Assessing the causal relationship of birth weight and childhood obesity on osteoarthritis: a Mendelian randomization study.

Obesity is associated with osteoarthritis (OA), but few studies have used fetal origin to explore the association. Our study aims to disentangle the causality between birth weight, childhood obesity, and adult OA using Mendelian randomization (MR). We identified single nucleotide polymorphisms (SNPs) related to birth weight (n = 298,142) and childhood obesity (n = 24,160) from two genome-wide association studies contributed by the Early Growth Genetics Consortium. Summary statistics of OA and its phenotypes (knee, hip, spine, hand, thumb, and finger OA) from the Genetics of Osteoarthritis Consortium (n = 826,690) were used to estimate the effects of SNPs on OA. Multivariable MR (MVMR) was conducted to investigate the independent effects of exposures. It turned out that genetically predicted standard deviation increase in birth weight was not associated with OA. In contrast, there was a marginally positive effect of childhood obesity on total [odds ratio (OR) = 1.07, 95% confidence interval (CI) = 1.00, 1.15 using IVW], knee (OR = 1.13, 95% CI = 1.05, 1.22 using weighted median), hip (OR = 1.13, 95% CI = 1.04, 1.24 using IVW), and spine OA (OR = 1.12, 95% CI = 1.03, 1.22 using IVW), but not hand, thumb, or finger OA. MVMR indicated a potential adulthood body mass index-dependent causal pathway between childhood obesity and OA. In conclusion, no association of birth weight with OA was suggested. Childhood obesity, however, showed a causality with OA in weight-bearing joints, which seems to be a general association of obesity with OA.

The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration.

It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.

Exercise following joint distraction inhibits muscle wasting and delays the progression of post-traumatic osteoarthritis in rabbits by activating PGC-1α in skeletal muscle.

OBJECTIVE: Muscle wasting frequently occurs following joint trauma. Previous research has demonstrated that joint distraction in combination with treadmill exercise (TRE) can mitigate intra-articular inflammation and cartilage damage, consequently delaying the advancement of post-traumatic osteoarthritis (PTOA). However, the precise mechanism underlying this phenomenon remains unclear. Hence, the purpose of this study was to examine whether the mechanism by which TRE following joint distraction delays the progression of PTOA involves the activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as its impact on muscle wasting. METHODS: Quadriceps samples were collected from patients with osteoarthritis (OA) and normal patients with distal femoral fractures, and the expression of PGC-1α was measured. The hinged external fixator was implanted in the rabbit PTOA model. One week after surgery, a PGC-1α agonist or inhibitor was administered for 4 weeks prior to TRE. Western blot analysis was performed to detect the expression of PGC-1α and Muscle atrophy gene 1 (Atrogin-1). We employed the enzyme-linked immunosorbent assay (ELISA) technique to examine pro-inflammatory factors. Additionally, we utilized quantitative real-time polymerase chain reaction (qRT-PCR) to analyze genes associated with cartilage regeneration. Synovial inflammation and cartilage damage were evaluated through hematoxylin-eosin staining. Furthermore, we employed Masson's trichrome staining and Alcian blue staining to analyze cartilage damage. RESULTS: The decreased expression of PGC-1α in skeletal muscle in patients with OA is correlated with the severity of OA. In the rabbit PTOA model, TRE following joint distraction inhibited the expressions of muscle wasting genes, including Atrogin-1 and muscle ring finger 1 (MuRF1), as well as inflammatory factors such as interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in skeletal muscle, potentially through the activation of PGC-1α. Concurrently, the production of IL-1ß, IL-6, TNF-α, nitric oxide (NO), and malondialdehyde (MDA) in the synovial fluid was down-regulated, while the expression of type II collagen (Col2a1), Aggrecan (AGN), SRY-box 9 (SOX9) in the cartilage, and superoxide dismutase (SOD) in the synovial fluid was up-regulated. Additionally, histological staining results demonstrated that TRE after joint distraction reduced cartilage degeneration, leading to a significant decrease in OARSI scores.TRE following joint distraction could activate PGC-1α, inhibit Atrogin-1 expression in skeletal muscle, and reduce C-telopeptides of type II collagen (CTX-II) in the blood compared to joint distraction alone. CONCLUSION: Following joint distraction, TRE might promote the activation of PGC-1α in skeletal muscle during PTOA progression to exert anti-inflammatory effects in skeletal muscle and joint cavity, thereby inhibiting muscle wasting and promoting cartilage regeneration, making it a potential therapeutic intervention for treating PTOA.

Increased alcohol intake is associated with radiographic severity of knee and hand osteoarthritis in men.

Observational studies have shown controversial associations between alcohol intake and radiographic osteoarthritis (OA). This study investigated whether this association was causal using a Mendelian randomization (MR) study in a population-based cohort in Korean. The study enrolled 2429 subjects (1058 men, 1371 women) from the Dong-gu Study. X-rays of the hand and knee joints were scored using a semi-quantitative grading system to calculate the total score of the hand and knee joints. ALDH2 rs671 genotyping was performed by high-resolution melting analysis. MR instrumental variable analysis and observational multivariable regression analysis were used to estimate the association between genetically predicted alcohol intake and the radiographic severity of OA. Subjects with the G/G genotype had a higher current alcohol intake than those with the G/A and A/A genotypes in both men and women (all P < 0.001). Men with the G/G genotype had higher total knee (P < 0.001) and hand scores (P = 0.042) compared to those with the G/A and A/A genotypes after adjusting for age and body mass index, but not in women. In the observational multivariable regression analysis, each alcohol drink per day in men was associated with increased knee (P = 0.001) and hand joint scores (P = 0.013) after adjustment, but not in women. In our MR analysis, utilizing ALDH2 rs671 genotypes as instrumental variables for alcohol consumption, has shown a significant link between each additional daily alcohol drink and increased radiographic joint severity in men.

Farming and the risk of developing osteoarthritis in Alberta, Canada.

INTRODUCTION: Because farming is a physically demanding occupation, farmers may be susceptible to developing osteoarthritis (OA). The aim of this study was to determine the risk of developing OA in Canadian farm, non-farm rural and urban residents. METHODS: A retrospective cohort study of five Alberta health administrative databases examined the risk of developing OA among three groups: farm (n=143 431), non-farm rural (n=143 431) and urban (n=143 431) residents over the fiscal years 2000-2001 through 2020-2021. The algorithm for OA ascertainment defined cases based on criteria including one hospital admission, two physician visits within a 2-year interval, or two ambulatory care visits within 2 years. Incidence rates, lifetime risk, and mortality rates were calculated. Cox proportional hazard models compared the incidence of OA for the three groups over the 21 years. RESULTS: A total of 26 957 OA cases were identified among 1 706 256 person-years (PYs) in the farm cohort. The crude incidence rate of OA over a period of 21 years ranged from 19.1 (95% confidence interval (CI) 18.6-19.6) per 1000 PYs in 2001 to 10.0 (95% CI 9.6-10.5) per 1000 PYs in 2021. The overall incidence rate was higher in the farm group (15.8 (95%CI 15.6-16.0) per 1000 PYs) as compared to the non-farm rural (14.7 (95%CI 14.5-14.9) per 1000 PYs) and the urban groups (13.3 (95%CI 13.1-13.4) per 1000 PYs). After adjusting for age and sex, the farm (6%; 95%CI 4-8%), and non-farm rural (9%; 95%CI 7-12%) groups had higher incidence rates than the urban group. The unadjusted non-injury mortality rate for the farm group with OA was lower (13.2 (95%CI 12.9-13.5) per 1000 PYs) than both the urban (14.5; 95%CI 14.1-14.8) and rural (18.0; 95%CI 17.6-18.4) groups. After adjusting for mortality, the lifetime risk of developing OA was 27.7% for farm residents, 25.6% for the non-farm rural cohort, and 24.0% for the urban cohort. CONCLUSION: When accounting for age and sex, farm and non-farm rural residents have a higher risk of developing OA as compared to the urban population. The higher mortality-adjusted lifetime risk of developing OA among farm residents highlights the necessity of specific interventions aimed at reducing the impact of this condition in rural communities. Further research is required to identify specific occupational and lifestyle risk factors associated with OA among farmers and to develop effective strategies for prevention and management.

Gene expression and immune infiltration analysis comparing lesioned and preserved subchondral bone in osteoarthritis.

Background: Osteoarthritis (OA) is a degenerative disease requiring additional research. This study compared gene expression and immune infiltration between lesioned and preserved subchondral bone. The results were validated using multiple tissue datasets and experiments. Methods: Differentially expressed genes (DEGs) between the lesioned and preserved tibial plateaus of OA patients were identified in the GSE51588 dataset. Moreover, functional annotation and protein-protein interaction (PPI) network analyses were performed on the lesioned and preserved sides to explore potential therapeutic targets in OA subchondral bones. In addition, multiple tissues were used to screen coexpressed genes, and the expression levels of identified candidate DEGs in OA were measured by quantitative real-time polymerase chain reaction. Finally, an immune infiltration analysis was conducted. Results: A total of 1,010 DEGs were identified, 423 upregulated and 587 downregulated. The biological process (BP) terms enriched in the upregulated genes included "skeletal system development", "sister chromatid cohesion", and "ossification". Pathways were enriched in "Wnt signaling pathway" and "proteoglycans in cancer". The BP terms enriched in the downregulated genes included "inflammatory response", "xenobiotic metabolic process", and "positive regulation of inflammatory response". The enriched pathways included "neuroactive ligand-receptor interaction" and "AMP-activated protein kinase signaling". JUN, tumor necrosis factor α, and interleukin-1ß were the hub genes in the PPI network. Collagen XI A1 and leucine-rich repeat-containing 15 were screened from multiple datasets and experimentally validated. Immune infiltration analyses showed fewer infiltrating adipocytes and endothelial cells in the lesioned versus preserved samples. Conclusion: Our findings provide valuable information for future studies on the pathogenic mechanism of OA and potential therapeutic and diagnostic targets.

IL24 Expression in Synovial Myofibroblasts: Implications for Female Osteoarthritis Pain through Propensity Score Matching Analysis.

(1) Introduction: Despite documented clinical and pain discrepancies between male and female osteoarthritis (OA) patients, the underlying mechanisms remain unclear. Synovial myofibroblasts, implicated in synovial fibrosis and OA-related pain, offer a potential explanation for these sex differences. Additionally, interleukin-24 (IL24), known for its role in autoimmune disorders and potential myofibroblast production, adds complexity to understanding sex-specific variations in OA. We investigate its role in OA and its contribution to observed sex differences. (2) Methods: To assess gender-specific variations, we analyzed myofibroblast marker expression and IL24 levels in synovial tissue samples from propensity-matched male and female OA patients (each n = 34). Gene expression was quantified using quantitative polymerase chain reaction (qPCR). The association between IL24 expression levels and pain severity, measured by a visual analog scale (VAS), was examined to understand the link between IL24 and OA pain. Synovial fibroblast subsets, including CD45-CD31-CD39- (fibroblast) and CD45-CD31-CD39+ (myofibroblast), were magnetically isolated from female patients (n = 5), and IL24 expression was compared between these subsets. (3) Results: Females exhibited significantly higher expression of myofibroblast markers (MYH11, ET1, ENTPD2) and IL24 compared to males. IL24 expression positively correlated with pain severity in females, while no correlation was observed in males. Further exploration revealed that the myofibroblast fraction highly expressed IL24 compared to the fibroblast fraction in both male and female samples. There was no difference in the myofibroblast fraction between males and females. (4) Conclusions: Our study highlights the gender-specific role of myofibroblasts and IL24 in OA pathogenesis. Elevated IL24 levels in females, correlating with pain severity, suggest its involvement in OA pain experiences. The potential therapeutic implications of IL24, demonstrated in autoimmune disorders, open avenues for targeted interventions. Notwithstanding the limitations of the study, our findings contribute to understanding OA's multifaceted nature and advocate for future research exploring mechanistic underpinnings and clinical applications of IL24 in synovial myofibroblasts. Additionally, future research directions should focus on elucidating the precise mechanisms by which IL24 contributes to OA pathology and exploring its potential as a therapeutic target for personalized medicine approaches.

Spinosin ameliorates osteoarthritis through enhancing the Nrf2/HO-1 signaling pathway.

Osteoarthritis (OA) is a common degenerative joint disease in the elderly, while oxidative stress-induced chondrocyte degeneration plays a key role in the pathologic progression of OA. One possible reason is that the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), which acts as the intracellular defense factor against oxidative stress, is significantly inhibited in chondrocytes. Spinosin (SPI) is a potent Nrf2 agonist, but its effect on OA is still unknown. In this study, we found that SPI can alleviate tert-Butyl hydroperoxide (TBHP)-induced extracellular matrix degradation of chondrocytes. Additionally, SPI can effectively activate Nrf2, heme oxygenase-1 (HO-1), and NADPH quinone oxidoreductase 1 (NQO1) in chondrocytes under the TBHP environment. When Nrf2 was silenced by siRNA, the cartilage protective effect of SPI was also weakened. Finally, SPI showed good alleviative effects on OA in mice. Thus, SPI can ameliorate oxidative stress-induced chondrocyte dysfunction and exhibit a chondroprotective effect through activating the Nrf2/HO-1 pathway, which may provide a novel and promising option for the treatment of OA.

Association between the dietary inflammatory index and all-cause mortality in osteoarthritis.

BACKGROUND: To investigate the association between the Dietary Inflammatory Index (DII) and all-cause mortality in patients with osteoarthritis (OA). METHODS: In this retrospective cohort study, data on OA patients were obtained from the National Health and Nutrition Examination Survey (NHANES) 2003-2018. OA diagnosis was self-reported. The study population was divided into low and high DII groups based on the DII's median. All-cause mortality was the outcome, which was determined via linkage to the National Death Index (NDI) until 31 December 2019. Multivariable Cox regression analyses were employed to investigate the association between the DII and all-cause mortality. The survival of the low and high DII groups was exhibited by Kaplan-Meier curves. Furthermore, subgroup analyses were carried out in terms of age and comorbidity. RESULTS: A total of 3804 patients with OA were included, with 1902 (50%) in the low DII group and 1902 (50%) in the high DII group. Patients with a high DII had a significantly greater risk of all-cause mortality than those with a low DII (HR = 1.21, 95%CI: 1.02-1.44, P = 0.025). A high DII was associated with a significantly increased risk of all-cause mortality compared with a low DII in patients aged ≥ 65 years [hazard ratio (HR) = 1.28, 95% confidence level (CI): 1.07-1.53, P = 0.006). Hypertensive patients with a high DII had a significantly greater risk of all-cause mortality than those with a low DII (HR = 1.25, 95%CI: 1.03-1.52, P = 0.025). For patients with cardiovascular disease (CVD), a high DII was associated with a significantly higher risk of all-cause mortality than a low DII (HR = 1.43, 95%CI: 1.17-1.75, P < 0.001). A high DII was associated with a significantly greater risk of all-cause mortality, as compared with a low DII in patients with chronic kidney disease (CKD) (HR = 1.22, 95%CI: 1.02-1.45, P = 0.026). CONCLUSION: The DII was positively associated with the risk of all-cause mortality in patients with OA. This association differed by age, hypertension, CVD, and CKD. Adherence to diet with a low DII may be beneficial in prognosis improvement.

Dysregulation of Glypicans and Notum in Osteoarthritis: Plasma Levels, Bone Marrow Mesenchymal Stromal Cells and Osteoblasts.

In this study of the alterations of Glypicans 1 to 6 (GPCs) and Notum in plasma, bone marrow mesenchymal stromal cells (BM-MSCs) and osteoblasts in Osteoarthritis (OA), the levels of GPCs and Notum in the plasma of 25 patients and 24 healthy subjects were measured. In addition, BM-MSCs from eight OA patients and eight healthy donors were cultured over a period of 21 days using both a culture medium and an osteogenic medium. Protein and gene expression levels of GPCs and Notum were determined using ELISA and qPCR at 0, 7, 14 and 21 days. GPC5 and Notum levels decreased in the plasma of OA patients, while the BM-MSCs of OA patients showed downexpression of GPC6 and upregulation of Notum. A decrease in GPC5 and Notum proteins and an increase in GPC3 were found. During osteogenic differentiation, elevated GPCs 2, 4, 5, 6 and Notum mRNA levels and decreased GPC3 were observed in patients with OA. Furthermore, the protein levels of GPC2, GPC5 and Notum decreased, while the levels of GPC3 increased. Glypicans and Notum were altered in BM-MSCs and during osteogenic differentiation from patients with OA. The alterations found point to GPC5 and Notum as new candidate biomarkers of OA pathology.

Protective Effects of an Oligo-Fucoidan-Based Formula against Osteoarthritis Development via iNOS and COX-2 Suppression following Monosodium Iodoacetate Injection.

Osteoarthritis (OA) is a debilitating joint disorder characterized by cartilage degradation and chronic inflammation, accompanied by high oxidative stress. In this study, we utilized the monosodium iodoacetate (MIA)-induced OA model to investigate the efficacy of oligo-fucoidan-based formula (FF) intervention in mitigating OA progression. Through its capacity to alleviate joint bearing function and inflammation, improvements in cartilage integrity following oligo-fucoidan-based formula intervention were observed, highlighting its protective effects against cartilage degeneration and structural damage. Furthermore, the oligo-fucoidan-based formula modulated the p38 signaling pathway, along with downregulating cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, contributing to its beneficial effects. Our study provides valuable insights into targeted interventions for OA management and calls for further clinical investigations to validate these preclinical findings and to explore the translational potential of an oligo-fucoidan-based formula in human OA patients.

Combinatory Nanovesicle with siRNA-Loaded Extracellular Vesicle and IGF-1 for Osteoarthritis Treatments.

Extracellular vesicles (EVs) have been found to have the characteristics of their parent cells. Based on the characteristics of these EVs, various studies on disease treatment using mesenchymal stem cell (MSC)-derived EVs with regenerative activity have been actively conducted. The therapeutic nature of MSC-derived EVs has been shown in several studies, but in recent years, there have been many efforts to functionalize EVs to give them more potent therapeutic effects. Strategies for functionalizing EVs include endogenous and exogenous methods. In this study, human umbilical cord MSC (UCMSC)-derived EVs were selected for optimum OA treatments with expectation via bioinformatics analysis based on antibody array. And we created a novel nanovesicle system called the IGF-si-EV, which has the properties of both cartilage regeneration and long-term retention in the lesion site, attaching positively charged insulin-like growth factor-1 (IGF-1) to the surface of the UCMSC-derived Evs carrying siRNA, which inhibits MMP13. The downregulation of inflammation-related cytokine (MMP13, NF-kB, and IL-6) and the upregulation of cartilage-regeneration-related factors (Col2, Acan) were achieved with IGF-si-EV. Moreover, the ability of IGF-si-EV to remain in the lesion site for a long time has been proven through an ex vivo system. Collectively, the final constructed IGF-si-EV can be proposed as an effective OA treatment through its successful MMP13 inhibition, chondroprotective effect, and cartilage adhesion ability. We also believe that this EV-based nanoparticle-manufacturing technology can be applied as a platform technology for various diseases.

A finite element model of human hindfoot and its application in supramalleolar osteotomy.

BACKGROUND: The majority of the ankle osteoarthritis cases are posttraumatic and affect younger patients with a longer projected life span. Hence, joint-preserving surgery, such as supramalleolar osteotomy becomes popular among young patients, especially those with asymmetric arthritis due to alignment deformities. However, there is a lack of biomechanical studies on postoperative evaluation of stress at ankle joints. We aimed to construct a verifiable finite element model of the human hindfoot, and to explore the effect of different osteotomy parameters on the treatment of varus ankle arthritis. METHODS: The bones of the hindfoot are reconstructed using normal CT tomography data from healthy volunteers, while the cartilages and ligaments are determined from the literature. The finite element calculation results are compared with the weight-bearing CT (WBCT) data to validate the model. By setting different model parameters, such as the osteotomy height (L) and the osteotomy distraction distance (h), the effects of different surgical parameters on the contact stress of the ankle joint surface are compared. FINDINGS: The alignment and the deformation of hindfoot bones as determined by the finite element analysis aligns closely with the data obtained from WBCT. The maximum contact stress of the ankle joint surface calculated by this model increases with the increase of the varus angle. The maximum contact stresses as a function of the L and h of the ankle joint surface are determined. INTERPRETATION: The relationship between surgical parameters and stress at the ankle joint in our study could further help guiding the planning of the supramalleolar osteotomy according to the varus/valgus alignment of the patients.

Predicting the potential mechanism of radix chimonanthi pracecocis in treating osteoarthritis by network pharmacology analysis combined with experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Chimonanthi Pracecocis (RCP), also known as Tiekuaizi, widely used by the Miao community in Guizhou, exhibits diverse biological activities and holds promise for the treatment of osteoarthritis (OA). However, there is a lack of contemporary pharmacological research in this area. AIMS OF THE STUDY: This study aims to explore the potential of targets and mechanisms of RCP in the treatment of OA. MATERIALS AND METHODS: The chemical components of RCP were identified using UPLC-MS/MS, and active components were determined based on the Lipinski rule. RCP and OA-related targets were retrieved from public databases such as TCMSP and GeneCards. Network pharmacology approaches were employed to identify key genes. The limma package (version 3.40.2) in R 4.3.2 was used to screen for differentially expressed genes (DEGs) between OA and healthy individuals in GSE82107. DEGs were analyzed using an independent sample t-test and receiver operating characteristic analysis in GraphPad Prism 9.5.1. Additionally, molecular docking (SYBYL2.1.1) was used to analyze the binding interactions between the active components and target proteins. Finally, we established a papain-induced osteoarthritis (OA) rat model and treated it with RCP aqueous extract by gavage. We validated relevant indicators using real-time fluorescence quantitative polymerase chain reaction, Western blot, immunohistochemistry, and enzyme-linked immunosorbent assays. RESULTS: Seven active components and 53 targets were identified. The results of GO and KEGG enrichment analyses confirmed the significant role of RCP in the regulation of pyroptosis. Hypoxia-inducible factor-1α (HIF-1α) was identified as a key gene involved in the main biological functions. Molecular docking analysis revealed that Praecoxin, Isofraxidin, Esculin, and Naringenin can bind to the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) (T-Score >5). Additionally, Praecoxin can bind to HIF-1α (T-Score >5). In vivo experiments demonstrated that RCP significantly affects the NLRP3 inflammasome, which is regulated by the HIF-1α pathway. RCP inhibited pyroptosis and reduced synovial inflammation. CONCLUSIONS: This study confirmed the efficacy of RCP aqueous extract in the treatment of OA and identified seven active components (esculin, dihydrokaempferol, naringenin, praecoxin, carnosol, hydroxyvalerenic acid, isofraxidin) that may play an anti-pyroptosis role in the treatment of OA by downregulating the expression of HIF-1α and NLRP3 inflammasome.

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.

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.

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.

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.