Regulation of cytokine and chemokine expression by histone lysine methyltransferase MLL1 in rheumatoid arthritis synovial fibroblasts.

Histone lysine methylation is thought to play a role in the pathogenesis of rheumatoid arthritis (RA). We previously reported aberrant expression of the gene encoding mixed-lineage leukemia 1 (MLL1), which catalyzes methylation of histone H3 lysine 4 (H3K4), in RA synovial fibroblasts (SFs). The aim of this study was to elucidate the involvement of MLL1 in the activated phenotype of RASFs. SFs were isolated from synovial tissues obtained from patients with RA or osteoarthritis (OA) during total knee joint replacement. MLL1 mRNA and protein levels were determined after stimulation with tumor necrosis factor α (TNFα). We also examined changes in trimethylation of H3K4 (H3K4me3) levels in the promoters of RA-associated genes (matrix-degrading enzymes, cytokines, and chemokines) and the mRNA levels upon small interfering RNA-mediated depletion of MLL1 in RASFs. We then determined the levels of H3K4me3 and mRNAs following treatment with the WD repeat domain 5 (WDR5)/MLL1 inhibitor MM-102. H3K4me3 levels in the gene promoters were also compared between RASFs and OASFs. After TNFα stimulation, MLL1 mRNA and protein levels were higher in RASFs than OASFs. Silencing of MLL1 significantly reduced H3K4me3 levels in the promoters of several cytokine (interleukin-6 [IL-6], IL-15) and chemokine (C-C motif chemokine ligand 2 [CCL2], CCL5, C-X-C motif chemokine ligand 9 [CXCL9], CXCL10, CXCL11, and C-X3-C motif chemokine ligand 1 [CX3CL1]) genes in RASFs. Correspondingly, the mRNA levels of these genes were significantly decreased. MM-102 significantly reduced the promoter H3K4me3 and mRNA levels of the CCL5, CXCL9, CXCL10, and CXCL11 genes in RASFs. In addition, H3K4me3 levels in the promoters of the IL-6, IL-15, CCL2, CCL5, CXCL9, CXCL10, CXCL11, and CX3CL1 genes were significantly higher in RASFs than OASFs. Our findings suggest that MLL1 regulates the expression of particular cytokines and chemokines in RASFs and is associated with the pathogenesis of RA. These results could lead to new therapies for RA.

Histological and immunohistochemical analyses of articular cartilage during onset and progression of pre- and early-stage osteoarthritis in a rodent model.

Early diagnosis and treatment of pre- and early-stage osteoarthritis (OA) is important. However, the cellular and cartilaginous changes occurring during these stages remain unclear. We investigated the histological and immunohistochemical changes over time between pre- and early-stage OA in a rat model of traumatic injury. Thirty-six male rats were divided into two groups, control and OA groups, based on destabilization of the medial meniscus. Histological and immunohistochemical analyses of articular cartilage were performed on days 1, 3, 7, 10, and 14 postoperatively. Cell density of proteins associated with cartilage degradation increased from postoperative day one. On postoperative day three, histological changes, including chondrocyte death, reduced matrix staining, and superficial fibrillation, were observed. Simultaneously, a compensatory increase in matrix staining was observed. The Osteoarthritis Research Society International score increased from postoperative day seven, indicating thinner cartilage. On postoperative day 10, the positive cell density decreased, whereas histological changes progressed with fissuring and matrix loss. The proteoglycan 4-positive cell density increased on postoperative day seven. These findings will help establish an experimental model and clarify the mechanism of the onset and progression of pre- and early-stage traumatic OA.

A randomized controlled clinical trial of concentrated growth factor combined with sodium hyaluronate in the treatment of temporomandibular joint osteoarthritis.

OBJECTIVE: To investigate the effect of concentrated growth factor (CGF) combined with sodium hyaluronate (SH) on temporomandibular joint osteoarthritis (TMJOA). METHODS: Sixty patients with TMJOA who were diagnosed by cone-beam computed tomography (CBCT) between March 2020 and March 2023 at the Stomatological Hospital of Xi'an Jiaotong University were randomly divided into a control group (n = 30) and an experimental group (n = 30). The patients in the experimental group were treated with CGF + SH, and those in the control group were treated with SH only. The visual analogue scale (VAS) score indicating pain in the temporomandibular joint (TMJ) area; the Helkimo Clinical Dysfunction Index (Di); and changes in condylar CBCT at the first visit and 2 weeks, 3 months and 6 months after treatment were recorded. The CBCT data of the patients in the experimental and control groups were collected, and the three-dimensional CBCT image sequences were imported into Mimics Medical 19.0 software in DICOM format for condylar reconstruction. RESULTS: The VAS scores at 2 weeks, 3 months and 6 months after treatment were significantly lower in the experimental group than in the control group (P < 0.05), and the pain in the experimental group was significantly relieved. The Di was significantly lower in the experimental group than in the control group (P < 0.05), and the clinical function of the TMJ improved. After treatment, the CBCT score was significantly lower in the experimental group than in the control group (P < 0.05), and the condylar bone cortex was obviously repaired. Observation of the condylar bone cortex by three-dimensional reconstruction showed the same results as those obtained by CBCT. CONCLUSION: CGF combined with SH is effective in the treatment of TMJOA and can improve muscle pain, TMJ pain, Impaired TMJ function, Impaired range of movement, Pain on movement of the mandible and promote bone repair. THE REGISTRATION NUMBER (TRN): ChiCTR2400082712. THE DATE OF REGISTRATION: April 5, 2024.

Increased Risk of 90-Day Complications in Patients With Fibromyalgia Undergoing Total Shoulder Arthroplasty.

INTRODUCTION: Anatomic and reverse total shoulder arthroplasties (TSAs) are effective treatment options for end-stage glenohumeral osteoarthritis. Those undergoing TSA may also have fibromyalgia, a musculoskeletal condition. However, the association of fibromyalgia with shorter and longer term outcomes after TSA has not been well characterized. METHODS: Patients undergoing TSA for osteoarthritis indications were identified in the PearlDiver M165 database from January 2016 to October 2022. Exclusion criteria included age younger than 18 years, shoulder infection, neoplasm, or trauma within 90 days before surgery, and inactivity in the database within 90 days of surgery. Patients with fibromyalgia were matched in a 1:4 ratio to patients without based on age, sex, and Elixhauser Comorbidity Index. Ninety-day adverse events were compared using univariable and multivariable analyses. Five-year revision-free survival was compared using the log-rank test. RESULTS: Of 163,565 TSA patients, fibromyalgia was identified for 9,035 (5.52%). After matching, cohorts of 30,770 non-fibromyalgia patients and 7,738 patients with fibromyalgia were identified. Multivariable analyses demonstrated patients with fibromyalgia were at independently increased odds ratios (ORs) for the following 90-day complications (decreasing OR order): urinary tract infection (OR = 4.49), wound dehiscence (OR = 3.63), pneumonia (OR = 3.46), emergency department visit (OR = 3.45), sepsis (OR = 3.15), surgical site infection (OR = 2.82), cardiac events (OR = 2.72), acute kidney injury (OR = 2.65), deep vein thrombosis (OR = 2.48), hematoma (OR = 2.03), and pulmonary embolism (OR = 2.01) (P < 0.05 for each). These individual complications contributed to the increased odds of aggregated minor adverse events (OR = 3.68), all adverse events (OR = 3.48), and severe adverse events (OR = 2.68) (P < 0.05 for each). No statistically significant difference was observed in 5-year revision-free survival between groups. DISCUSSION: This study found TSA patients with fibromyalgia to be at increased risk of adverse events within 90 days of surgery. Proper surgical planning and patient counseling are crucial to this population. Nonetheless, it was reassuring that those with fibromyalgia had similar 5-year revision-free survival compared with those without.

Systematic review and network meta-analysis on the efficacy and safety of parmacotherapy for hand osteoarthritis.

OBJECTIVE: Hand osteoarthritis poses a significant health challenge globally due to its increasing prevalence and the substantial burden on individuals and the society. In current clinical practice, treatment options for hand osteoarthritis encompass a range of approaches, including biological agents, antimetabolic drugs, neuromuscular blockers, anti-inflammatory drugs, hormone medications, pain relievers, new synergistic drugs, and other medications. Despite the diverse array of treatments, determining the optimal regimen remains elusive. This study seeks to conduct a network meta-analysis to assess the effectiveness and safety of various drug intervention measures in the treatment of hand osteoarthritis. The findings aim to provide evidence-based support for the clinical management of hand osteoarthritis. METHODS: We performed a comprehensive search across PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials was conducted until September 15th, 2022, to identify relevant randomized controlled trials. After meticulous screening and data extraction, the Cochrane Handbook's risk of bias assessment tool was applied to evaluate study quality. Data synthesis was carried out using Stata 15.1 software. RESULTS: 21 studies with data for 3965 patients were meta-analyzed, involving 20 distinct Western medicine agents. GCSB-5, a specific herbal complex that mainly regulate pain in hand osteoarthritis, showed the greatest reduction in pain [WMD = -13.00, 95% CI (-26.69, 0.69)]. CRx-102, s specific medication characterized by its significant effect for relieving joint stiffness symptoms, remarkably mitigated stiffness [WMD = -7.50, 95% CI (-8.90, -6.10)]. Chondroitin sulfate displayed the highest incidence of adverse events [RR = 0.26, 95% CI (0.06, 1.22)]. No substantial variation in functional index for hand osteoarthritis score improvement was identified between distinct agents and placebo. CONCLUSIONS: In summary, GCSB-5 and CRx-102 exhibit efficacy in alleviating pain and stiffness in HOA, respectively. However, cautious interpretation of the results is advised. Tailored treatment decisions based on individual contexts are imperative.

Baicalin nanodelivery system based on functionalized metal-organic framework for targeted therapy of osteoarthritis by modulating macrophage polarization.

Intra-articular drugs used to treat osteoarthritis (OA) often suffer from poor pharmacokinetics and stability. Nano-platforms as drug delivery systems for drug delivery are promising for OA therapy. In this study, we reported an M1 macrophage-targeted delivery system Bai@FA-UIO-66-NH2 based on folic acid (FA) -modified metal-organic framework (MOF) loaded with baicalin (Bai) as antioxidant agent for OA therapy. With outstanding biocompatibility and high drug loading efficiency, Bai@FA-UIO-66-NH2 could be specifically uptaken by LPS-induced macrophages to serve as a potent ROS scavenger, gradually releasing Bai at the subcellular level to reduce ROS production, modulate macrophage polarization to M2, leading to alleviation of synovial inflammation in OA joints. The synergistic effect of Bai@FA-UIO-66-NH2 on macrophage polarization and ROS scavenging significantly improved the therapeutic efficacy of OA, which may provide a new insight into the design of OA precision therapy.

Occupational tasks associated with shoulder pain and upper extremity disability: a cross-sectional study in the Johnston County Osteoarthritis Project.

BACKGROUND: Shoulder pain is a leading cause of disability. Occupations requiring high upper extremity demands may put workers at greater risk of shoulder injury and resulting pain. We examined associations of occupation with shoulder pain and upper extremity disability in the Johnston County Osteoarthritis Project. METHODS: Work industry and occupational tasks for the longest job held were collected from participants. At follow-up ranging from 4-10 years later, participants were asked about shoulder symptoms (pain, aching, or stiffness occurring most days of 1 month in the last year) and given a 9-item, modified Disabilities Arm Shoulder and Hand (DASH) questionnaire to categorize disability from 0-4 (none-worst). Logistic regression and cumulative logit regression models were used to estimate associations with prevalent shoulder symptoms and with worse disability category, respectively. Models were adjusted for cohort, age, sex, race, education and time to follow-up. Sex- and race-stratified associations were evaluated. RESULTS: Among 1560 included participants, mean age was 62 years (standard deviation ± 9 years); 32% were men, and 31% were Black. Compared to the managerial/professional industry, higher odds of both shoulder symptoms and worse upper extremity disability were seen for most industrial groups with physically demanding jobs, particularly the service industry. Work that often or always required lifting/moving > 10 lbs. was associated with higher odds of shoulder symptoms. Work that sometimes or always required heavy work while standing was associated with higher odds of shoulder symptoms, and this association was stronger among men and White workers. CONCLUSION: Physically demanding occupations were associated with increased occurrence of shoulder pain and disability. Mitigating specific physical work demands may reduce shoulder-related disability.

ß1-Integrin-Mediated Uptake of Chondrocyte Extracellular Vesicles Regulates Chondrocyte Homeostasis.

Osteoarthritis (OA) is the most prevalent age-related degenerative disorder, which severely reduces the quality of life of those affected. Whilst management strategies exist, no cures are currently available. Virtually all joint resident cells generate extracellular vesicles (EVs), and alterations in chondrocyte EVs during OA have previously been reported. Herein, we investigated factors influencing chondrocyte EV release and the functional role that these EVs exhibit. Both 2D and 3D models of culturing C28I/2 chondrocytes were used for generating chondrocyte EVs. We assessed the effect of these EVs on chondrogenic gene expression as well as their uptake by chondrocytes. Collectively, the data demonstrated that chondrocyte EVs are sequestered within the cartilage ECM and that a bi-directional relationship exists between chondrocyte EV release and changes in chondrogenic differentiation. Finally, we demonstrated that the uptake of chondrocyte EVs is at least partially dependent on ß1-integrin. These results indicate that chondrocyte EVs have an autocrine homeostatic role that maintains chondrocyte phenotype. How this role is perturbed under OA conditions remains the subject of future work.

Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice.

BACKGROUND: Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. MATERIALS AND METHODS: To determine whether Dspp+/- mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/-, and Dspp homozygous (Dspp-/-) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/- mice over time, condyles of Dspp+/- and WT mice were analyzed radiologically, histologically, and immunohistochemically. RESULTS: Micro-CT and histomorphometric analyses revealed that Dspp+/- and Dspp-/- mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp-/- mice which exhibited tooth loss, Dspp+/- mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/- mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/- mice showed increased distribution of osteoclasts in the subchondral bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. CONCLUSIONS: Dspp+/- mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

Association between hyperuricemia and the risk of mortality in patients with osteoarthritis: A study based on the National Health and Nutrition Examination Survey database.

BACKGROUND: The purpose of this study was to evaluate the relationship between hyperuricemia and the risks of all-cause mortality and cardiovascular disease (CVD) mortality in patients with osteoarthritis (OA). METHODS: A retrospective cohort study was performed on 3,971 patients using data from the National Health and Nutrition Examination Survey database between 1999 and 2018. OA was diagnosed through specific questions and responses. The weighted COX regression models were used to explore the factors associated with all-cause mortality/CVD mortality in OA patients. Subgroup analyses were conducted based on age, gender, hypertension, dyslipidemia, CVD, and chronic kidney disease (CKD). Hazard ratio (HR) and 95% confidence interval (95% CI) were measured as the evaluation indexes. RESULTS: During the duration of follow-up time (116.38 ± 2.19 months), 33.69% (1,338 patients) experienced all-cause mortality, and 11.36% (451 patients) died from CVD. Hyperuricemia was associated with higher risks of all-cause mortality (HR: 1.22, 95% CI: 1.06-1.41, P = 0.008) and CVD mortality (HR: 1.32, 95% CI: 1.02-1.72, P = 0.036) in OA patients. Subgroup analyses showed that hyperuricemia was related to the risk of all-cause mortality in OA patients aged >65 years (HR: 1.17, 95% CI: 1.01-1.36, P = 0.042), in all male patients (HR: 1.41, 95% CI: 1.10-1.80, P = 0.006), those diagnosed with hypertension (HR: 1.17, 95% CI: 1.01-1.37, P = 0.049), dyslipidemia (HR: 1.18, 95% CI: 1.01-1.39, P = 0.041), CVD (HR: 1.30, 95% CI: 1.09-1.55, P = 0.004), and CKD (HR: 1.31, 95% CI: 1.01-1.70, P = 0.046). The association between hyperuricemia and a higher risk of CVD mortality was found in OA patients aged ≤ 65 years (HR: 1.90, 95% CI: 1.06-3.41, P = 0.032), who did not suffer from diabetes (HR: 1.36, 95% CI: 1.01-1.86, P = 0.048), who did not suffer from hypertension (HR: 2.56, 95% CI: 1.12-5.86, P = 0.026), and who did not suffer from dyslipidemia (HR: 2.39, 95% CI: 1.15-4.97, P = 0.020). CONCLUSION: These findings emphasize the importance of monitoring serum uric acid levels in OA patients for potentially reducing mortality associated with the disease.

Inverse association of the systemic immune-inflammation index with serum anti-ageing protein Klotho levels in individuals with osteoarthritis: A cross-sectional study.

BACKGROUND: The association between the systemic immune-inflammation index (SII) and the serum soluble-Klotho concentration (pg/ml) in osteoarthritis (OA) patients is unknown. This study aimed to investigate the relationship between the SII and serum soluble-Klotho levels in OA patients. METHODS: All study data were obtained from the National Health and Nutrition Examination Survey (NHANES) database (n = 1852 OA patients; age range = 40-79 years). The SII and serum Klotho measurement data are from the NHANES mobile examination centre. The SII values were divided into quartiles (Q1-4: 0.02-3.36, 3.36-4.78, 4.79-6.70, and 6.70-41.75). A multivariate linear regression model was constructed to evaluate the association between the SII and serum Klotho levels in OA patients; interaction tests were conducted to test the stability of the statistical results. RESULTS: Multivariate linear regression revealed a negative linear relationship between the SII and serum Klotho concentration in OA patients (ß = -6.05; 95% CI: -9.72, -2.39). Compared to Q1, Q4 was associated with lower serum Klotho concentrations (ß = -59.93; 95% CI: -96.57, -23.28). Compared with that of Q1, the ß value of Q2-Q4 showed a downwards trend as the SII increased (Ptrend <0.001). The stratified analysis results indicated that the SII had a greater sensitivity in predicting serum Klotho concentrations in OA patients aged 60-79 years (Pinteraction = 0.028). CONCLUSIONS: There was a significant negative linear correlation between the SII and serum Klotho concentration in OA patients. The SII can serve as a predictive indicator of serum Klotho concentrations in OA patients. Klotho may be a potential anti-inflammatory drug for OA treatment.

Mume Fructus reduces interleukin-1 beta-induced cartilage degradation via MAPK downregulation in rat articular chondrocytes.

Osteoarthritis is the most prevalent type of degenerative arthritis. It is characterized by persistent pain, joint dysfunction, and physical disability. Pain relief and inflammation control are prioritised during osteoarthritis treatment Mume Fructus (Omae), a fumigated product of the Prunus mume fruit, is used as a traditional medicine in several Asian countries. However, its therapeutic mechanism of action and effects on osteoarthritis and articular chondrocytes remain unknown. In this study, we analyzed the anti-osteoarthritis and articular regenerative effects of Mume Fructus extract on rat chondrocytes. Mume Fructus treatment reduced the interleukin-1ß-induced expression of matrix metalloproteinase 3, matrix metalloproteinase 13, and a disintegrin and metalloproteinase with thrombospondin type 1 motifs 5. Additionally, it enhanced collagen type II alpha 1 chain and aggrecan accumulation in rat chondrocytes. Furthermore, Mume Fructus treatment regulated the inflammatory cytokine levels, mitogen-activated protein kinase phosphorylation, and nuclear factor-kappa B activation. Overall, our results demonstrated that Mume Fructus inhibits osteoarthritis progression by inhibiting the nuclear factor-kappa B and mitogen-activated protein kinase pathways to reduce the levels of inflammatory cytokines and prevent cartilage degeneration. Therefore, Mume Fructus may be a potential therapeutic option for osteoarthritis.

No genetic causal association between circulating alpha-tocopherol levels and osteoarthritis, a two-sample Mendelian randomization analysis.

The causal association between vitamin E status and osteoarthritis (OA) remains controversial in previous epidemiological studies. We employed a Mendelian randomization (MR) analysis to explore the causal relationship between circulating alpha-tocopherol levels (main forms of vitamin E in our body) and OA. The instrumental variables (IVs) of circulating alpha-tocopherol levels were obtained from a Genome-wide association study (GWAS) dataset of 7781 individuals of European descent. The outcome of OA was derived from the UK biobank. Two-sample MR analysis was used to estimate the causal relationship between circulating alpha-tocopherol levels and OA. The inverse-variance weighted (IVW) method was the primary analysis in this analysis. We used the MR-Egger method to determine horizontal pleiotropic in this work. The heterogeneity effect of instrumental IVs was detected by MR-Egger and IVW analyses. Sensitivity analysis was performed by removing single nucleotide polymorphism (SNP) one by one. Three SNPs (rs964184, rs2108622, and rs11057830) (P < 5E-8) strongly associated with circulating alpha-tocopherol levels were used in this analysis. The IVW-random effect indicated no causal relationship between circulating alpha-tocopherol levels and clinically diagnosed OA (OR = 0.880, 95% CI 0.626, 1.236, P = 0.461). Similarly, IVW analysis showed no causal association between circulating alpha-tocopherol levels and self-reported OA (OR = 0.980, 95% CI 0.954, 1.006, P = 0.139). Other methods of MR analyses and sensitivity analyses revealed consistent findings. MR-Egger and IVW methods indicated no significant heterogeneity between IVs. The MR-Egger intercept showed no horizontal pleiotropic. The results of this linear Mendelian randomization study indicate no causal association between genetically predicted alpha-tocopherol levels and the progression of OA. Alpha-tocopherol may not provide beneficial and more favorable outcomes for the progression of OA. Further MR analysis based on updated GWASs with more IVs is required to verify the results of our study.

A study on volumetric change of mandibular condyles with osteoarthritis using cone-beam computed tomography.

This study aimed to quantitatively assess three-dimensional changes in the mandibular condyle with osteoarthritis using cone-beam computed tomography (CBCT). Pre- and post-treatment CBCT images of temporomandibular joints (TMJs) from 66 patients were used to assess longitudinal changes in condylar volume within individual patients using 3D slicer software. Total volume difference (dV), net increase (dV + , bone deposition), and net decrease (dV- , bone resorption) after treatment were analyzed based on clinical and radiological factors. Condyles with surface erosion at their first visit showed significantly decreased volume after treatment compared to condyles without erosion (p < 0.05). Amounts of bone resorption and deposition were higher in condyles with surface erosion (both p < 0.01). In patients with condylar erosion, the presence of joint pain was associated with a decrease in condylar volume and an increase in net resorption (both p < 0.01). When both joint pain and condylar erosion were present, patients with parafunctional habits showed reduced condylar volume after treatment (p < 0.05). Condylar volume change after treatment was negatively correlated with the duration of pain relief (R = - 0.501, p < 0.05). These results indicate that condylar erosion and TMJ pain could be significant variables affecting TMJ volume changes after treatment. Establishing appropriate treatment strategies is crucial for managing condylar erosion and TMJ pain.

[The current status and future prospects of mesenchymal stem cell transplantation for the treatment of knee articular cartilage injuries and osteoarthritis].

The prevalence of articular cartilage injuries and osteoarthritis (OA) is high, affecting a wide range of individuals. The self-repair ability of cartilage tissue is poor, and once damaged, it will irreversibly progress to OA. Mesenchymal stem cells (MSCs) play an important role in the field of regenerative medicine and are considered one of the most promising seed cells for cartilage repair and regeneration. In this article, based on the latest clinical research findings from both domestic and international sources, the theoretical basis, treatment goals, significance, sources, characteristics, clinical implementation plans, and efficacy of using MSCs for the treatment of cartilage injuries or osteoarthritis are reviewed. The article also discusses the challenges faced and future directions that need to be addressed in the clinical application of MSCs.

Pain control and functional recovery as therapeutic goals in patients with chronic musculoskeletal pain: two experiences with tapentadol hydrochloride.

OBJECTIVE: This study aimed to evaluate pain control, functioning, and quality of life (QoL) recovery in patients with chronic low back pain (cLBP) or post-traumatic osteoarthritis (OA) pain in the ankle/foot area, treated with tapentadol prolonged release and unresponsive to other treatments. PATIENTS AND METHODS: Two observational retrospective studies were conducted using clinical practice datasets of patients with chronic pain in cLBP and OA foot/ankle at different time points (total follow-up=60-90 days). The studies assessed pain intensity by the Numerical Rating Scale (NRS) pain scale (patients were classified as responder in case of ≥30% pain reduction), QoL by the 5-level EQ-5D (EQ-5D-5L) questionnaire, patient satisfaction by the 7-point Patients' Global Impression of Change (PGIC) scale; cLBP health status by the Roland Morris Disability Questionnaire (RMDQ); foot and ankle functional status by European Foot and Ankle Society (EFAS) score; and treatment-related AEs. RESULTS: For the cLBP setting, 37 patients were enrolled, of which 86.50% were classified as responders (n=32; CI: 75.5% ÷ 97.5%). For the foot/ankle OA pain setting, 21 patients were enrolled. Pain assessment at final follow-up was available only for 11 patients, of which 72.73% (n=8; CI: 39.0% ÷ 94.0%) were classified as responders. Statistically significant improvements were seen in the RMDQ, EQ-5D-5L, and PGIC scores in cLBP. Improvements in the EFAS, EQ-5D-5L, and PGIC scores were seen in OA as well. The incidence of treatment-related adverse reactions was low in both studies. CONCLUSIONS: In the study population, tapentadol prolonged release was effective and well tolerated in treating cLBP and post-traumatic foot/ankle OA chronic pain when used in a multimodal manner. The reduction in pain was accompanied by clinically relevant improvements in patients' functionality and QoL.

Emerging technology has a brilliant future: the CRISPR-Cas system for senescence, inflammation, and cartilage repair in osteoarthritis.

Osteoarthritis (OA), known as one of the most common types of aseptic inflammation of the musculoskeletal system, is characterized by chronic pain and whole-joint lesions. With cellular and molecular changes including senescence, inflammatory alterations, and subsequent cartilage defects, OA eventually leads to a series of adverse outcomes such as pain and disability. CRISPR-Cas-related technology has been proposed and explored as a gene therapy, offering potential gene-editing tools that are in the spotlight. Considering the genetic and multigene regulatory mechanisms of OA, we systematically review current studies on CRISPR-Cas technology for improving OA in terms of senescence, inflammation, and cartilage damage and summarize various strategies for delivering CRISPR products, hoping to provide a new perspective for the treatment of OA by taking advantage of CRISPR technology.

SKP2-mediated ubiquitination and degradation of KLF11 promotes osteoarthritis via modulation of JMJD3/NOTCH1 pathway.

Osteoarthritis (OA) is the main cause of cartilage damage and disability. This study explored the biological function of S-phase kinase-associated protein 2 (SKP2) and Kruppel-like factor 11 (KLF11) in OA progression and its underlying mechanisms. C28/I2 chondrocytes were stimulated with IL-1ß to mimic OA in vitro. We found that SKP2, Jumonji domain-containing protein D3 (JMJD3), and Notch receptor 1 (NOTCH1) were upregulated, while KLF11 was downregulated in IL-1ß-stimulated chondrocytes. SKP2/JMJD3 silencing or KLF11 overexpression repressed apoptosis and extracellular matrix (ECM) degradation in chondrocytes. Mechanistically, SKP2 triggered the ubiquitination and degradation of KLF11 to transcriptionally activate JMJD3, which resulted in activation of NOTCH1 through inhibiting H3K27me3. What's more, the in vivo study found that KLF11 overexpression delayed OA development in rats via restraining apoptosis and maintaining the balance of ECM metabolism. Taken together, ubiquitination and degradation of KLF11 regulated by SKP2 contributed to OA progression by activation of JMJD3/NOTCH1 pathway. Our findings provide promising therapeutic targets for OA.

Three-Dimensional Printed Total Talus Replacement with a Concurrent Total Ankle Arthroplasty as a Personalized Approach for Advanced Ankle Osteoarthritis A Case Repor.

Ankle arthritis is becoming more common and can be pain-ful and debilitating. As the disease progresses, degenera-tive cystic changes may be found in the distal fibula, distal tibia, and talus. After failure of non-operative modalities, arthrodesis is often considered the surgical intervention of choice, but this leaves the patient with reduced range of motion, altered gait, and can negatively impact adjacent joints of the foot. Total ankle arthroplasty has been found to be an effective surgical option for ankle arthritis but is contraindicated in patients with talar collapse. When this is the case, a more personalized approach for preserving ankle motion is necessary. We present the case of a 65-year-old male with severe right ankle arthritis and talar collapse treated with a custom three-dimensionally printed talus and concurrent total ankle replacement with 2-year follow-up.

Identification and verification of a novel signature that combines cuproptosis-related genes with ferroptosis-related genes in osteoarthritis using bioinformatics analysis and experimental validation.

BACKGROUND: Exploring the pathogenesis of osteoarthritis (OA) is important for its prevention, diagnosis, and treatment. Therefore, we aimed to construct novel signature genes (c-FRGs) combining cuproptosis-related genes (CRGs) with ferroptosis-related genes (FRGs) to explore the pathogenesis of OA and aid in its treatment. MATERIALS AND METHODS: Differentially expressed c-FRGs (c-FDEGs) were obtained using R software. Enrichment analysis was performed and a protein-protein interaction (PPI) network was constructed based on these c-FDEGs. Then, seven hub genes were screened. Three machine learning methods and verification experiments were used to identify four signature biomarkers from c-FDEGs, after which gene set enrichment analysis, gene set variation analysis, single-sample gene set enrichment analysis, immune function analysis, drug prediction, and ceRNA network analysis were performed based on these signature biomarkers. Subsequently, a disease model of OA was constructed using these biomarkers and validated on the GSE82107 dataset. Finally, we analyzed the distribution of the expression of these c-FDEGs in various cell populations. RESULTS: A total of 63 FRGs were found to be closely associated with 11 CRGs, and 40 c-FDEGs were identified. Bioenrichment analysis showed that they were mainly associated with inflammation, external cellular stimulation, and autophagy. CDKN1A, FZD7, GABARAPL2, and SLC39A14 were identified as OA signature biomarkers, and their corresponding miRNAs and lncRNAs were predicted. Finally, scRNA-seq data analysis showed that the differentially expressed c-FRGs had significantly different expression distributions across the cell populations. CONCLUSION: Four genes, namely CDKN1A, FZD7, GABARAPL2, and SLC39A14, are excellent biomarkers and prospective therapeutic targets for OA.