Distinct metabolic programs induced by TGF-β1 and BMP2 in human articular chondrocytes with osteoarthritis

Objectives: Cellular energy metabolism is important for the function of all tissues, including cartilage. Recent studies indicate that superficial and deep subpopulations of articular chondrocytes (ACs) have distinct metabolic profiles. At the cellular and molecular level, osteoarthritis (OA) is characterised by alteration from a healthy homoeostatic state towards a catabolic state. Several molecular pathways, including transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signalling, have been identified as critical players in the pathogenesis and progression of OA. However, the manner in which these factors influence cellular energy metabolism in ACs is not well understood. This study investigates the effect of TGF-β or BMP signalling on energy metabolism in human articular chondrocytes (hACs). Methods: ACs were isolated from residual macroscopically full thickness and intact cartilage from the femoral condyle of human samples obtained from patients with OA. ACs were treated with Vehicle (control), TGF-β1 or BMP2 for 48–72 hours. Metabolic assays were performed to determine glucose consumption, lactate production and adenosine triphosphate (ATP) production, whereas the mitochondrial stress test was performed to determine oxygen consumption rate. Protein was isolated to assess translational activity and was evaluated using Western blot. Results: We showed that TGF-β1, known to maintain chondrocyte homoeostasis, stimulated glycolysis by upregulating key glycolytic factors, such as glucose transporter 1 (Glut1) and hexokinase II, while reducing oxidative phosphorylation in hACs. In contrast, BMP2 enhanced mitochondrial metabolism and oxidative phosphorylation and had a minimal effect on key glycolytic regulators. Conclusions: Our data revealed distinct metabolic programs induced by TGF-β1 and BMP2 in hACs, suggesting that the regulation of cellular metabolism may represent a new mechanism underlying the pathogenesis of OA. The translational potential of this article: The findings define the regulation of energy metabolism as a potential novel therapeutic approach for the treatment of OA

How do you know it is true? integrity in research and publications: AOA critical issue

High-quality medical care is the result of clinical decisions based upon scientific principles garnered from basic, translational, and clinical research. Information regarding the natural history of diseases and their responses to various treatments is introduced into the medical literature through the approximately one million PubMed journal articles published each year. Pharmaceutical and device companies, universities, departments, and researchers all stand to gain from research publication. Basic and translational research is highly competitive. Success in obtaining research funding and career advancement requires scientific publication in the medical literature. Clinical research findings can lead to changes in the pattern of orthopaedic practice and have implications for the utilization of pharmaceuticals and orthopaedic devices. Research findings can be biased by ownership of patents and materials, funding sources, and consulting arrangements. The current high-stakes research environment has been characterized by an increase in plagiarism, falsification or manipulation of data, selected presentation of results, research bias, and inappropriate statistical analyses. It is the responsibility of the orthopaedic community to work collaboratively with industry, universities, departments, and medical researchers and educators to ensure the integrity of the content of the orthopaedic literature and to enable the incorporation of best practices in the care of orthopaedic patients

Patient-Reported Outcomes Measurement Information System physical function correlates with Toronto Extremity Salvage Score in an orthopaedic oncology population

Background: The National Institute of Health\u27s Patient-Reported Outcomes Measurement Information System (PROMIS) uses computerised-adaptive testing to reduce survey burden and improve sensitivity. PROMIS is being used across medical and surgical disciplines but has not been studied in orthopaedic oncology. Questions/purposes: The aim of the study was to compare PROMIS measures with upper extremity (UE) and lower extremity (LE) Toronto Extremity Salvage Score (TESS) by assessing the following: (1) responder burden, (2) correlation between scores and (3) floor/ceiling effects. Patients and methods: This cross-sectional trial analysed all 97 adult patients treated surgically for a bone or soft tissue tumour at a tertiary institution between November 2015 and March 2016. TESS (UE or LE) and PROMIS (Physical Function, Pain Interference and Depression) surveys were administered preoperatively. Pearson correlations between each PROMIS domain and TESS were calculated, as were floor/ceiling effects of each outcome measure. Results: (1) Completion of three PROMIS questionnaires required a mean total of 16.8 (+/- 5.8 standard deviation) questions, compared with 31 and 32 questions for the LE and UE TESS questionnaires, respectively. (2) The PROMIS Physical Function scores demonstrated a strong positive correlation with the LE TESS (r = 0.84; 95% confidence interval [CI], 0.72-0.91; p \u3c 0.001) and moderate positive correlation with the UE TESS (r = 0.64; 95% CI, 0.34-0.83; p = 0.055). The PROMIS Depression scores demonstrated a weak negative correlation with both the LE TESS (r = -0.38; 95% CI, -0.61 to -0.10; p = 0.010) and with UE TESS (r = -0.38; 95% CI, -0.67 to -0.01; p = 0.055). The PROMIS Pain Interference scores demonstrated a strong negative correlation with the LE TESS (r = -0.71; 95% CI, -0.83 to -0.52; p \u3c 0.001) and a moderate negative correlation with the UE TESS (r = -0.62; 95% CI, -0.81 to -0.30; p = 0.001). (3) The UE TESS had a range of scores from 16 to 100 with a 27% ceiling effect and no floor effect, and the LE TESS had a range from 10 to 98 with no floor or ceiling effect. There was no floor or ceiling effect for any PROMIS measures. Conclusions: In an orthopaedic oncology population, the PROMIS Physical Function and Pain Interference scores correlate with the TESS and have the benefit of reduced survey burden and ceiling effect. The PROMIS Depression scores may provide additional information regarding patient outcomes not captured by the TESS. Level of Evidence: Level III. The translational potential of this article: Patient reported outcome measures asses patients\u27 symptoms, function and health-related quality of life and are designed to capture more clinical information than can be gathered by objective medial testing alone. As reimbursements and the understanding of patient outcomes are becoming tied to performance on PROMIS measures, it is an important step to establish how PROMIS measures correlate and compare to traditional legacy measures

Dnmt3b ablation impairs fracture repair through upregulation of Notch pathway

We previously established that DNA methyltransferase 3b (Dnmt3b) is the sole Dnmt responsive to fracture repair and that Dnmt3b expression is induced in progenitor cells during fracture repair. In the current study, we confirmed that Dnmt3b ablation in mesenchymal progenitor cells (MPCs) resulted in impaired endochondral ossification, delayed fracture repair, and reduced mechanical strength of the newly formed bone in Prx1-Cre;Dnmt3bf/f (Dnmt3bPrx1) mice. Mechanistically, deletion of Dnmt3b in MPCs led to reduced chondrogenic and osteogenic differentiation in vitro. We further identified Rbpjκ as a downstream target of Dnmt3b in MPCs. In fact, we located 2 Dnmt3b binding sites in the murine proximal Rbpjκ promoter and gene body and confirmed Dnmt3b interaction with the 2 binding sites by ChIP assays. Luciferase assays showed functional utilization of the Dnmt3b binding sites in murine C3H10T1/2 cells. Importantly, we showed that the MPC differentiation defect observed in Dnmt3b deficiency cells was due to the upregulation of Rbpjκ, evident by restored MPC differentiation upon Rbpjκ inhibition. Consistent with in vitro findings, Rbpjκ blockage via dual antiplatelet therapy reversed the differentiation defect and accelerated fracture repair in Dnmt3bPrx1 mice. Collectively, our data suggest that Dnmt3b suppresses Notch signaling during MPC differentiation and is necessary for normal fracture repair

Safety of overlapping inpatient orthopaedic surgery: A multicenter study

BackgroundAlthough overlapping surgery is used to maximize efficiency, more empirical data are needed to guide patient safety. We conducted a retrospective cohort study to evaluate the safety of overlapping inpatient orthopaedic surgery, as judged by the occurrence of perioperative complications.MethodsAll inpatient orthopaedic surgical procedures performed at 5 academic institutions from January 1, 2015, to December 31, 2015, were included. Overlapping surgery was defined as 2 skin incisions open simultaneously for 1 surgeon. In comparing patients who underwent overlapping surgery with those who underwent non-overlapping surgery, the primary outcome was the occurrence of a perioperative complication within 30 days of the surgical procedure, and secondary outcomes included all-cause 30-day readmission, length of stay, and mortality. To determine if there was an association between overlapping surgery and a perioperative complication, we tested for non-inferiority of overlapping surgery, assuming a null hypothesis of an increased risk of 50%. We used an inverse probability of treatment weighted regression model adjusted for institution, procedure type, demographic characteristics (age, sex, race, comorbidities), admission type, admission severity of illness, and clustering by surgeon.ResultsAmong 14,135 cases, the frequency of overlapping surgery was 40%. The frequencies of perioperative complications were 1% in the overlapping surgery group and 2% in the non-overlapping surgery group. The overlapping surgery group was non-inferior to the non-overlapping surgery group (odds ratio [OR], 0.61 [90% confidence interval (CI), 0.45 to 0.83]; p < 0.001), with reduced odds of perioperative complications (OR, 0.61 [95% CI, 0.43 to 0.88]; p = 0.009). For secondary outcomes, there was a significantly lower chance of all-cause 30-day readmission in the overlapping surgery group (OR, 0.67 [95% CI, 0.52 to 0.87]; p = 0.003) and shorter length of stay (e, 0.94 [95% CI, 0.89 to 0.99]; p = 0.012). There was no difference in mortality.ConclusionsOur results suggest that overlapping inpatient orthopaedic surgery does not introduce additional perioperative risk for the complications that we evaluated. The suitability of this practice should be determined by individual surgeons on a case-by-case basis with appropriate informed consent.Level of evidenceTherapeutic Level III. See Instructions for Authors for a complete description of levels of evidence