Aims. This study aimed to explore the biological and clinical importance of dysregulated key genes in osteoarthritis (OA) patients at the cartilage level to find potential biomarkers and targets for diagnosing and treating OA. Methods. Six sets of gene expression profiles were obtained from the Gene Expression Omnibus database. Differential expression analysis, weighted gene coexpression network analysis (WGCNA), and multiple machine-learning algorithms were used to screen crucial genes in osteoarthritic cartilage, and genome enrichment and functional annotation analyses were used to decipher the related categories of gene function. Single-sample gene set enrichment analysis was performed to analyze immune cell infiltration. Correlation analysis was used to explore the relationship among the hub genes and immune cells, as well as markers related to articular cartilage degradation and bone mineralization. Results. A total of 46 genes were obtained from the intersection of significantly upregulated genes in osteoarthritic cartilage and the key module genes screened by WGCNA. Functional annotation analysis revealed that these genes were closely related to pathological responses associated with OA, such as inflammation and immunity. Four key dysregulated genes (cartilage acidic protein 1 (CRTAC1), iodothyronine deiodinase 2 (DIO2), angiopoietin-related protein 2 (ANGPTL2), and MAGE family member D1 (MAGED1)) were identified after using machine-learning algorithms. These genes had high diagnostic value in both the training cohort and external validation cohort (receiver operating characteristic > 0.8). The upregulated expression of these hub genes in osteoarthritic cartilage signified higher levels of immune infiltration as well as the expression of metalloproteinases and mineralization markers, suggesting harmful biological alterations and indicating that these hub genes play an important role in the pathogenesis of OA. A competing endogenous RNA network was constructed to reveal the underlying post-transcriptional regulatory mechanisms. Conclusion. The current study explores and validates a dysregulated key gene set in osteoarthritic cartilage that is capable of accurately diagnosing OA and characterizing the biological alterations in osteoarthritic cartilage; this may become a promising indicator in clinical decision-making. This study indicates that dysregulated key genes play an important role in the development and progression of OA, and may be potential therapeutic targets. Cite this article: Bone Joint Res 2024;13(2):66–82

Abstract. Introduction. Synovitis impacts osteoarthritis symptomatology and progression. The transcription factors controlling synovial gene expression have not been described. This study analyses gene expression in synovium samples from 16 patients with osteoarthritis with 9 undergoing arthroscopic and 8 knee trauma surgery for non-arthritic pathologies. Methodology. Intra-operative synovial biopsies were immersed in RNAlater at 4oC before storage at -80oC. Total RNA was extracted using RNAeasy. After purification, RT-PCR and quality assessment, cDNA was applied to Affymetrix Clariom D microarray gene chips. Bioinformatics analyses were performed. Linear models were prepared in limma with gender and BMI factors incorporated sequentially for each pathology comparison, generating 12 models of probes differentially expressed at FDR p<0.05 and Bayes number, B>0. Data analysis of differently expressed genes utilized Ingenuity Pathway Analysis and Cytoscape with Cluego and Cytohubba plug-ins. Results. Amongst the 2084 genes with significantly differential expression (DEG), 135 had transcription regulator capabilities and 121 a nuclear location. IPA analysis of OATKR and arthroscopic tissue comparison DEG identified 12 nuclear transcription factors linked to 31 DEG whose encoded proteins located within cytoplasmic and cell membrane compartments. All 12 were significantly up-regulated and acting in pathways up-regulating transcription of DNA and RNA, cell survival and angiogenesis while down-regulating senescence and apoptosis. NFE2L2, integral to the TGF-beta signalling pathway, was identified as a bottleneck gene. Conclusion. This analysis indicates the complexity of synovial gene expression regulation and offers target genes and pathways for evaluation during osteoarthritis pathogenesis

Objectives. Normal sagittal spine-pelvis-lower extremity alignment is crucial in humans for maintaining an ergonomic upright standing posture, and pathogenesis in any segment leads to poor balance. The present study aimed to investigate how this sagittal alignment can be affected by severe knee osteoarthritis (KOA), and whether associated changes corresponded with symptoms of lower back pain (LBP) in this patient population. Methods. Lateral radiograph films in an upright standing position were obtained from 59 patients with severe KOA and 58 asymptomatic controls free from KOA. Sagittal alignment of the spine, pelvis, hip and proximal femur was quantified by measuring several radiographic parameters. Global balance was accessed according to the relative position of the C7 plumb line to the sacrum and femoral heads. The presence of chronic LBP was documented. Comparisons between the two groups were carried by independent samples t-tests or chi-squared test. Results. Patients with severe KOA showed significant backward femoral inclination (FI), hip flexion, forward spinal inclination, and higher prevalence of global imbalance (27.1% versus 3.4%, p < 0.001) compared with controls. In addition, patients with FI of 10° (n = 23) showed reduced lumbar lordosis and significant forward spinal inclination compared with controls, whereas those with FI > 10° (n = 36) presented with significant pelvic anteversion and hip flexion. A total of 39 patients with KOA (66.1%) suffered from LBP. There was no significant difference in sagittal alignment between KOA patients with and without LBP. Conclusions. The sagittal alignment of spine-pelvis-lower extremity axis was significantly influenced by severe KOA. The lumbar spine served as the primary source of compensation, while hip flexion and pelvic anteversion increased for further compensation. Changes in sagittal alignment may not be involved in the pathogenesis of LBP in this patient population. Cite this article: W. J. Wang, F. Liu, Y.W. Zhu, M.H. Sun, Y. Qiu, W. J. Weng. Sagittal alignment of the spine-pelvis-lower extremity axis in patients with severe knee osteoarthritis: A radiographic study. Bone Joint Res 2016;5:198–205. DOI:10.1302/2046-3758.55.2000538

Previous studies support the important role of vascular endothelial growth factor (VEGF) and syndecan-4 in the pathogenesis of osteoarthritis (OA). Both VEGF and syndecan-4 are expressed by chondrocytes and both are involved in the regulation of matrix metalloproteinase-3, resulting in the activation of aggrecanase II (ADAMTS-5), which is essential in the pathogenesis of OA. However, the relationship between VEGF and syndecan-4 has not been established. As a pilot study, we assayed the expression of VEGF and syndecan-4 in cartilage samples and cultured chondrocytes from osteoarthritic knee joints and analysed the relationship between these two factors. Specimens were collected from 21 female patients (29 knees) who underwent total knee replacement due to severe medial OA of the knee (Kellgren–Lawrence grade 4). Articular cartilage samples, obtained from bone and cartilage excised during surgery, were analysed and used for chondrocyte culture. We found that the levels of expression of VEGF and syndecan-4 mRNA did not differ significantly between medial femoral cartilage with severe degenerative changes and lateral femoral cartilage that appeared grossly normal (p = 0.443 and 0.622, respectively). Likewise, the levels of expression of VEGF and syndecan-4 mRNA were similar in cultured chondrocytes from medial and lateral femoral cartilage. The levels of expression of VEGF and syndecan-4 mRNAs were significantly and positively correlated in cartilage explant (r = 0.601, p = 0.003) but not in cultured chondrocytes. These results suggest that there is a close relationship between VEGF and syndecan-4 in the cartilage of patients with OA. Further studies are needed to determine the exact pathway by which these two factors interact in the pathogenesis of OA. Cite this article: Bone Joint J 2014;96-B:1319–24

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As has been shown in larger animal models, knee immobilization can lead to arthrofibrotic phenotypes. Our study included 168 C57BL/6J female mice, with 24 serving as controls, and 144 undergoing a knee procedure to induce a contracture without osteoarthritis (OA).

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Metal particles detached from metal-on-metal hip prostheses (MoM-THA) have been shown to cause inflammation and destruction of tissues. To further explore this, we investigated the histopathology (aseptic lymphocyte-dominated vasculitis-associated lesions (ALVAL) score) and metal concentrations of the periprosthetic tissues obtained from patients who underwent revision knee arthroplasty. We also aimed to investigate whether accumulated metal debris was associated with ALVAL-type reactions in the synovium.

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The antidiabetic agent metformin inhibits fibrosis in various organs. This study aims to elucidate the effects of hyperglycaemia and metformin on knee joint capsule fibrosis in mice.

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Adenosine, lidocaine, and Mg²⁺ (ALM) therapy exerts differential immuno-inflammatory responses in males and females early after anterior cruciate ligament (ACL) reconstruction (ACLR). Our aim was to investigate sex-specific effects of ALM therapy on joint tissue repair and recovery 28 days after surgery.

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Stiffness is a common complication after total knee arthroplasty (TKA). Pathogenesis is not understood, treatment options are limited, and diagnosis is challenging. The aim of this study was to investigate if MRI can be used to visualize intra-articular scarring in patients with stiff, painful knee arthroplasties.

We prospectively examined the physical and imaging findings, including MRI, of 23 patients with spontaneous osteonecrosis of the knee after obtaining informed consent to acquire tissue specimens at surgery. There were four men and 19 women, with a mean age of 67.5 years (58 to 77). Plain radiographs were designated as stages 1, 2, 3 or 4 according to the classification of Koshino. Five knees were classified as stage 1, five as stage 2, seven as stage 3 and six as stage 4. The histological specimens were stained with haematoxylin and eosin and tetrachrome.

In the early stages of the condition, a subchondral fracture was noted in the absence of any features of osteonecrosis, whereas in advanced stages, osteonecrotic lesions were confined to the area distal to the site of the fracture which showed impaired healing. In such cases, formation of cartilage and fibrous tissue, occurred indicating delayed or nonunion. These findings strongly suggest that the histopathology at each stage of spontaneous osteonecrosis is characterised by different types of repair reaction for subchondral fractures.

The outcome of arthroscopic medial release of 255 knees in 173 patients for varying grades of osteoarthritis involving the medial compartment is reported. All operations were performed by a single surgeon between January 2001 and May 2003. The Knee Society score for pain and the patient’s subjective satisfaction were used for the outcome evaluation. Overall, satisfactory outcome was reported for 197 knees (77.3%) and the mean Knee Society score for pain improved from 17.6 (95% confidence interval, 16.7 to 18.5), pre-operatively to 39.4 (95% confidence interval, 37.9 to 41.1) (p < 0.001). There were minor manageable complications of persistent effusion in 16 knees and prolonged wound discomfort in 11. In total, 15 of the 21 knees with poor results were converted to total knee replacements and two other patients (three knees) were offered this option after a mean period of 16 months.

Based on these observations arthroscopic medial release is an effective treatment for osteoarthritis of the medial compartment of the knee joint and can be expected to reduce the pain in the majority of patients for at least four years post-operatively.

Peri-prosthetic patellar fracture following resurfacing as part of total knee replacement (TKR) is an infrequent yet challenging complication. This case-control study was performed to identify clinical, radiological and surgical factors that increase the risk of developing a spontaneous patellar fracture after TKR. Patellar fractures were identified in 74 patients (88 knees) from a series of 7866 consecutive TKRs conducted between 1998 and 2009. After excluding those with a previous history of extensor mechanism realignment or a clear traumatic event, a metal-backed patella, any uncemented component or subsequent infection, the remaining 64 fractures were compared with a matched group of TKRs with an excellent outcome defined by the Knee Society score. The mean age of patients with a fracture was 70 years (51 to 81) at the time of TKR. Patellar fractures were detected at a mean of 13.4 months (2 to 84) after surgery. The incidence of patellar fracture was found to be strongly associated with the number of previous knee operations, greater pre-operative mechanical malalignment, smaller post-operative patellar tendon length, thinner post-resection patellar thickness, and a lower post-operative Insall-Salvati ratio.

An understanding of the risk factors associated with spontaneous patellar fracture following TKR provides a valuable insight into prevention of this challenging complication.

Smoking is known to have an adverse effect on wound healing and musculoskeletal conditions. This case-controlled study looked at whether smoking has a deleterious effect in the outcome of autologous chondrocyte implantation for the treatment of full thickness chondral defects of the knee.

The mean Modified Cincinatti Knee score was statistically significantly lower in smokers (n = 48) than in non-smokers (n = 66) both before and after surgery (p < 0.05). Smokers experienced significantly less improvement in the knee score two years after surgery (p < 0.05). Graft failures were only seen in smokers (p = 0.016). There was a strong negative correlation between the number of cigarettes smoked and the outcome following surgery (Pearson’s correlation coefficient −0.65, p = 0.004).

These results suggest that patients who smoke have worse pre-operative function and obtain less benefit from this procedure than non-smokers. The counselling of patients undergoing autologous chondrocyte implantation should include smoking, not only as a general cardiopulmonary risk but also because poorer results can be expected in smokers following this procedure.

Polyethylene particulate wear debris continues to be implicated in the aetiology of aseptic loosening following knee arthroplasty. The Oxford unicompartmental knee arthroplasty employs a spherical femoral component and a fully congruous meniscal bearing to increase contact area and theoretically reduce the potential for polyethylene wear. This study measures the in vivo ten-year linear wear of the device, using a roentgenstereophotogrammetric technique.

In this in vivo study, seven medial Oxford unicompartmental prostheses, which had been implanted ten years previously were studied. Stereo pairs of radiographs were acquired for each patient and the films were analysed using a roentgen stereophotogrammetric analysis calibration and a computer-aided design model silhouette-fitting technique. Penetration of the femoral component into the original volume of the bearing was our estimate of linear wear. In addition, eight control patients were examined less than three weeks post-insertion of an Oxford prosthesis, where no wear would be expected. The control group showed no measured wear and suggested a system accuracy of 0.1 mm. At ten years, the mean linear wear rate was 0.02 mm/year.

The results from this in vivo study confirm that the device has low ten-year linear wear in clinical practice. This may offer the device a survival advantage in the long term.