Osteoarthritis (OA) is the most common form of arthritis. It is characterized by progressive destruction of articular cartilage and the development of chronic pain and constitutes a considerable ...socioeconomic burden. Currently, pharmacological treatments mostly aim to relieve the OA symptoms associated with inflammation and pain. However, with increasing understanding of OA pathology, several potential therapeutic targets have been identified, enabling the development of disease-modifying OA drugs (DMOADs). By targeting inflammatory cytokines, matrix-degrading enzymes, the Wnt pathway, and OA-associated pain, DMOADs successfully modulate the degenerative changes in osteoarthritic cartilage. Moreover, regenerative approaches aim to counterbalance the loss of cartilage matrix by stimulating chondrogenesis in endogenous stem cells and matrix anabolism in chondrocytes. Emerging strategies include the development of senolytic drugs or RNA therapeutics to eliminate the cellular or molecular sources of factors driving OA. This review describes the current developmental status of DMOADs and the corresponding results from preclinical and clinical trials and discusses the potential of emerging therapeutic approaches to treat OA.
Aging and mechanical overload are prominent risk factors for osteoarthritis (OA), which lead to an imbalance in redox homeostasis. The resulting state of oxidative stress drives the pathological ...transition of chondrocytes during OA development. However, the specific molecular pathways involved in disrupting chondrocyte redox homeostasis remain unclear. Here, we show that selenophosphate synthetase 1 (SEPHS1) expression is downregulated in human and mouse OA cartilage. SEPHS1 downregulation impairs the cellular capacity to synthesize a class of selenoproteins with oxidoreductase functions in chondrocytes, thereby elevating the level of reactive oxygen species (ROS) and facilitating chondrocyte senescence. Cartilage-specific Sephs1 knockout in adult mice causes aging-associated OA, and augments post-traumatic OA, which is rescued by supplementation of N-acetylcysteine (NAC). Selenium-deficient feeding and Sephs1 knockout have synergistic effects in exacerbating OA pathogenesis in mice. Therefore, we propose that SEPHS1 is an essential regulator of selenium metabolism and redox homeostasis, and its dysregulation governs the progression of OA.
Objective
Interferon regulatory factor 1 (IRF1) is a transcriptional regulator conventionally associated with immunomodulation. Recent molecular analyses mapping DNA binding sites of IRF1 have ...suggested its potential function in DNA repair. However, the physiologic significance of this noncanonical function remains unexplored. Here, we investigated the role of IRF1 in osteoarthritis (OA), a condition marked by senescence and chronic joint inflammation.
Methods
OA progression was examined in wild‐type and Irf1−/− mice using histologic assessments and microcomputed tomography analysis of whole‐joint OA manifestations and behavioral assessments of joint pain. An integrated analysis of assay for transposase‐accessible chromatin with sequencing and whole transcriptome data was conducted for the functional assessment of IRF1 in chondrocytes. The role of IRF1 in DNA repair and senescence was investigated by assaying γ‐H2AX foci and senescence‐associated beta‐galactosidase activity.
Results
Our genome‐wide investigation of IRF1 footprinting in chondrocytes revealed its primary occupancies in the promoters of DNA repair genes without noticeable footprint patterns in those of interferon‐responsive genes. Chondrocytes lacking IRF1 accumulated irreversible DNA damage under oxidative stress, facilitating their entry into cellular senescence. IRF1 was down‐regulated in the cartilage of human and mouse OA. Although IRF1 overexpression did not elicit an inflammatory response in joints or affect OA development, genetic deletion of Irf1 caused enhanced chondrocyte senescence and exacerbated post‐traumatic OA in mice.
Conclusion
IRF1 offers DNA damage surveillance in chondrocytes, protecting them from oxidative stress associated with OA risk factors. Our study provides a crucial and cautionary perspective that compromising IRF1 activity renders chondrocytes vulnerable to cellular senescence and promotes OA development.
This study aimed to (1) evaluate the preoperative Hb cut-off value for transfusion after unilateral and bilateral staged (1 week apart) TKAs, respectively, and (2) determine whether cause of ...preoperative anemia can affect transfusion rate after TKA. A total of 951 patients who underwent TKA (unilateral: 605, bilateral staged: 346) from 2016 to 2019 were reviewed retrospectively. Patient demographics, comorbidities, preoperative Hb level, surgery types, and cause of anemia were evaluated as possible risk factors. The cut-off values for preoperative Hb level to reduce transfusion after TKA were evaluated in each surgery type. Preoperative Hb level, surgery type, and cardiac disease were identified as the risk factors for transfusion after TKA, and preoperative Hb levels of 11.8 (AUC 0.88) and 12.8 (AUC 0.76) were the cut-off values for transfusion after unilateral and staged bilateral TKAs, respectively. Although transfusion rate was higher in anemia with iron deficiency (ID) group than anemia without ID group, preoperative Hb level was also lower in anemia with ID group than anemia without ID group. Single use of preoperative Hb level with different cut-offs depending on the surgery types can be useful indicator for preoperative optimization regardless of cause of anemia.
Implant material is a more important factor for periprosthetic tibial bone resorption than implant design after total knee arthroplasty (TKA). The virtual perturbation study was planned to perform ...using single case of proximal tibia model. We determined whether the implant materials' stiffness affects the degree of periprosthetic tibial bone resorption, and whether the effect of material change with the same implant design differed according to the proximal tibial plateau areas.
This three-dimensional finite element analysis included two cobalt-chromium (CoCr) and two titanium (Ti) tibial implants with different designs. They were implanted into the proximal tibial model reconstructed using extracted images from computed tomography. The degree of bone resorption or formation was measured using the strain energy density after applying axial load. The same analysis was performed after exchanging the materials while maintaining the design of each implant.
The degree of periprosthetic tibial bone resorption was not determined by the type of implant materials alone. When the implant materials were changed from Ti to CoCr, the bone resorption in the medial compartment increased and vice versa. The effect of material composition's change on anterior and posterior areas varied accordingly.
Although the degree of bone resorption was associated with implant materials, it differed depending on the design of each implant. The effect on the degree of bone resorption according to the materials after TKA should be evaluated while concomitantly considering design.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. Despite efforts to reconstruct cartilage matrix in osteoarthritic ...joints, it has been a difficult task as adult cartilage exhibits marginal repair capacity. Here we report the identification of tankyrase as a regulator of the cartilage anabolism axis based on systems-level factor analysis of mouse reference populations. Tankyrase inhibition drives the expression of a cartilage-signature matrisome and elicits a transcriptomic pattern that is inversely correlated with OA progression. Furthermore, tankyrase inhibitors ameliorate surgically induced OA in mice, and stem cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway. Our findings provide insights into the development of future OA therapies aimed at reconstruction of articular cartilage.
Abstract
Background
The Kellgren-Lawrence (KL) grading system is the most widely used method to classify the severity of osteoarthritis (OA) of the knee. However, due to ambiguity of terminology, the ...KL system showed inferior inter- and intra-observer reliability. For a more reliable evaluation, we recently developed novel deep learning (DL) software known as MediAI-OA to extract each radiographic feature of knee OA and to grade OA severity based on the KL system.
Methods
This research used data from the Osteoarthritis Initiative for training and validation of MediAI-OA. 44,193 radiographs and 810 radiographs were set as the training data and used as validation data, respectively. This AI model was developed to automatically quantify the degree of joint space narrowing (JSN) of medial and lateral tibiofemoral joint, to automatically detect osteophytes in four regions (medial distal femur, lateral distal femur, medial proximal tibia and lateral proximal tibia) of the knee joint, to classify the KL grade, and present the results of these three OA features together. The model was tested by using 400 test datasets, and the results were compared to the ground truth. The accuracy of the JSN quantification and osteophyte detection was evaluated. The KL grade classification performance was evaluated by precision, recall, F1 score, accuracy, and Cohen's kappa coefficient. In addition, we defined KL grade 2 or higher as clinically significant OA, and accuracy of OA diagnosis were obtained.
Results
The mean squared error of JSN rate quantification was 0.067 and average osteophyte detection accuracy of the MediAI-OA was 0.84. The accuracy of KL grading was 0.83, and the kappa coefficient between the AI model and ground truth was 0.768, which demonstrated substantial consistency. The OA diagnosis accuracy of this software was 0.92.
Conclusions
The novel DL software known as MediAI-OA demonstrated satisfactory performance comparable to that of experienced orthopedic surgeons and radiologists for analyzing features of knee OA, KL grading and OA diagnosis. Therefore, reliable KL grading can be performed and the burden of the radiologist can be reduced by using MediAI-OA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction At present, information about clinical efficacy and adverse events of controlled release (CR) form of pelubiprofen, a prodrug of 2-arylopropionic acid with relatively selective effects ...on cyclooxygenase-2 activity, remains scarce. In this study, we sought to determine non-inferiority of pelubiprofen CR 90 mg/day compared to aceclofenac 200 mg/day regarding clinical efficacy and adverse events after a 4-week course of medication in the patients with symptomatic knee osteoarthritis. Materials and methods A total of 191 patients were randomly assigned to take either pelubiprofen CR 90 mg (n = 95) or aceclofenac 200 mg (n = 96). The primary outcome variable was non-inferiority of pain reduction between baseline and week 4 when assessed using a 100 mm pain visual analogue scale (VAS). Pelubiprofen was considered non-inferior to aceclofenac if the upper limit of the one-sided 97.5% confidence interval for the difference in terms of pain VAS was above 15 mm (the average change of pain VAS in the pelubiprofen group-pain VAS reduction in the aceclofenac group). Secondary outcome variables were the changes in 100 mm pain VAS at week 2 versus baseline, K-Western Ontario, and McMaster University Arthritis Index (K-WOMAC) changes at weeks 2 and 4 as compared to baseline, patient global assessment at weeks 2 and 4. The frequency and amount of rescue medicine usage at weeks 2 and 4 were also evaluated as the secondary outcome variable. For safety analysis, adverse events, clinical laboratory tests, vital signs, and physical examinations were assessed and conducted at each follow-up visit. Results At week 4, the pain VAS values were significantly reduced in both groups receiving either pelubiprofen CR 90 mg or aceclofenac 200 mg as compared to the baseline. However, the pelubiprofen group and the aceclofenac group respectively showed the pain VAS changes of -22 and -21.9 in the pre-protocol set and -20.8 and -21.7 in the full analysis set, confirming non-inferiority. The pelubiprofen CR 90 mg showed a reduced incidence of adverse events compared to the aceclofenac 200 mg (p = 0.005). Conclusions Pelubiprofen CR 90 mg is as effective as aceclofenac 200 mg with reduced adverse events for the treatment of symptomatic knee osteoarthritis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this study was to assess the overall clinical results and range of motion (ROM) after total knee arthroplasty (TKA) in patients with preoperative stiffness. We also aimed to determine ...whether the severity or cause of the stiffness can affect the clinical outcome after surgery. This retrospective study included 122 knees (117 patients) with follow-up of more than 2 years (mean age, 64.3 years). TKA was performed using posterior-stabilized, varus-valgus constrained (VVC), and hinged prostheses. To determine the effect of the severity of stiffness on the clinical outcome, the subjects were divided into two groups: the severe group (preoperative ROM ≤ 50°; 18 knees) and the moderate group (preoperative ROM, 50°-90°; 104 knees). Then, clinical results and ROM were compared according to the severity or cause of preoperative stiffness. After surgery, preoperative ROM (mean, 78°; range, 25°- 90°) was improved (mean, 107°; range, 70°- 130°). The severe group more frequently used the VVC or hinged prostheses (72% vs. 18%). Furthermore, the severe group had worse knee and function scores as well as more complications (33% vs. 13%), even though the severe group had a greater ROM increment (47° vs. 27°) after surgery. Patients with osteoarthritis and rheumatoid arthritis showed better ROM and clinical results compared to patients with infectious or traumatic arthritis. Although TKA in stiff knees can be successful, the results are inferior in knees with severe stiffness and knees with infectious or traumatic arthritis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although the use of intra-articular polynucleotide (IA PN) injection as a viscosupplement for knee osteoarthritis (OA) treatment has been proposed, its efficacy and safety compared to high molecular ...weight hyaluronic acid (HMWHA) injection has not yet been established. The present double-blind, multicenter, randomized controlled trial aimed to investigate the efficacy and safety of IA PN injection compared to IA HMWHA injection. A total of 60 patients (15 men, 45 women, 64.5 ± 7.5 years) with knee OA (Kellgren-Lawrence grade 1-4) were randomly allocated to each group. All patients were given three IA injections of PN (n = 30) or HMWHA (n = 30) at intervals of 1 week. The primary endpoint was the change rate in weight-bearing pain (WBP) 16 weeks from the baseline. The secondary endpoint included multiple measurements: the change rate in WBP rate at 8 weeks; the change rate in pain level at rest and during walking at 8 and 16 weeks; the Korean-Western Ontario and McMaster University Osteoarthritis index; the Euro-Quality of Life-5 Dimension; Clinical Global Impression, Patient Global Impression at 8 and16 weeks, and total consumption of rescue medicine. The mean change rate in the WBP at 16 weeks from the baseline was - 54.0 ± 38.1% in the IA PN group and - 42.8 (± 35.8%) in the IA HMWHA group, and there was no significant difference between the two groups (p = 0.296). All secondary endpoints related with pain and functional outcome also showed no significant difference between the two groups. Pain at the injection site and swelling were reported as adverse events, and the incidence was similar between the two groups. IA PN showed comparable efficacy and safety to IA HMWHA at 3 times injection with an interval of 1 week. IA PN can be useful alternative to IA HMWHA for the treatment of knee OA.
PDF
