Autologous Collagen-Induced Chondrogenesis: From Bench to Clinical Development.

Microfracture is a common technique that uses bone marrow components to stimulate cartilage regeneration. However, the clinical results of microfracture range from poor to good. To enhance cartilage healing, several reinforcing techniques have been developed, including porcine-derived collagen scaffold, hyaluronic acid, and chitosan. Autologous collagen-induced chondrogenesis (ACIC) is a single-step surgical technique for cartilage regeneration that combines gel-type atelocollagen scaffolding with microfracture. Even though ACIC is a relatively new technique, literature show excellent clinical results. In addition, all procedures of ACIC are performed arthroscopically, which is increasing in preference among surgeons and patients. The ACIC technique also is called the Shetty-Kim technique because it was developed from the works of A.A. Shetty and S.J. Kim. This is an up-to-date review of the history of ACIC.

Volume index as a new measure of cartilage loss: a retrospective MRI-based study of chondral injury patterns in adult patients with knee pain.

BACKGROUND: Knee pain is one of the commonest symptoms in patients who attend the Orthopaedic outpatient clinics. Chondral defects result in a painful knee. Incidence of chondral defect is reported to be between 5 and 10% over the age of 40. It is well documented that chondral defects can lead to osteoarthritis. Early detection of these lesions and cartilage repair surgery can delay the onset of osteoarthritis. The purpose of this study is to highlight the incidence, associations and correlations between opposing cartilage defects in patients who present to the knee clinic with pain. METHODS: A retrospective analysis was carried out on patients who had Magnetic Resonance Imaging scans for painful knees between June 2017 and May 2019. About 227 consecutive knees were studied for the incidence of chondral defects, number of lesions, grade and size of lesion, geographical location and associated pathology in the knee. RESULTS: All the 227 patients had chondral lesions. Most patients had 2-3 lesions (66.1%) with patellar lesions (76.6%) being the commonest followed by medial femoral condyle (59.9%). Significant correlation was found in grade and size between opposing surface lesions in patella-trochlea, Medial Femoral Condyle-Medial Tibial Plateau and Lateral Femoral Condyle-Lateral Tibial Plateau. Females were more predisposed to patella lesions. Significance between age and lesions were established. CONCLUSION: Incidence of cartilage defects in the knee is very high. Kissing lesions must be considered when treating cartilage lesions. Volume index could be a promising method to quantify lesions.

Soluble CCR2 gene therapy controls joint inflammation, cartilage damage, and the progression of osteoarthritis by targeting MCP-1 in a monosodium iodoacetate (MIA)-induced OA rat model.

BACKGROUND: Osteoarthritis (OA) is the most common type of degenerative arthritis and affects the entire joint, causing pain, joint inflammation, and cartilage damage. Various risk factors are implicated in causing OA, and in recent years, a lot of research and interest have been directed toward chronic low-grade inflammation in OA. Monocyte chemoattractant protein-1 (MCP-1; also called CCL2) acts through C-C chemokine receptor type 2 (CCR2) in monocytes and is a chemotactic factor of monocytes that plays an important role in the initiation of inflammation. The targeting of CCL2-CCR2 is being studied as part of various topics including the treatment of OA. METHODS: In this study, we evaluated the potential therapeutic effects the sCCR2 E3 gene may exert on OA. The effects of sCCR2 E3 were investigated in animal experiments consisting of intra-articular injection of sCCR2 E3 in a monosodium iodoacetate (MIA)-induced OA rat model. The effects after intra-articular injection of sCCR2 E3 (fusion protein encoding 20 amino acids of the E3 domain of the CCL2 receptor) in a monosodium iodoacetate-induced OA rat model were compared to those in rats treated with empty vector (mock treatment) and full-length sCCR2. RESULTS: Pain improved with expression of the sCCR2 gene. Improved bone resorption upon sCCR2 E3 gene activation was confirmed via bone analyses using micro-computed tomography. Histologic analyses showed that the sCCR2 E3 gene exerted protective effects against cartilage damage and anti-inflammatory effects on joints and the intestine. CONCLUSIONS: These results show that sCCR2 E3 therapy is effective in reducing pain severity, inhibiting cartilage destruction, and suppressing intestinal damage and inflammation. Thus, sCCR2 E3 may be a potential therapy for OA.

Validity of the Morse Fall Scale and the Johns Hopkins Fall Risk Assessment Tool for fall risk assessment in an acute care setting.

AIMS AND OBJECTIVES: To evaluate the measured fall risk score that more accurately reflects the changeable conditions in acute care settings, and to efficiently evaluate the association between falls and fall risk score. BACKGROUND: The Morse Fall Scale (MFS) is a well-known easy-to-use tool, while the Johns Hopkins Fall Risk Assessment Tool (JHFRAT) consists of items with high specificity. Evaluating suitable fall-risk assessment tools to measure these changeable conditions may contribute to preventing falls in acute care settings. DESIGN: Retrospective case-control study using the STROBE checklist. METHODS: In an acute care setting (708-bedded university hospital with a regional emergency medical centre), the non-fall group was adjusted to fall group using propensity score matching. According to the fall rate of 3-5%, non-fall groups for each tool were selected (1386 and 1947) from the before adjusted data, and the fall groups included 42 and 59. The applied covariates were individual characteristics that ordinarily changed such as age, gender, diagnostic department and hospitalisation period. The adjusted data were analysed using generalised estimating equations and mixed effect model. RESULTS: After adjustment, the fall group measured using the JHFRAT had a significantly higher difference between the initial and re-measured total score than the non-fall group. The JHFRAT, especially with the re-measured score, had a higher AUC value for predicting falls than the MFS. MFS's sensitivity was 85.7%, and specificity was 58.8% at 50 points; for JHFRAT, these were 67.8% and 80.2% at 14 points, respectively. These cut-off points were used to evaluate validity during tool development and are commonly used as reference scores. CONCLUSIONS: JHFRAT more accurately reflects acute changeable conditions related to fall risk measurements after admission. RELEVANCE TO CLINICAL PRACTICE: JHFRAT may be useful for effective fall prevention activities in acute care settings.

Cartilage Regeneration Using Human Umbilical Cord Blood Derived Mesenchymal Stem Cells: A Systematic Review and Meta-Analysis.

Background and Objectives: Human umbilical-cord-blood-derived mesenchymal stem cells (hUCB-MSCs) have recently been used in clinical cartilage regeneration procedures with the expectation of improved regeneration capacity. However, the number of studies using hUCB-MSCs is still insufficient, and long-term follow-up results after use are insufficient, indicating the need for additional data and research. We have attempted to prove the efficacy and safety of hUCB-MSC treatment in a comprehensive analysis by including all subjects with knee articular cartilage defect or osteoarthritis who have undergone cartilage repair surgery using hUCB-MSCs. We conducted a meta-analysis and demonstrated efficacy and safety based on a systematic review. Materials and Methods: This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. For this study, we searched the PubMed, Embase, Web of Science, Scopus, and Cochrane Library literature databases up to June 2022. A total of seven studies were included, and quality assessment was performed for each included study using the Newcastle−Ottawa Quality Assessment Scale. Statistical analysis was performed on the extracted pooled clinical outcome data, and subgroup analyses were completed. Results: A total of 570 patients were included in the analysis. In pooled analysis, the final follow-up International Knee Documentation Committee (IKDC) score showed a significant increase (mean difference (MD), −32.82; 95% confidence interval (CI), −38.32 to −27.32; p < 0.00001) with significant heterogeneity (I2 = 93%, p < 0.00001) compared to the preoperative score. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at final follow-up were significantly decreased (MD, 30.73; 95% CI, 24.10−37.36; p < 0.00001) compared to the preoperative scores, with significant heterogeneity (I2 = 95%, p < 0.00001). The visual analog scale (VAS) score at final follow-up was significantly decreased (MD, 4.81; 95% CI, 3.17−6.46; p < 0.00001) compared to the preoperative score, with significant heterogeneity (I2 = 98%, p < 0.00001). Two studies evaluated the modified Magnetic Resonance Observation of Cartilage Repair Tissue (M-MOCART) score and confirmed sufficient improvement. In a study analyzing a group treated with bone marrow aspiration concentrate (BMAC), there was no significant difference in clinical outcome or M-MOCART score, and the post-treatment International Cartilage Repair Society (ICRS) grade increased. Conclusion: This analysis demonstrated the safety, efficacy, and quality of repaired cartilage following hUCB-MSC therapy. However, there was no clear difference in the comparison with BMAC. In the future, comparative studies with other stem cell therapies or cartilage repair procedures should be published to support the superior effect of hUCB-MSC therapy to improve treatment of cartilage defect or osteoarthritis.

Metformin Augments Anti-Inflammatory and Chondroprotective Properties of Mesenchymal Stem Cells in Experimental Osteoarthritis.

Mesenchymal stem cells (MSCs) can protect against cartilage breakdown in osteoarthritis (OA) via their immunomodulatory capacities. However, the optimization strategy for using MSCs remains challenging. This study's objective was to identify the in vivo effects of metformin-stimulated adipose tissue-derived human MSCs (Ad-hMSCs) in OA. An animal model of OA was established by intra-articular injection of monosodium iodoacetate into rats. OA rats were divided into a control group and two therapy groups (treated with Ad-hMSCs or metformin-stimulated Ad-hMSCs). Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Our data show that metformin increased IL-10 and IDO expression in Ad-hMSCs and decreased high-mobility group box 1 protein, IL-1ß, and IL-6 expression. Metformin increased the migration capacity of Ad-hMSCs with upregulation of chemokine expression. In cocultures, metformin-stimulated Ad-hMSCs inhibited the mRNA expression of RUNX2, COL X, VEGF, MMP1, MMP3, and MMP13 in IL-1ß-stimulated OA chondrocytes and increased the expression of TIMP1 and TIMP3. The antinociceptive activity and chondroprotective effects were greater in OA rats treated with metformin-stimulated Ad-hMSCs than in those treated with unstimulated Ad-hMSCs. TGF-ß expression in subchondral bone of OA joints was attenuated more in OA rats treated with metformin-stimulated Ad-hMSCs. Our findings suggest that metformin offers a promising option for the clinical application of Ad-hMSCs as a cell therapy for OA.

TRIM24-RIP3 axis perturbation accelerates osteoarthritis pathogenesis.

OBJECTIVES: Recently, necroptosis has attracted increasing attention in arthritis research; however, it remains unclear whether its regulation is involved in osteoarthritis (OA) pathogenesis. Since receptor-interacting protein kinase-3 (RIP3) plays a pivotal role in necroptosis and its dysregulation is involved in various pathological processes, we investigated the role of the RIP3 axis in OA pathogenesis. METHODS: Experimental OA was induced in wild-type or Rip3 knockout mice by surgery to destabilise the medial meniscus (DMM) or the intra-articular injection of adenovirus carrying a target gene (Ad-Rip3 and Ad-Trim24 shRNA). RIP3 expression was examined in OA cartilage from human patients; Trim24, a negative regulator of RIP3, was identified by microarray and in silico analysis. Connectivity map (CMap) and in silico binding approaches were used to identify RIP3 inhibitors and to examine their direct regulation of RIP3 activation in OA pathogenesis. RESULTS: RIP3 expression was markedly higher in damaged cartilage from patients with OA than in undamaged cartilage. In the mouse model, adenoviral RIP3 overexpression accelerated cartilage disruption, whereas Rip3 depletion reduced DMM-induced OA pathogenesis. Additionally, TRIM24 knockdown upregulated RIP3 expression; its downregulation promoted OA pathogenesis in knee joint tissues. The CMap approach and in silico binding assay identified AZ-628 as a potent RIP3 inhibitor and demonstrated that it abolished RIP3-mediated OA pathogenesis by inhibiting RIP3 kinase activity. CONCLUSIONS: TRIM24-RIP3 axis perturbation promotes OA chronicity by activating RIP3 kinase, suggesting that the therapeutic manipulation of this pathway could provide new avenues for treating OA.

Articular cartilage repair using autologous collagen-induced chondrogenesis (ACIC): a pragmatic and cost-effective enhancement of a traditional technique.

PURPOSE: The autologous collagen-induced chondrogenesis technique is described, and the results of a 6-year follow-up clinical study using this technique are presented. METHODS: 30 patients with International Cartilage Repair Society (ICRS) Grade III/IVa symptomatic chondral defects of the knee treated with enhanced microdrilling using atelocollagen were prospectively examined in this clinical series. The median age of the patients was 39.0 years (range 19-61 years). Patients were followed up to 72 months. Clinical evaluation was performed using functional knee scores and radiologically. Both quantitative and qualitative assessments were performed. RESULTS: Statistically significant and clinically relevant improvement was observed in 2 years and was sustained for the 6 years of the study observation. At 6 years, the mean Lysholm score was 79.7 (SD 6.8) compared to 52.6 (SD 10.7) pre-operatively (p < 0.05). The symptomatic Knee Injury and Osteoarthritis Outcome Score (KOOS) improved from 68.3 (SD 11.4) to 90.2 (SD 4.3) (p < 0.05). The subjective International Knee Documentation Committee (IKDC) also showed improvement from 39.1 (SD 4.1) to 81.6 (SD 7.8) (p < 0.05). The calculated T2* relaxation times were 26.0 (SD 4.2) seconds and 30.3 (SD 6.2) seconds for the repair tissue and native cartilage, respectively. The average magnetic resonance observation of cartilage repair tissue (MOCART) score was 78.5 (SD 9.6) for all lesions. CONCLUSION: The enhanced microdrilling using atelocollagen is an enhancement of the traditional microfracture method using an off-the-shelf product. When used to treat moderate to severe chondral lesions, this enhancement produces hyaline-like cartilage with a corresponding improvement in symptoms. LEVEL OF EVIDENCE: IV.

Enhancement of Healing of Long Tubular Bone Defects in Rabbits Using a Mixture of Atelocollagen Gel and Bone Marrow Aspirate Concentrate.

We evaluated the bone-forming potential of a mixture of atelocollagen and bone marrow aspirate concentrate which was transplanted into bone defects. Radial shaft defects of about 10 mm in size were created in 30 New Zealand white rabbits. Ten rabbits in the control group were not treated further, 10 rabbits in the first experimental group (E1) received an atelocollagen injection, and 10 rabbits in the second experimental group (E2) received an injection of a mixture of atelocollagen and bone marrow aspirate concentrate. The groups were compared radiologically at 8 weeks. Osteogenesis in group E2 progressed more rapidly than that in the other groups, and osteogenesis in group E1 progressed faster than that in the control group. Thus, the administration of a mixture of atelocollagen and bone marrow aspirate concentrate in bone defects was found to enhance bone defect healing.

Does size difference in allogeneic cancellous bone granules loaded with differentiated autologous cultured osteoblasts affect osteogenic potential?

We study the efficacy of bone regeneration by using two differently sized allogeneic cancellous bone granules loaded with autologous cultured osteoblasts in a rabbit model. Critical-sized bone defects of the radial shaft were made in 40 New Zealand White rabbits. Small allogeneic bone granules (150-300 µm in diameter) loaded with cultured differentiated autologous osteoblasts were implanted into one forearm (SBG group) and large bone granules (500-710 µm) loaded with osteoblasts were implanted into the forearm of the other side (LBG group). Radiographic evaluations were performed at 3, 6, 9 and 12 weeks and histology and micro-CT image analysis were carried out at 6 and 12 weeks post-implantation. On radiographic evaluation, the LBG group showed a higher bone quantity index at 3 and 6 weeks post-implantation (P < 0.05) but statistical significance was lost at 9 and 12 weeks. The progression of biological processes of the SBG group was faster than that of the LBG group. On micro-CT image analysis, the LBG group revealed a higher total bone volume and surface area than the SBG group at 6 weeks (P < 0.05) but the difference decreased at 12 weeks and was without statistical significance. Histological evaluation also revealed faster progression of new bone formation and maturation in the SBG group. Thus, the two differently sized allogeneic bone granules loaded with co-cultured autologous osteoblasts show no differences in the amount of bone regeneration, although the SBG group exhibits faster progression of bone regeneration and remodeling. This method might therefore provide benefits, such as a short healing time and easy application in an injectable form, in a clinical setting.

Correction: Hill et al. A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of a Krill Oil, Astaxanthin, and Oral Hyaluronic Acid Complex on Joint Health in People with Mild Osteoarthritis. Nutrients 2023, 15, 3769.

In the original publication [...].

Femoral anteversion linked to the inability to squat: Analysis of CT images in the patient and control groups.

Many patients who cannot squat well in a neutral toe position can only squat in an excessively out-toeing position. This excessive out-toeing squat is thought to be caused by rotational problems of the lower extremities. In this study, we aimed to identify the cause for the inability to squat by measuring and comparing femoral and tibial torsion between an excessive out-toeing squat patient group and a control group representing the general population. Between 2008 and 2022, a patient group comprising 50 lower extremities with excessive out-toeing squats was established. A control group representing the general population was selected from patients aged 0 to 29 years, who underwent lower-extremity CT angiography between 2012 and 2022, using the Clinical Data Warehouse with exclusion criteria applied. A total of 94 lower extremities were included in the control group. The femoral torsional angle (FTA) and tibial torsional angle (TTA) of both groups were measured and compared using Student t test. Additionally, 30 each of those with the highest and lowest 30 FTA values were selected from the patient and control groups, and the TTA was compared between the high- and low-FTA groups using Student t test. The mean FTA was 0.34° (SD, 11.11°) in the patient group and 10.14° (SD, 11.85°) in the control group, with a mean difference of 9.8° and P < .001. The mean TTA was 27.95° (SD, 7.82°) in the patient group and 32.67 ° (SD, 7.58°) in the control group, with a mean difference of 4.72° (P = .001). The mean TTA was 34.3° (SD, 7.72°) in the high-FTA group and 28.17° (SD, 8.35°) in the low-FTA group, with a mean difference of 6.13° (P = .005). Patients with excessive out-toeing squat showed lower FTA and TTA values than the general population. Furthermore, although a correlation between FTA and TTA was not established through Pearson correlation analysis, a tendency was observed where a decrease in FTA was associated with a decrease in TTA. Based on these results, decreased FTA was demonstrated to be one of the major causes of excessive out-toeing squats.

Autologous collagen-induced chondrogenesis using fibrin and atelocollagen mixture.

For articular cartilage defect treatment, many treatment modalities have been developed. We evaluate the cartilage repair potential of an atelocollagen and fibrin mixture transplanted to cartilage defects. A circular, articular cartilage defect 4 mm in diameter was made in the trochlear region in each of 20 New Zealand white rabbits. The 10 rabbits in the control group were kept without treatment and the 10 rabbits in the experimental group underwent injection of atelocollagen mixed with fibrin. At week 12 following surgery the cartilage was observed and histologically compared in both groups. The surface of the newly generated cartilage was very smooth and even, and we also noted that the entire area was completely regenerated in the experimental group. The control group showed incomplete and irregular cartilage formation in the defect. Regarding the histological scoring, comparison of the two groups differed significantly (p < 0.001). Injection of a mixture of atelocollagen and fibrin used to treat articular cartilage defects of the knee appears to be an effective method for cartilage regeneration.

Treatment of osteonecrosis in the knee joint of a rabbit using autologous cultured osteoblasts.

BACKGROUND: [corrected] To develop a successful treatment modality for osteonecrosis, an appropriate animal model is essential. We have proposed a new osteonecrosis model that shows the total amount of necrosis and in which we observed new bone formation after transplanting autologous cultured osteoblasts. MATERIALS AND METHODS: The femoral condyles of the right knees of New Zealand white rabbits were exposed after dissecting the ligaments surrounding the distal femur. After which, the metaphyseal-diaphyseal junction was cut using a saw, and the entire femoral condyle was isolated. After three liquid nitrogen treatments, the isolated femoral condyle was internally fixated to the femoral shaft using two or three Kirschner wires. Bone marrow isolated from the iliac crest was cultivated to differentiate it into osteoblasts, and the cultured cells were then injected into the necrotic bone. RESULTS: Viable osteocytes with well-stained nuclei were not present in the necrotic areas at any stage of the development of the osteonecrosis model within 24 wk after osteonecrosis induction. However, new bone formation with osteocytes and blood vessels was observed in the necrotic bone 12 wk after transplanting the autologous cultured osteoblasts. CONCLUSIONS: The distal femoral condyle of the rabbit is an appropriate model for demonstrating osteonecrosis and treatment evaluation owing to its easy reproducibility and treatment interpretation. Therefore, autologous cultured osteoblast treatment would seem to be a potentially successful treatment modality for osteonecrosis.

Repair tissue quality after arthroscopic autologous collagen-induced chondrogenesis (ACIC) assessed via T2* mapping.

OBJECTIVE: A novel single-stage approach using arthroscopic microdrilling and atelocollagen/fibrin-gel application is employed for cartilage repair of the knee. The purpose of our study was to investigate the morphological and biochemical MRI outcome after this technique. MATERIALS AND METHODS: A retrospective case series of ten patients (mean age 45 years) with symptomatic chondral defects in the knee who were treated arthroscopically with microdrilling and atelocollagen application was analyzed. All defects were ICRS grade III or IV and the sizes were 2-8 cm(2) intra-operatively. All patients underwent morphological MRI and T2-star mapping at 1.5 T at 1-year follow-up. The magnetic resonance observation of cartilage repair tissue (MOCART) score was assessed. T2* relaxation time values of repair tissue and a healthy native cartilage area was assessed by means of region of interest analysis on the T2* maps. RESULTS: The mean MOCART score at 1-year follow-up was 71.7 ± 21.0 ranging from 25 to 95. The mean T2* relaxation times were 30.6 ± 11.3 ms and 28.8 ± 6.8 ms for the repair tissue and surrounding native cartilage, respectively. The T2* ratio between the repair tissue and native cartilage was 105% ± 30%, indicating repair tissue properties similar to native cartilage. CONCLUSIONS: An arthroscopic single-stage procedure using microdrilling in combination with atelocollagen gel and fibrin-glue can provide satisfactory MRI results at 1-year follow-up, with good cartilage defect filling. The T2* values in the repair tissue achieved similar values compared to normal hyaline cartilage.

Characteristics of multi-ligament knee injuries accompanied with patellar tendon disruption.

PURPOSE: Patella tendon rupture with multi-ligament injury is a rare injury. We observed patients with patella tendon rupture (or patella inferior pole fracture) with multi-ligament injury. This study intends to inspect the mechanism of the injury and classify them. METHODS: This is a case series involving patients from two hospitals. Twelve patients who had patella tendon rupture (PTR) with multi-ligament injury were studied. RESULTS: The incidence of multi-ligament injury in patella tendon rupture patients found to be 13% in retrospective search. Two types of injury were observed. First type is relatively low energy injury involving ACL and patella tendon which does not involve rupture of PCL. Second type is high energy injury involving PCL and patella tendon. Treatment differed among the patients, due to severity of trauma. Two-staged operation was the basis of treatment. Patella tendon was repaired in first stage. Reconstruction of ligaments was done in second stage. The patients who had infection or stiffness did not have a second surgery. CONCLUSION: Patella tendon rupture with multi-ligament injury can be classified into low energy rotational injury and high energy dashboard injury. Two-staged surgery is the basis of treatment.

A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of a Krill Oil, Astaxanthin, and Oral Hyaluronic Acid Complex on Joint Health in People with Mild Osteoarthritis.

Osteoarthritis is a significant global health problem. Many patients seek more effective alternatives to nonsteroidal anti-inflammatory medicines or commercial supplements to manage joint pain and inflammation. FlexPro MD® (FP-MD) combines krill oil, astaxanthin, and lower molecular weight hyaluronic acid to support joint health. A 12-week, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of FP-MD and placebo once daily in participants (n = 100) with mild osteoarthritis of the knee or hip joint. For the primary endpoint of joint pain score, per-protocol participants (n = 75) in the FP-MD group (n = 37) had a statistically significantly greater mean reduction from baseline in the Korean Visual Analog Scale (K-VAS) at week 12 compared with participants in the placebo group (n = 38) (20.8 ± 16.16 mm vs. 10.6 ± 17.58, p = 0.0105). The Korean Western Ontario and McMaster Universities Osteoarthritis Index (K-WOMAC) total score was also significantly improved in the FP-MD group at week 12 compared with placebo (-13.0 ± 13.62 vs. -5.5 ± 18.08, p = 0.0489), especially an improvement in pain score (-2.5 ± 2.92 vs. -1.3 ± 3.94, p = 0.02635). FP-MD group had greater improvement in joint function scoring by investigator assessment (p = 0.0127) and by group participants (p = 0.0070). A statistically significantly greater number of patients reported adverse events in the placebo group compared with the FP-MD group (16% vs. 4%, p = 0.0455), most commonly gastrointestinal disorders in both of the groups. These findings suggest that FP-MD is well tolerated and can be effectively used to address joint pain in patients diagnosed with mild osteoarthritis, the main symptom of this condition.

Blockade of Activin Receptor IIB Protects Arthritis Pathogenesis by Non-Amplification of Activin A-ACVR2B-NOX4 Axis Pathway.

Although activin receptor IIB (ACVR2B) is emerging as a novel pathogenic receptor, its ligand and assembled components (or assembly) are totally unknown in the context of osteoarthritis (OA) pathogenesis. The present results suggest that upregulation of ACVR2B and its assembly could affect osteoarthritic cartilage destruction. It is shown that the ACVR2B ligand, activin A, regulates catabolic factor expression through ACVR2B in OA development. Activin A Tg mice (Col2a1-Inhba) exhibit enhanced cartilage destruction, whereas heterozygous activin A KO mice (Inhba+/- ) show protection from cartilage destruction. In silico analysis suggests that the Activin A-ACVR2B axis is involved in Nox4-dependent ROS production. Activin A Tg:Nox4 KO (Col2a1-Inhba:Nox4-/- ) mice show inhibition of experimental OA pathogenesis. NOX4 directly binds to the C-terminal binding site on ACVR2B-ACVR1B and amplifies the pathogenic signal for cartilage destruction through SMAD2/3 signaling. Together, the findings reveal that the ACVR2B assembly, which comprises Activin A, ACVR2B, ACVR1B, Nox4, and AP-1-induced HIF-2α, accelerates OA development. Furthermore, it is shown that shRNA-mediated ACVR2B knockdown or trapping ligands of ACVR2B abrogate OA development by competitively disrupting the ACVR2B-Activin A interaction. These results suggest that the ACVR2B assembly is required to amplify osteoarthritic cartilage destruction and could be a potential therapeutic target in efforts to treat OA.

Prussian blue nanozymes coated with Pluronic attenuate inflammatory osteoarthritis by blocking c-Jun N-terminal kinase phosphorylation.

Osteoarthritis (OA) is a degenerative joint disorder associated with inflammation, functional disability, and high socioeconomic costs. The development of effective therapies against inflammatory OA has been limited owing to its complex and multifactorial nature. The efficacy of Prussian blue nanozymes coated with Pluronic (PPBzymes), US Food and Drug Administration-approved components, and their mechanisms of action have been described in this study, and PPBzymes have been characterized as a new OA therapeutic. Spherical PPBzymes were developed via nucleation and stabilization of Prussian blue inside Pluronic micelles. A uniformly distributed diameter of approximately 204 nm was obtained, which was maintained after storage in an aqueous solution and biological buffer. This indicates that PPBzymes are stable and could have biomedical applications. In vitro data revealed that PPBzymes promote cartilage generation and reduce cartilage degradation. Moreover, intra-articular injections with PPBzymes into mouse joints revealed their long-term stability and effective uptake into the cartilage matrix. Furthermore, intra-articular PPBzymes injections attenuated cartilage degradation without exhibiting cytotoxicity toward the synovial membrane, lungs, and liver. Notably, based on proteome microarray data, PPBzymes specifically block the JNK phosphorylation, which modulates inflammatory OA pathogenesis. These findings indicate that PPBzymes might represent a biocompatible and effective nanotherapeutic for obstructing JNK phosphorylation.

Tannic acid, an IL-1ß-direct binding compound, ameliorates IL-1ß-induced inflammation and cartilage degradation by hindering IL-1ß-IL-1R1 interaction.

Interleukin-1ß (IL-1ß) is one of the most potent pro-inflammatory cytokines implicated in a wide range of autoinflammatory, autoimmune, infectious, and degenerative diseases. Therefore, many researchers have focused on developing therapeutic molecules that inhibit IL-1ß-IL-1 receptor 1 (IL-1R1) interaction for the treatment of IL-1-related diseases. Among IL-1-related diseases, osteoarthritis (OA), is characterized by progressive cartilage destruction, chondrocyte inflammation, and extracellular matrix (ECM) degradation. Tannic acid (TA) has been proposed to have multiple beneficial effects, including anti-inflammatory, anti-oxidant, and anti-tumor activities. However, it is unclear whether TA plays a role in anti-IL-1ß activity by blocking IL-1ß-IL-1R1 interaction in OA. In this study, we report the anti-IL-1ß activity of TA in the progression of OA in both in vitro human OA chondrocytes and in vivo rat OA models. Herein, using-ELISA-based screening, natural compound candidates capable of inhibiting the IL-1ß-IL-1R1 interaction were identified. Among selected candidates, TA showed hindering IL-1ß-IL-1R1 interaction by direct binding to IL-1ß using surface plasmon resonance (SPR) assay. In addition, TA inhibited IL-1ß bioactivity in HEK-Blue IL-1-dependent reporter cell line. TA also inhibited IL-1ß-induced expression of inducible nitric oxide synthase (NOS2), cyclooxygenase-2 (COX-2), IL-6, tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and prostaglandin E2 (PGE2) in human OA chondrocytes. Moreover, TA downregulated IL-1ß-stimulated matrix metalloproteinase (MMP)3, MMP13, ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)4, and ADAMTS5, while upregulating collagen type II (COL2A1) and aggrecan (ACAN). Mechanistically, we confirmed that TA suppressed IL-1ß-induced MAPK and NF-κB activation. The protective effects of TA were also observed in a monosodium iodoacetamide (MIA)-induced rat OA model by reducing pain and cartilage degradation and inhibiting IL-1ß-mediated inflammation. Collectively, our results provide evidence that TA plays a potential role in OA and IL-1ß-related diseases by hindering IL-1ß-IL-1R1 interaction and suppressing IL-1ß bioactivity.