ObjectivesTo investigate how the genetic susceptibility gene DIO2 confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches.MethodsEpigenetically regulated expression of DIO2 was explored by assessing methylation of positional CpG-dinucleotides and the respective DIO2 expression in OA-affected and macroscopically preserved articular cartilage from end-stage OA patients. In a human in vitro chondrogenesis model, we measured the effects when thyroid signalling during culturing was either enhanced (excess T3 or lentiviral induced DIO2 overexpression) or decreased (iopanoic acid).ResultsOA-related changes in methylation at a specific CpG dinucleotide upstream of DIO2 caused significant upregulation of its expression (β=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (β=5.58, p=0.0006). During in vitro chondrogenesis, DIO2 overexpression resulted in a significant reduced capacity of chondrocytes to deposit extracellular matrix (ECM) components, concurrent with significant induction of ECM degrading enzymes (ADAMTS5, MMP13) and markers of mineralisation (ALPL, COL1A1). Given their concurrent and significant upregulation of expression, this process is likely mediated via HIF-2α/RUNX2 signalling. In contrast, we showed that inhibiting deiodinases during in vitro chondrogenesis contributed to prolonged cartilage homeostasis as reflected by significant increased deposition of ECM components and attenuated upregulation of matrix degrading enzymes.ConclusionsOur findings show how genetic variation at DIO2 could confer risk to OA and raised the possibility that counteracting thyroid signalling may be a novel therapeutic approach.

Our findings reveal consistent DMRs between knee and hip articular cartilage that marked transcriptomic differences among HOX genes, which were not reflecting the temporal sequential HOX expression pattern during development. This implies distinct mechanisms for maintaining cartilage integrity in adulthood, thereby contributing to our understanding of cartilage homeostasis and future tissue regeneration approaches.

Objective. To identify osteoarthritis (OA) progressionmodulating pathways in articular cartilage and their respective regulatory epigenetic and genetic determinants in end-stage disease.Methods. Transcriptional activity of CpG was assessed using gene expression data and DNA methylation data for preserved and lesional articular cartilage samples. Disease-responsive transcriptionally active CpG were identified by means of differential methylation between preserved and lesional cartilage. Transcriptionally relevant genetic determinants were addressed by means of single-nucleotide polymorphisms (SNPs) proximal to the OA-responsive transcriptionally active CpG. Statistical analyses were corrected for age, sex, joint, and technical covariates. A random effect was included to correct for possible correlations between paired samples.Results. Of 9,838 transcribed genes in articular cartilage, 2,324 correlated with the methylation status of 3,748 transcriptionally active CpG; both negative (n 5 1,741) and positive (n 5 2,007) correlations were observed. Hypomethylation and hypermethylation (false discovery rate of <0.05, |Db| > 0.05) were observed for 62 and 25 transcriptionally active CpG, respectively, covering 70 unique genes. Enrichment for developmental and extracellular matrix maintenance pathways indicated possible reactivation of endochondral ossification. Finally, we observed 31 and 26 genes for which methylation and expression, respectively, were additionally affected by genetic variation.Conclusion. We identified tissue-specific genes involved in OA disease progression, reflected by genetic and pathologic epigenetic regulation of transcription, primarily at genes involved in development. Therefore, transcriptionally active SNPs near these genes may serve as putative susceptibility alleles. Our results constitute an important step toward understanding the reported widespread epigenetic changes occurring in OA articular cartilage and toward subsequent development of treatments targeting disease-driving pathways.Osteoarthritis (OA) is the most prevalent arthritis among the elderly (1) and is currently recognized as a disease of the whole joint (2). A well-described hallmark of OA is articular cartilage degradation (3). The single cell type present in articular cartilage is the articular chondrocyte, which is a highly specialized, maturation-arrested, nonproliferating cell. To ensure articular cartilage integrity throughout life, the articular chondrocyte needs to adapt its behavior in response to external signals, such as mechanical stress, aging, or microtraumas (4). To facilitate

ObjectivesTo assess the learning curve of the direct superior approach (DSA) for total hip arthroplasty (THA) and to compare surgical, clinical, and radiological results with a matched control group using the mini posterior approach (MPA).MethodsA prospective cohort study was performed from October 2016 to May 2017 including our first 52 patients undergoing THA using the DSA. Patients with primary osteoarthritis or osteonecrosis and a body mass index (BMI) < 35 who were eligible for surgery were included. As a control group, 52 patients who underwent the MPA were included, matched based on age, BMI, and ASA classification. In the DSA group, damage to the iliotibial tract and the distal external rotators, including the external obturator and quadriceps femoris muscles, was avoided. Outcome measures were collected, including surgical time, blood loss, postoperative pain, length of stay, implant position, use of walking aids, patient reported outcome measures (PROM), and complications. Unpaired t‐tests were used to analyze differences between the DSA and the MPA group in surgical time, blood loss, length of stay, and acetabular and femoral component position. χ2‐tests were used to analyze mobility and the number of complications. Two‐way repeated measures ANOVA was used to analyze pain scores and PROM between the DSA and the MPA groups.ResultsThe mean surgical time of 61 min (SD 8) in the DSA group was longer (P < 0.001) compared to that in the MPA group, 46 min (SD 12). No differences were found in blood loss, postoperative pain, or mean length of stay in the hospital. After 6 weeks, 94% of the patients in the DSA group were able to walk inside their home without walking aids compared to 90% in the MPA group. The mobility scores were not different after follow up of 6 weeks and 1 year (P = 0.12 and P = 0.36 respectively). All PROM improved postoperatively in both the DSA and the MPA group (P < 0.01). Acetabular cup and femoral stem position were not compromised by the DSA. Complications included two Vancouver B2 periprosthetic fractures in the DSA group, of which there was one surgical‐related fracture and one fracture after a traffic accident. Complications in the MPA group included one periprosthetic fracture, two hip dislocations, and one ischial neuropathy. No infections or thromboembolic events were observed. The 1‐year complication rate was not different between the MPA and DSA groups (P = 0.40).ConclusionThe DSA can be safely introduced as no learning curve in the prosthesis position or the complication rate was found.

There was a high variability among the outcome measures used, with measures within the ICF component Body Functions being most common. These results underscore the need for the development and usage of outcome measures representing all domains of health status in patients with NBPP.

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Level II-prospective comparative study.