Interferon-gamma signaling promotes cartilage regeneration after injury.

Osteoarthritis is a common chronic disease and major cause of disability and chronic pain in ageing populations. In this pathology, the entire joint is involved, and the regeneration of articular cartilage still remains one of the main challenges. Here, we investigated the molecular mechanisms underlying cartilage regeneration in young mice using a full-thickness cartilage injury (FTCI) model. FTCI-induced cartilage defects were created in the femoral trochlea of young and adult C57BL/6 mice. To identify key molecules and pathways involved in the early response to cartilage injury, we performed RNA sequencing (RNA-seq) analysis of cartilage RNA at 3 days after injury. Young mice showed superior cartilage regeneration compared to adult mice after cartilage injury. RNA-seq analysis revealed significant upregulation of genes associated with the immune response, particularly in the IFN-γ signaling pathway and qRT-PCR analysis showed macrophage polarization in the early phase of cartilage regeneration (3 days) in young mice after injury, which might promote the removal of damaged or necrotic cells and initiate cartilage regeneration in response to injury. IFN-γR1- and IFN-γ-deficient mice exhibited impaired cartilage regeneration following cartilage injury. DMM-induced and spontaneous OA phenotypes were exacerbated in IFN-γR1-/- mice than in wild-type mice. Our data support the hypothesis that IFN-γ signaling is necessary for cartilage regeneration, as well as for the amelioration of post-traumatic and age-induced OA.

How the Plants for Joints multidisciplinary lifestyle intervention achieved its effects: a mixed methods process evaluation.

BACKGROUND: Plants for Joints (PFJ) is a multidisciplinary intervention centered around a whole-food plant-based diet, physical activity, and sleep and stress management. The PFJ intervention successfully improved disease activity and symptoms in people with rheumatoid arthritis (RA) or osteoarthritis (OA), respectively, and metabolic health. To investigate how these effects were achieved a mixed methods process evaluation was conducted to understand the context, implementation, and mechanism of impact of the PFJ intervention. Also, the relationship between degree of implementation and lifestyle changes was explored. METHODS: Quantitative and qualitative data were collected across the evaluation domains context (i.e. reach), implementation (i.e. recruitment and delivery), and mechanism of impact (i.e. responsiveness) of both the participants and coaches (incl. dietitians, sport coaches) according to the UK MRC guidelines for process evaluations. Data was collected from the participants via focus groups and questionnaires after the intervention, and interviews with coaches. Qualitative data were analyzed thematically, and quantitative data were assessed with descriptive statistics and linear regression analyses. Degree of implementation was quantified using a theory-driven implementation index score composed of different process evaluation constructs. RESULTS: Of the 155 participants who participated in the PFJ intervention, 106 (68%) took part in the questionnaire and 34 (22%) attended a focus group. Participants felt the intervention was complete, coherent, and would recommend the intervention to others (mean score 9.2 (SD 1.4) out of 10). Participants felt heard and empowered to take control of their lifestyle and health outcomes. Components perceived as most useful were self-monitoring, social support, practical and theoretical information, and (individual) guidance by the multidisciplinary team. Participants perceived the intervention as feasible, and many indicated it effectively improved their health outcomes. In an explorative analysis there was no significant difference in healthy lifestyle changes across implementation index score groups. CONCLUSION: This process evaluation offers important insights into why the PFJ intervention works and how the intervention can be optimized for future implementation. Results indicating the intervention's high satisfaction, feasibility, and perceived effectiveness, further support the use of plant-based lifestyle interventions as an additional treatment option for patients with RA, OA, or other chronic diseases. TRIAL REGISTRATION: International Clinical Trial Registry Platform numbers: NL7800, NL7801, and NL7802, all registered 17-06-2019.

Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints.

Osteoarthritis (OA) is a painful, incurable disease affecting over 500 million people. Recent clinical trials of the nerve growth factor (NGF) inhibitors in OA patients have suggested adverse effects of NGF inhibition on joint structure. Here we report that nerve growth factor receptor (NGFR) is upregulated in skeletal cells during OA and plays an essential role in the remodeling and repair of osteoarthritic joints. Specifically, NGFR is expressed in osteochondral cells but not in skeletal progenitor cells and induced by TNFα to attenuate NF-κB activation, maintaining proper BMP-SMAD1 signaling and suppressing RANKL expression in mice. NGFR deficiency hyper-activates NF-κB in murine osteoarthritic joints, which impairs bone formation and enhances bone resorption as exemplified by a reduction in subchondral bone and osteophytes. In human OA cartilage, NGFR is also negatively associated with NF-κB activation. Together, this study suggests a role of NGFR in limiting inflammation for repair of diseased skeletal tissues.

Anti-Inflammatory, Analgesic, Functional Improvement, and Chondroprotective Effects of Erigeron breviscapus (Vant.) Hand.-Mazz. Extract in Osteoarthritis: An In Vivo and In Vitro Study.

Osteoarthritis (OA) is a degenerative bone disease characterized by inflammation as a primary pathology and currently lacks therapeutic interventions to impede its progression. Erigeron breviscapus (Vant.) Hand.-Mazz. (EB) is an east Asian herbal medicine with a long history of use and a wide range of confirmed efficacy against cardiovascular and central nervous system diseases. The purpose of this study is to evaluate whether EB is worthy of further investigation as a treatment for OA based on anti-inflammatory activity. This study aims to assess the potential of EB as a treatment for OA, focusing on its anti-inflammatory properties. Analgesic effects, functional improvements, and inhibition of cartilage destruction induced by EB were evaluated in acetic acid-induced peripheral pain mice and monosodium iodoacetate-induced OA rat models. Additionally, the anti-inflammatory effect of EB was assessed in serum and cartilage tissue in vivo, as well as in lipopolysaccharide-induced RAW 264.7 cells. EB demonstrated a significant alleviation of pain, functional impairment, and cartilage degradation in OA along with a notable inhibition of pro-inflammatory cytokines, including interleukin-1ß, interleukin-6, matrix metalloproteinases 13, and nitric oxide synthase 2, both in vitro and in vivo, in a dose-dependent manner compared to the active control. Accordingly, EB merits further exploration as a potential disease-modifying drug for OA, capable of mitigating the multifaceted pathology of osteoarthritis through its anti-inflammatory properties. Nonetheless, additional validation through a broader experimental design is essential to substantiate the findings of this study.

Unicompartmental Knee Arthroplasty for Osteoarthritis Eliminates Lateral Thrust: Associations between Lateral Thrust Detected by Inertial Measurement Units and Clinical Outcomes.

The purpose of this study was to investigate the relationship between clinical outcomes and lateral thrust before and after unicompartmental knee arthroplasty (UKA) using inertial measurement sensor units. Eleven knees were evaluated with gait analysis. The varus angular velocity was used to evaluate lateral thrust. The femorotibial angle (FTA) and hip-knee-ankle angle (HKA) were used to evaluate lower-limb alignment, and the Oxford Knee Score (OKS) and Japanese Orthopaedic Association Score (JOA) were used to evaluate clinical outcomes. The mean pre-UKA peak varus velocity was 37.1 ± 9.8°/s, and that for post-UKA was 28.8 ± 9.1°/s (p = 0.00003), such that instabilities clearly improved. Assuming the definition of lateral thrust is when the varus angular velocity is more than 28.1°/s, 81.8% of patients had lateral thrust preoperatively, but this decreased to 55.6% postoperatively, such that the symptoms and objective findings improved. Both OKS and JOA improved after surgery. In addition, HKA was -7.9° preoperatively and -5.8° postoperatively (p = 0.024), and FTA was 181.4° preoperatively and 178.4° postoperatively (p = 0.012). There was a positive correlation between postoperative JOA and FTA, indicating that changes in postoperative alignment affected clinical outcomes. This study quantitatively evaluated the disappearance of lateral thrust by UKA, and it found that the stability can be achieved by UKA for unstable knees with lateral thrust.

Nanoparticle-Mediated Multiple Modulation of Bone Microenvironment To Tackle Osteoarthritis.

Development of nanomedicines that can collaboratively scavenge reactive oxygen species (ROS) and inhibit inflammatory cytokines, along with osteogenesis promotion, is essential for efficient osteoarthritis (OA) treatment. Herein, we report the design of a ROS-responsive nanomedicine formulation based on fibronectin (FN)-coated polymer nanoparticles (NPs) loaded with azabisdimethylphoaphonate-terminated phosphorus dendrimers (G4-TBP). The constructed G4-TBP NPs-FN with a size of 268 nm are stable under physiological conditions, can be specifically taken up by macrophages through the FN-mediated targeting, and can be dissociated in the oxidative inflammatory microenvironment. The G4-TBP NPs-FN loaded with G4-TBP dendrimer having intrinsic anti-inflammatory property and FN having both anti-inflammatory and antioxidative properties display integrated functions of ROS scavenging, hypoxia attenuation, and macrophage M2 polarization, thus protecting macrophages from apoptosis and creating designed bone immune microenvironment for stem cell osteogenic differentiation. These characteristics of the G4-TBP NPs-FN lead to their effective treatment of an OA model in vivo to reduce pathological changes of joints including synovitis inhibition and cartilage matrix degradation and simultaneously promote osteogenic differentiation for bone repair. The developed nanomedicine formulation combining the advantages of both bioactive phosphorus dendrimers and FN to treat OA may be developed for immunomodulatory therapy of different inflammatory diseases.

FTH1 protects against osteoarthritis by MAPK pathway inhibition of extracellular matrix degradation.

OBJECTIVE: Ferritin heavy chain 1 (FTH1) is an important subunit of ferro-storing proteins and is indispensable for iron metabolism. Though it has been extensively studied in numerous organs and diseases, the relationship between FTH1 and osteoarthritis (OA) is unclear. DESIGN: Primary murine chondrocytes and cartilage explants were treated with FTH1 siRNA for 72 h. Mice were injected with adenovirus expressing FTH1 after destabilized medial meniscus (DMM) surgery. These approaches were used to determine the effect of FTH1 expression on the pathophysiology of OA. RESULTS: FTH1 expression was down regulated in OA patients and mice after DMM surgery. Knock down of FTH1 induced articular cartilage damage and extracellular matrix degradation in cartilage explants. Further, over expression of FTH1 reduced the susceptibility of chondrocytes to ferroptosis and reversed decrements in SOX9 and aggrecan after DMM surgery. Moreover, FTH1 relieved OA by inhibition of the chondrocyte MAPK pathway. CONCLUSION: This study found FTH1 to play an essential role in extracellular matrix degradation, ferroptosis, and chondrocytes senescence during OA progression. Further, injection of adenovirus expressing FTH1 may be a potential strategy for OA prevention and therapy.

[Ligusticum cycloprolactam inhibits IL-1ß-induced apoptosis and inflammation of rat chondrocytes via HMGB1/TLR4/NF-κB signaling pathway].

Chondrocytes are unique resident cells in the articular cartilage, and the pathological changes of them can lead to the occurrence of osteoarthritis(OA). Ligusticum cycloprolactam(LIGc) are derivatives of Z-ligustilide(LIG), a pharmacodynamic marker of Angelica sinensis, which has various biological functions such as anti-inflammation and inhibition of cell apoptosis. However, its protective effect on chondrocytes in the case of OA and the underlying mechanism remain unclear. This study conducted in vitro experiments to explore the molecular mechanism of LIGc in protecting chondrocytes from OA. The inflammation model of rat OA chondrocyte model was established by using interleukin-1ß(IL-1ß) to induce. LIGc alone and combined with glycyrrhizic acid(GA), a blocker of the high mobility group box-1 protein(HMGB1)/Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) signaling pathway, were used to intervene in the model, and the therapeutic effects were systematically evaluated. The viability of chondrocytes treated with different concentrations of LIGc was measured by the cell counting kit-8(CCK-8), and the optimal LIGc concentration was screened out. Annexin V-FITC/PI apoptosis detection kit was employed to examine the apoptosis of chondrocytes in each group. The enzyme-linked immunosorbent assay(ELISA) was employed to measure the expression of cyclooxygenase-2(COX-2), prostaglandin-2(PGE2), and tumor necrosis factor-alpha(TNF-α) in the supernatant of chondrocytes in each group. Western blot was employed to determine the protein levels of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), caspase-3, HMGB1, TLR4, and NF-κB p65. The mRNA levels of HMGB1, TLR4, NF-κB p65, and myeloid differentiation factor 88(MyD88) in chondrocytes were determined by real-time fluorescent quantitative PCR(RT-qPCR). The safe concentration range of LIGc on chondrocytes was determined by CCK-8, and then the optimal concentration of LIGc for exerting the effect was clarified. Under the intervention of IL-1ß, the rat chondrocyte model of OA was successfully established. The modeled chondrocytes showed increased apoptosis rate, promoted expression of COX-2, PGE2, and TNF-α, up-regulated protein levels of Bax, caspase-3, HMGB1, TLR4, and NF-κB p65 and mRNA levels of HMGB1, TLR4, NF-κB p65, and MyD88, and down-regulated protein level of Bcl-2. However, LIGc reversed the IL-1ß-induced changes of the above factors. Moreover, LIGc combined with GA showed more significant reversal effect than LIGc alone. These fin-dings indicate that LIGc extracted and derived from the traditional Chinese medicine A. sinensis can inhibit the inflammatory response of chondrocytes and reduce the apoptosis of chondrocytes, and this effect may be related to the HMGB1/TLR4/NF-κB signaling pathway. The pharmacological effect of LIGc on protecting chondrocytes has potential value in delaying the progression of OA and improving the clinical symptoms of patients, and deserves further study.

Icariin alleviates the apoptosis of chondrocytes in osteoarthritis through regulating SIRT-1-Nrf2-HO-1 signaling.

Icariin has shown the potential to treat osteoarthritis (OA), but the specific mechanism still needs further exploration. Therefore, this study attempted to reveal the effect and mechanism of icariin on OA based on in vitro and in vivo experiments. In vivo, a mouse model of OA was established by cutting the anterior cruciate ligament, and 10 mg/kg icariin was given to mice orally. Then, the OA injury and pathological changes of cartilage tissue in mice were identified by OA index and hematoxylin and eosin staining. In vitro, the viability of C28/I2 cells incubated with different concentrations of icariin was detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide assay. Subsequently, C28/I2 cells induced by IL-1ß were used as the cell model of OA, the expression of Sirtuin (SIRT)-1 in cells was knocked down, and icariin was added for intervention. Next, western blot was used to observe the expression level of sirtuin 1 (SIRT-1)-Nrf2-heme oxygenase 1 (HO-1) signaling pathway-related proteins in cells of each group. Besides, cell viability and apoptosis were detected by MTT and apoptosis assay, and DNA damage was observed by comet assay. In vivo experiments, intragastric administration of icariin could effectively reduce the OA index of mice, improve the pathological changes of cartilage tissue, and obviously activated the SIRT-1-Nrf2-HO-1 signaling pathway. In vitro experiments, icariin did not exhibit toxic effect on C28/I2 cells, but could activate the SIRT-1-Nrf2-HO-1 signaling pathway, improve the viability, reduce the level of apoptosis and relieve the DNA damage in OA cells; however, these effects were inhibited by si- SIRT-1. Icariin can improve the symptoms of OA by activating the SIRT-1-Nrf2-HO-1 signaling pathway.

Hypobaric hypoxia aggravates osteoarthritis via the alteration of the oxygen environment and bone remodeling in the subchondral zone.

A high prevalence of osteoarthritis (OA) has been observed among individuals living at high altitudes, and hypobaric hypoxia (HH) can cause bone mass and strength deterioration. However, the effect of HH on OA remains unclear. In this study, we aimed to explore the impact of HH on OA and its potential mechanisms. A rat knee OA model was established by surgery, and the rats were bred in an HH chamber simulating a high-altitude environment. Micro-computed tomography (Micro-CT), histological analysis, and RNA sequencing were performed to evaluate the effects of HH on OA in vivo. A hypoxic co-culture model of osteoclasts and osteoblasts was also established to determine their effects on chondrogenesis in vitro. Cartilage degeneration significantly worsened in the HH-OA group compared to that in the normoxia-OA (N-OA) group, 4 weeks after surgery. Micro-CT analysis revealed more deteriorated bone mass in the HH-OA group than in the N-OA group. Decreased hypoxia levels in the cartilage and enhanced hypoxia levels in the subchondral bone were observed in the HH-OA group. Furthermore, chondrocytes cultured in a conditioned medium from the hypoxic co-culture model showed decreased anabolism and extracellular matrix compared to those in the normoxic model. RNA sequencing analysis of the subchondral bone indicated that the glycolytic signaling pathway was highly activated in the HH-OA group. HH-related OA progression was associated with alterations in the oxygen environment and bone remodeling in the subchondral zone, which provided new insights into the pathogenesis of OA.

Skeletal interoception in osteoarthritis.

The interoception maintains proper physiological conditions and metabolic homeostasis by releasing regulatory signals after perceving changes in the internal state of the organism. Among its various forms, skeletal interoception specifically regulates the metabolic homeostasis of bones. Osteoarthritis (OA) is a complex joint disorder involving cartilage, subchondral bone, and synovium. The subchondral bone undergoes continuous remodeling to adapt to dynamic joint loads. Recent findings highlight that skeletal interoception mediated by aberrant mechanical loads contributes to pathological remodeling of the subchondral bone, resulting in subchondral bone sclerosis in OA. The skeletal interoception is also a potential mechanism for chronic synovial inflammation in OA. In this review, we offer a general overview of interoception, specifically skeletal interoception, subchondral bone microenviroment and the aberrant subchondral remedeling. We also discuss the role of skeletal interoception in abnormal subchondral bone remodeling and synovial inflammation in OA, as well as the potential prospects and challenges in exploring novel OA therapies that target skeletal interoception.

Data-driven identification of predictive risk biomarkers for subgroups of osteoarthritis using interpretable machine learning.

Osteoarthritis (OA) is increasing in prevalence and has a severe impact on patients' lives. However, our understanding of biomarkers driving OA risk remains limited. We developed a model predicting the five-year risk of OA diagnosis, integrating retrospective clinical, lifestyle and biomarker data from the UK Biobank (19,120 patients with OA, ROC-AUC: 0.72, 95%CI (0.71-0.73)). Higher age, BMI and prescription of non-steroidal anti-inflammatory drugs contributed most to increased OA risk prediction ahead of diagnosis. We identified 14 subgroups of OA risk profiles. These subgroups were validated in an independent set of patients evaluating the 11-year OA risk, with 88% of patients being uniquely assigned to one of the 14 subgroups. Individual OA risk profiles were characterised by personalised biomarkers. Omics integration demonstrated the predictive importance of key OA genes and pathways (e.g., GDF5 and TGF-ß signalling) and OA-specific biomarkers (e.g., CRTAC1 and COL9A1). In summary, this work identifies opportunities for personalised OA prevention and insights into its underlying pathogenesis.

Health-related quality of life in patients with conditions affecting the hand: meta-analysis.

BACKGROUND: Health state utility values provide the quality component of quality-adjusted life years and are essential for health economic analyses, such as the National Institute for Health and Care Excellence Technology Appraisal. The aims of this systematic review were to: catalogue utility values for health states experienced by patients with hand conditions; provide pooled utility estimates for common hand conditions; and determine how utilities have been estimated. METHODS: A PRISMA-compliant systematic review and meta-analysis was conducted (registered in PROSPERO, the international prospective register of systematic reviews (CRD42021226098)). Five databases were searched from inception until April 2023 (Embase, MEDLINE, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane Central Register of Controlled Trials (CENTRAL)). All studies that reported primary utility values for hand health states in adult patients were eligible for inclusion. Pooled utility estimates were determined across conditions and intervention status using random-effects meta-analysis. RESULTS: A total of 10 254 articles were identified; 57 studies met the full inclusion criteria and reported 363 distinct health state utility values. Health state utility values were estimated using a range of methods; the most common measure was the EQ-5D. Pooled utility estimates for carpal tunnel syndrome and hand osteoarthritis before surgical intervention were 0.69 (95% c.i. 0.66 to 0.73) and 0.63 (95% c.i. 0.60 to 0.67) respectively. CONCLUSION: Pooled utility estimates for patients with untreated carpal tunnel syndrome and hand osteoarthritis are 11% and 18% lower than age-matched population norms respectively. Hand conditions have a significant detrimental impact on health-related quality of life and this study provides catalogued utility values for use in future economic analyses to support the delivery of value-based hand surgery.

Overexpression of RAD54L attenuates osteoarthritis by suppressing the HIF-1α/VEGF signaling pathway: Bioinformatics analysis and experimental validation.

Osteoarthritis (OA) is a widespread chronic, progressive, degenerative joint disease that causes pain and disability. Current treatments for OA have limited effectiveness and new biomarkers need to be identified. Bioinformatics analysis was conducted to explore differentially expressed genes and DNA repair/recombination protein 54 L (RAD54L) was selected. We firstly overexpressed RAD54L in interleukin-1ß (IL-1ß)-induced human articular chondrocytes or in OA rats to investigate its effect on OA. Chondrocyte viability and apoptotic rate were measured by Cell Counting Kit-8 and flow cytometry, respectively. Then we evaluated OA severity in vivo by Hematoxylin-eosin staining and Osteoarthritis Research Society International standards. The expression of inflammatory mediators was tested by enzyme-linked immunosorbent assay. Finally, western blot was performed to determine the relative expression level of hypoxia-inducible factors 1α (HIF-1α) and vascular endothelial growth factor (VEGF). Overexpression of RAD54L promoted cell viability and attenuated apoptosis in IL-1ß-induced human chondrocytes. A lower Osteoarthritis Research Society International score and a remarkable alleviation of chondrocyte disordering and infiltration of inflammatory cells were found in cartilage tissues of OA rats after overexpressing RAD54L. The inflammatory response induced by OA was decreased by RAD54L overexpression in vitro and in vivo. In addition, RAD54L overexpression decreased the relative expression level of HIF-1α and VEGF. Overexpression of RAD54L could attenuate OA by suppressing the HIF-1α/VEGF signaling pathway, indicating that RAD54L may be a potential treatment target for OA.

Arthrodesis of distal interphalangeal and thumb interphalangeal joint: a retrospective cohort study of 149 cases.

BACKGROUND: Arthrodesis of finger joints is often the last line of treatment of severe pain due to osteoarthritis, rheumatoid arthritis, or mallet finger. At the Department of Orthopedic and Hand Surgery, Örebro University Hospital (ÖUH) in Sweden, the Kirschner-wire technique was standard until 2020, when the headless compression screw technique was introduced as a complement. There is no consensus on which method is superior. The purpose of this study was to examine the outcomes and complications associated with distal interphalangeal (DIP) joint and thumb interphalangeal (IP) joint arthrodesis, and to see whether these correlated with patient-dependent and treatment-related factors. METHODS: In a retrospective cohort study, we evaluated a total of 149 consecutive arthrodeses (118 DIP joint and 31 thumb IP joint) performed between 2012 and 2022. The primary outcome was risk factors for complications after arthrodesis. RESULTS: Osteoarthritis was the most common indication (56%) for arthrodesis. The majority of the patients were females (74%), and the median age was 62 (range 18-86). The complication frequency was 35%, with infection being the most common (25%). Time to completed follow up was < 12 weeks in the majority of the cases (58%). There were no significant differences in complication rate between the 136 joints operated using Kirschner wire and the 13 joints operated using headless compression screws. There was no significant increased risk of complications among smokers or patients with rheumatoid arthritis. Diabetes and surgeon experience had a significant influence on the risk of complication (p = 0.036 and p = 0.006, respectively). CONCLUSIONS: Osteoarthritis was the most common indication for arthrodesis and postoperative complications occurred at a rate similar to that reported in the existing literature. Diabetes and surgeon experience were identified as factors increasing the risk of postoperative complications in these DIP/thumb IP joint arthrodeses. However, there was no significant difference between the two techniques (Kirschner wire and headless compression screws) regarding complications. Further studies are needed in order to determine the optimal type of operation and choice of implant. TRIAL REGISTRATION: Researchweb CRIS #280,998, 26th of July 2023.

Specific isoforms of the ubiquitin ligase gene WWP2 are targets of osteoarthritis genetic risk via a differentially methylated DNA sequence.

BACKGROUND: Transitioning from a genetic association signal to an effector gene and a targetable molecular mechanism requires the application of functional fine-mapping tools such as reporter assays and genome editing. In this report, we undertook such studies on the osteoarthritis (OA) risk that is marked by single nucleotide polymorphism (SNP) rs34195470 (A > G). The OA risk-conferring G allele of this SNP associates with increased DNA methylation (DNAm) at two CpG dinucleotides within WWP2. This gene encodes a ubiquitin ligase and is the host gene of microRNA-140 (miR-140). WWP2 and miR-140 are both regulators of TGFß signaling. METHODS: Nucleic acids were extracted from adult OA (arthroplasty) and foetal cartilage. Samples were genotyped and DNAm quantified by pyrosequencing at the two CpGs plus 14 flanking CpGs. CpGs were tested for transcriptional regulatory effects using a chondrocyte cell line and reporter gene assay. DNAm was altered using epigenetic editing, with the impact on gene expression determined using RT-qPCR. In silico analysis complemented laboratory experiments. RESULTS: rs34195470 genotype associates with differential methylation at 14 of the 16 CpGs in OA cartilage, forming a methylation quantitative trait locus (mQTL). The mQTL is less pronounced in foetal cartilage (5/16 CpGs). The reporter assay revealed that the CpGs reside within a transcriptional regulator. Epigenetic editing to increase their DNAm resulted in altered expression of the full-length and N-terminal transcript isoforms of WWP2. No changes in expression were observed for the C-terminal isoform of WWP2 or for miR-140. CONCLUSIONS: As far as we are aware, this is the first experimental demonstration of an OA association signal targeting specific transcript isoforms of a gene. The WWP2 isoforms encode proteins with varying substrate specificities for the components of the TGFß signaling pathway. Future analysis should focus on the substrates regulated by the two WWP2 isoforms that are the targets of this genetic risk.

Clinical and ultrasound features of 46 children with suppurative osteoarthritis: experience from two centers.

OBJECTIVE: Diagnosing musculoskeletal infections in children is challenging. In recent years, with the advancement of ultrasound technology, high-resolution ultrasound has unique advantages for musculoskeletal children. The aim of this work is to summarize the ultrasonographic and clinical characteristics of children with pyogenic arthritis and osteomyelitis. This study provides a simpler and more effective diagnostic basis for clinical treatment. METHODS: Fifty children with osteomyelitis or arthritis were diagnosed via ultrasound, and the results of the ultrasound diagnosis were compared with those of magnetic resonance imaging and surgery. Clinical and ultrasound characteristics were also analyzed. RESULTS: Out of 50 patients, 46 were confirmed to have suppurative infection by surgical and microbiological examination. Among these 46 patients, 26 were diagnosed with osteomyelitis and 20 had arthritis. The manifestations of osteomyelitis were subperiosteal abscess (15 patients), bone destruction (17 patients), bone marrow abscess (9 patients), and adjacent joint abscess (13 patients). Osteomyelitis mostly affects the long bones of the limbs, femur and humerus (10 and 9 patients, respectively), followed by the ulna, radius, tibia and fibula (one patient each). The manifestations of arthritis were joint pus (20 patients) and joint capsule thickening (20 patients), and hip dislocation (8 patients). All the patients had arthritis involving the hip joint. CONCLUSION: Subperiosteal abscess, bone destruction, and joint abscess with dislocation are ultrasonographic features of pyogenic osteoarthritis. The findings of this work can improve the early diagnosis and differentiation of pyogenic osteoarthritis and provide a reliable basis for treatment.

Efecto de la resección de la grasa del paquete infrapatelar de la rodilla en el desarrollo de la artrosis. Estudio experimental en ovejas / Infrapatellar Fat Pad resection effect on the osteoarthritis development: Experimental study in sheep

Introducción: La grasa de las articulaciones sinoviales puede servir para el mantenimiento de la estructura articular. Nuestro objetivo es analizar la evolución de la degeneración articular en rodillas con y sin paquete adiposo. Material y metodología: En 6 ovejas se efectuó la sección del ligamento cruzado anterior en ambas rodillas, para provocar una artrosis. En un grupo se preservó el paquete adiposo y en otro grupo se extirpó completamente. Realizamos un estudio histológico y de biología molecular analizando la expresión, en la membrana sinovial, el hueso subcondral, cartílago, grasa, menisco y líquido sinovial, de RUNX2, PTHrP, catepsina-K y MCP1. Resultados: No encontramos diferencias morfológicas. Encontramos aumento de la expresión de RUNX2 en membrana sinovial, PTHrP y Catepsina K en líquido sinovial en el grupo sin grasa y aumento de la expresión RUNX2 en el menisco y MCP1 en líquido sinovial en el grupo con grasa. Conclusión: La grasa infrapatelar participa en el proceso inflamatorio que acompaña en la artrosis, pues la resección de la grasa de Hoffa altera los marcadores proinflamatorios, mientras que el modelo con la grasa intacta incrementa el marcador proinflamatorio MCP1 en líquido sinovial.(AU)

Introduction: The fat of the synovial joints can be used to maintain the joint structure. Our objective is to analyze the evolution of joint degeneration in knees with and without adipose pack. Material and methodology: In six sheep, the anterior cruciate ligament was sectioned in both knees, to cause osteoarthritis. In one group the fat pack was preserved and in another group it was completely removed. We performed a histological and molecular biology study analyzing the expression, in the synovial membrane, subchondral bone, cartilage, fat, meniscus, and synovial fluid, of RUNX2, PTHrP, cathepsin-K, and MCP1. Results: We did not find morphological differences. We found increased expression of RUNX2 in synovial membrane, PTHrP and Cathepsin K in synovial fluid in the group without fat, and increased expression of RUNX2 in the meniscus and MCP1 in synovial fluid in the group with fat. Conclusion: Infrapatellar fat participates in the inflammatory process that accompanies osteoarthritis, since Hoffa fat pad resection alters pro-inflammatory markers, while the model with intact fat increases the pro-inflammatory marker MCP1 in synovial fluid.(AU)

[Translated article] Infrapatellar fat pad resection effect on the osteoarthritis development: Experimental study in sheep / Efecto de la resección de la grasa del paquete infrapatelar de la rodilla en el desarrollo de la artrosis. Estudio experimental en ovejas

Introducción: La grasa de las articulaciones sinoviales puede servir para el mantenimiento de la estructura articular. Nuestro objetivo es analizar la evolución de la degeneración articular en rodillas con y sin paquete adiposo. Material y metodología: En 6 ovejas se efectuó la sección del ligamento cruzado anterior en ambas rodillas, para provocar una artrosis. En un grupo se preservó el paquete adiposo y en otro grupo se extirpó completamente. Realizamos un estudio histológico y de biología molecular analizando la expresión, en la membrana sinovial, el hueso subcondral, cartílago, grasa, menisco y líquido sinovial, de RUNX2, PTHrP, catepsina-K y MCP1. Resultados: No encontramos diferencias morfológicas. Encontramos aumento de la expresión de RUNX2 en membrana sinovial, PTHrP y Catepsina K en líquido sinovial en el grupo sin grasa y aumento de la expresión RUNX2 en el menisco y MCP1 en líquido sinovial en el grupo con grasa. Conclusión: La grasa infrapatelar participa en el proceso inflamatorio que acompaña en la artrosis, pues la resección de la grasa de Hoffa altera los marcadores proinflamatorios, mientras que el modelo con la grasa intacta incrementa el marcador proinflamatorio MCP1 en líquido sinovial.(AU)

Introduction: The fat of the synovial joints can be used to maintain the joint structure. Our objective is to analyze the evolution of joint degeneration in knees with and without adipose pack. Material and methodology: In six sheep, the anterior cruciate ligament was sectioned in both knees, to cause osteoarthritis. In one group the fat pack was preserved and in another group it was completely removed. We performed a histological and molecular biology study analyzing the expression, in the synovial membrane, subchondral bone, cartilage, fat, meniscus, and synovial fluid, of RUNX2, PTHrP, cathepsin-K, and MCP1. Results: We did not find morphological differences. We found increased expression of RUNX2 in synovial membrane, PTHrP and Cathepsin K in synovial fluid in the group without fat, and increased expression of RUNX2 in the meniscus and MCP1 in synovial fluid in the group with fat. Conclusion: Infrapatellar fat participates in the inflammatory process that accompanies osteoarthritis, since Hoffa fat pad resection alters pro-inflammatory markers, while the model with intact fat increases the pro-inflammatory marker MCP1 in synovial fluid.(AU)