysis.

OBJECTIVE: To assess the efficacy and safety of extracorporeal shockwave therapy (ESWT) combined with sodium hyaluronate (HA) for the treatment of knee osteoarthritis (KOA). METHODS: PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang database, China Science and Technology Journal Database, and SinoMed were searched from inception to July 2020. The quality of the randomized controlled trials was evaluated independently by two reviewers according to the criteria in the Cochrane Collaboration for Systematic Reviews. The identified articles were then screened individually using EndnoteX9 for eligibility in this Meta-analysis. The heterogeneity among the articles was evaluated using I2. RESULTS: A total of 17 studies, comprising 2000 individuals, were included in this Meta-analysis. The results showed that a significant improvement was observed in knee pain and function based on the clinical efficacy of ESWT combined with HA. Statistical analysis of clinical efficacy showed that [relative risk (RR) = 1.21, 95% confidence interval (CI) (1.12, 1.30), P < 0.01]. Statistical analysis of visual analog scale showed that [standardized mean difference (SMD) = －2.84, 95%CI (－4.01, －1.66), P < 0.01]. Western Ontario and McMaster University osteoarthritis index statistical analysis showed that [SMD = －1.57, 95% CI (－2.52, －0.61), P < 0.01]. Lysholm score statistical analysis showed that [SMD = 1.71, 95% CI (0.98, 2.44), P < 0.01]. In addition, only minor side effects, such as redness and swelling of the skin, were observed. CONCLUSIONS: Medium to low quality evidence showed that ESWT combined with HA offers an inexpensive, well-tolerated, safe, and effective method to improve pain and functionality in patients with KOA. However, tightly controlled, randomized, large multicenter trials are warranted to validate the current findings.

Miao medicine Gu Yan Xiao tincture inhibits mTOR to stimulate chondrocyte autophagy in a rabbit model of osteoarthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: The Gu Yan Xiao tincture, a blend of traditional Chinese herbs, is traditionally used for osteoarthritis and related pain. This study investigated its mechanism of action in order to rationalize and validate its therapeutic use. AIM OF THE STUDY: This study analyzed, in a rabbit model of knee osteoarthritis, whether and how Gu Yan Xiao tincture exerts therapeutic benefits by modulating chondrocyte autophagy. MATERIALS AND METHODS: The active constituents within the GYX tincture were identified using liquid chromatography-mass spectrometry. The rabbit model was established by injecting animals with type II collagenase intra-articularly, and the effects of topically applied tincture were examined on osteoarthritis lesions of the knee using histopathology, micro-computed tomography and x-ray imaging. Effects of the tincture were also evaluated on levels of inflammatory cytokines, matrix metalloproteases, and autophagy in chondrocytes. As a positive control, animals were treated with sodium diclofenac. RESULTS: The tincture mitigated the reduction in joint space, hyperplasia of the synovium and matrix metalloproteases in serum that occurred after injection of type II collagenase in rabbits. These therapeutic effects were associated with inhibition of mTOR and activation of autophagy in articular chondrocytes. Inhibiting mTOR with rapamycin potentiated the therapeutic effects of the tincture, while inhibiting autophagy with 3-methyladenine antagonized them. CONCLUSIONS: Gu Yan Xiao tincture mitigates tissue injury in a rabbit model of osteoarthritis, at least in part by inhibiting mTOR and thereby promoting autophagy in chondrocytes. These results rationalize the use of the tincture not only against osteoarthritis but also potentially other diseases involving inhibition of autophagy in bones and joints.

Proteome-Wide Mendelian Randomization and Colocalization Analysis Identify Therapeutic Targets for Knee and Hip Osteoarthritis.

Osteoarthritis (OA) is a common degenerative disease. Although some biomarkers and drug targets of OA have been discovered and employed, limitations and challenges still exist in the targeted therapy of OA. Mendelian randomization (MR) analysis has been regarded as a reliable analytic method to identify effective therapeutic targets. Thus, we aimed to identify novel therapeutic targets for OA and investigate their potential side effects based on MR analysis. In this study, two-sample MR, colocalization analysis, summary-data-based Mendelian randomization (SMR) and Mendelian randomization phenome-wide association study (MR-PheWAS) were conducted. We firstly analyzed data from 4907 plasma proteins to identify potential therapeutic targets associated with OA. In addition, blood expression quantitative trait loci (eQTLs) data sources were used to perform additional validation. A protein-protein interaction (PPI) network was also constructed to delve into the interactions among identified proteins. Then, MR-PheWASs were utilized to assess the potential side effects of core therapeutic targets. After MR analysis and FDR correction, we identified twelve proteins as potential therapeutic targets for knee OA or hip OA. Colocalization analysis and additional validation supported our findings, and PPI networks revealed the interactions among identified proteins. Finally, we identified MAPK3 (OR = 0.855, 95% CI: 0.791-0.923, p = 6.88 × 10-5) and GZMK (OR = 1.278, 95% CI: 1.131-1.444, p = 8.58 × 10-5) as the core therapeutic targets for knee OA, and ITIH1 (OR = 0.847, 95% CI: 0.784-0.915, p = 2.44 × 10-5) for hip OA. A further MR phenome-wide association study revealed the potential side effects of treatments targeting MAPK3, GZMK, and ITIH1. This comprehensive study indicates twelve plasma proteins with potential roles in knee and hip OA as therapeutic targets. This advancement holds promise for the progression of OA drug development, and paves the way for more efficacious treatments of OA.

Association of long-term use of non-steroidal anti-inflammatory drugs with knee osteoarthritis: a prospective multi-cohort study over 4-to-5 years.

This study examines the long-term impact of non-steroidal anti-inflammatory drugs (NSAIDs) on the progression of symptoms and structural deterioration of the joint in knee osteoarthritis. The study analyzes data from 4197 participants (8394 knees) across the Osteoarthritis Initiative (OAI), Multicenter Osteoarthritis Study (MOST), and Cohort Hip and Cohort Knee (CHECK) over 4-to-5 years. Adjustments were made for major covariates. We focussed on binary outcomes to assess the presence or absence of significant changes. We found that, relative to non-users, individuals using NSAIDs long-term were significantly more likely to experience aggravated symptoms exceeding the minimally clinically important difference, specifically, pain (OR: 2.04, 95% CI: 1.66-2.49), disability (OR: 2.21, 95% CI: 1.74-2.80), and stiffness (OR: 1.58, 95% CI: 1.29-1.93). Long-term users also faced a higher probability than non-users of having total knee replacement (OR: 3.13, 95% CI: 2.08-4.70), although no significant difference between long-term users and non-users was observed for structural deterioration in the knee joint (OR: 1.25, 95% CI: 0.94-1.65). While acknowledging the limitations of this study due to its observational design and the potential for bidirectional causality, these findings suggest that long-term NSAID use could accelerate the progression to total knee replacement by markedly exacerbating symptoms.

Effects of alendronate on cartilage lesions and micro-architecture deterioration of subchondral bone in patellofemoral osteoarthritic ovariectomized rats with patella-baja.

BACKGROUND: Patellofemoral osteoarthritis (PFJOA) is a subtype of knee OA, which is one of the main causes of anterior knee pain. The current study found an increased prevalence of OA in postmenopausal women, called postmenopausal OA. Therefore, we designed the ovariectomized rat model of patella baja-induced PFJOA. Alendronate (ALN) inhibits osteoclast-mediated bone loss, and has been reported the favorable result of a potential intervention option of OA treatment. However, the potential effects of ALN treatment on PFJOA in the ovariectomized rat model are unknown and need further investigation prior to exploration in the clinical research setting. In this study, the effects of ALN on articular cartilage degradation and subchondral bone microstructure were assessed in the ovariectomized PFJOA rat model for 10 weeks. METHODS: Patella baja and estrogen withdrawal were induced by patellar ligament shortening (PLS) and bilateral ovariectmomy surgeries in 3-month-old female Sprague-Dawley rats, respectively. Rats were randomly divided into five groups (n = 8): Sham + V; OVX + V, Sham + PLS + V, OVX + PLS + V, OVX + PLS + ALN (ALN: 70 µg/kg/week). Radiography was performed to evaluate patellar height ratios, and the progression of PFJOA was assessed by macroscopic and microscopic analyses, immunohistochemistry and micro-computed tomography (micro-CT). RESULTS: Our results found that the patella baja model prepared by PLS can successfully cause degeneration of articular cartilage and subchondral bone, resulting in changes of PFJOA. OVX caused a decrease in estrogen levels in rats, which aggravated the joint degeneration caused by PFJOA. Early application of ALN can delay the degenerative changes of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent, improve and maintain the micrometabolism and structural changes of cartilage and subchondral bone. CONCLUSION: The early application of ALN can delay the destruction of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent.

Structure-Guided Discovery of Potent and Selective CLK2 Inhibitors for the Treatment of Knee Osteoarthritis.

Osteoarthritis is the most common joint disorder. However, there are no disease-modifying drugs approved for OA treatment. CDC2-like kinase 2 (CLK2) could modulate Wnt signaling via alternative splicing of Wnt target genes and further affect bone differentiation, chondrocyte function, and inflammation, making CLK2 an attractive target for OA therapy. In this study, we designed and synthesized a series of highly potent CLK2 inhibitors based on Indazole 1. Among them, compound LQ23 showed more elevated inhibitory activity against CLK2 than the lead compound (IC50, 1.4 nM) with high CLK2/CLK3 selectivity (>70-fold). Furthermore, LQ23 showed outstanding antiosteoarthritis effects in vitro and in vivo, with the roles specific in decreased inflammatory cytokines, downregulated cartilage degradative enzymes, and increased joint cartilage via suppressing CLK2/Wnt signaling pathway. Overall, these data support LQ23 as a potential candidate for intra-articular knee OA therapy, leveraging its unique mechanism of action for targeted treatment.

Melatonin is a potential novel analgesic agent for osteoarthritis: Evidence from cohort studies in humans and preclinical research in rats.

Melatonin exhibits potential for pain relief and long-term safety profile. We examined the analgesic effects of oral melatonin on osteoarthritis (OA) and investigated the underlying mechanism. Using data from a UK primary care database, we conducted a cohort study in individuals with OA to compare the number of oral analgesic prescriptions and the risk of knee/hip replacement between melatonin initiators and hypnotic benzodiazepines (i.e., active comparator) initiators using quantile regression models and Cox-proportional hazard models, respectively. To elucidate causation, we examined the effects of melatonin on pain behaviors and explored several metabolites that may serve as potential regulatory agents of melatonin in the monoiodoacetate rat model of OA. Using data from another community-based cohort study, that is, the Xiangya OA Study, we verified the association between the key serum metabolite and incident symptomatic knee OA. Compared with the hypnotic benzodiazepines cohort (n = 8135), the melatonin cohort (n = 813) had significantly fewer subsequent prescriptions of oral analgesics (50th percentile: 5 vs. 7, 75th percentile: 19 vs. 29, and 99th percentile: 140 vs. 162) and experienced a lower risk of knee/hip replacement (hazard ratio = 0.47, 95% Cl: 0.30-0.73) during the follow-up period. In rats, oral melatonin alleviated pain behaviors and increased serum levels of glycine. There was an inverse association between baseline serum glycine levels and the risk of incident symptomatic knee OA in humans (n = 760). In conclusion, our findings indicate that oral melatonin shows significant potential to be a novel treatment for OA pain. The potential role of glycine in its analgesic mechanism warrants further investigation.

Periostial and cartilage morphology in knee osteoarthritis: beneficial effects of supplementation with Pycnogenol® + Centellicum®.

BACKGROUND: The aim of this registry study was to evaluate the progress of osteoarthrosis (OA) symptoms after the intake of a new standardized supplement combination (Pycnogenol® + Centellicum®, both Horphag Research) in a group of subjects with OA. METHODS: Supplemented subjects took daily 150 mg Pycnogenol® + 450 mg Centellicum® for 6 months. Another comparable group of subjects using only standard management (SM) was included as a reference. RESULTS: Forty-five subjects with a mean age of 42 years completed the study, 25 in the supplemented group and 20 in the SM group. There were no safety problems or tolerability issues with the supplements. The two groups, SM and SM + Pycnogenol® + Centellicum® were comparable for age and clinical characteristics at inclusion. The two main ultrasound characteristics of cartilage, its thickness and surface-irregularity were more improved with the supplements. Pain scores, C reactive protein, the level of fitness and the use of extra pain killers (as rescue medication) were all significantly improved at 6 months with the supplement combination compared to SM (P<0.05). Plasma free radicals, pain-free walking distance on treadmill and erythrocyte sedimentation rate (ESR) were significantly improved with the supplements compared to SM. CONCLUSIONS: The morphological improvement - visible with ultrasound - correlates with a decrease in clinical symptoms and with a more efficient ambulation without pain. SM along with the Pycnogenol® Centellicum® combination are useful to avoid drug treatments that may expose patients to some side effects over time.