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Appropriate animal models of osteoarthritis (OA) are essential to develop new treatment modalities for OA. A combination of surgical and chemical induction could be appropriate for OA models.Rabbit knee OA models developed by surgical induction (anterior cruciate ligament transection [ACLT]), chemical induction (monosodium iodoacetate [MIA] injection), and a combination of both were compared to assess compositional and structural destruction of the knee joint. Twenty-one New Zealand white rabbits were randomly divided into 3 groups to induce OA (group 1: ACLT, n = 3; group 2: MIA [3, 6, 9 mg] injection, n = 9; group 3: ACLT + MIA [3, 6, 9 mg] injection, n = 9).In all groups, the Modified Mankin score was significantly higher in the osteoarthritis-induced knee than in the control. Modified Mankin scores were compared by category. The ACLT group was observed to score high in cartilage structure. In the MIA group, chondrocytes and matrix staining showed higher scores, and the ACLT+MIA group scored higher in all categories for cartilage structure, chondrocytes, matrix staining, and tidemark integrity. The ACLT + 3 mg MIA showed definite OA characteristics such as cartilage surface destruction and degeneration of cartilage layers, and the ACLT + 6 mg MIA and ACLT + 9 mg MIA showed more prominent OA characteristics such as cartilage surface destruction, matrix disorganization, and osteophyte formation.The combination of MIA injection and ACLT could be an appropriate method for OA induction in rabbit models.

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.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.Retrospective case-control study using the STROBE checklist.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.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.JHFRAT more accurately reflects acute changeable conditions related to fall risk measurements after admission.JHFRAT may be useful for effective fall prevention activities in acute care settings.

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.

Osteoarthritis (OA) reduces the quality of life as a result of the pain caused by continuous joint destruction. Inactivated Lactobacillus (LA-1) ameliorated osteoarthritis and protected cartilage by modulating inflammation. In this study, we evaluated the mechanism by which live LA-1 ameliorated OA. To investigate the effect of live LA-1 on OA progression, we administered LA-1 into monosodium iodoacetate (MIA)-induced OA animals. The pain threshold, cartilage damage, and inflammation of the joint synovial membrane were improved by live LA-1. Furthermore, the analysis of intestinal tissues and feces in the disease model has been shown to affect the systems of the intestinal system and improve the microbiome environment. Interestingly, inflammation of the intestinal tissue was reduced, and the intestinal microbiome was altered by live LA-1. Live LA-1 administration led to an increase in the level of Faecalibacterium which is a short-chain fatty acid (SCFA) butyrate-producing bacteria. The daily supply of butyrate, a bacterial SCFA, showed a tendency to decrease necroptosis, a type of abnormal cell death, by inducing autophagy and reversing impaired autophagy by the inflammatory environment. These results suggest that OA is modulated by changes in the gut microbiome, suggesting that activation of autophagy can reduce aberrant cell death. In summary, live LA-1 or butyrate ameliorates OA progression by modulating the gut environment and autophagic flux. Our findings suggest the regulation of the gut microenvironment as a therapeutic target for OA.

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.

Background: Patellar tendinopathy is a common cause of limitations in daily life activities in young and/or active people. The patellar tendon consists of a complex of collagen fibers; therefore, collagen could be used as a scaffold in the treatment of patellar tendinopathy. Purpose: To evaluate the healing capacity of injected atelocollagen as a treatment scaffold for patellar tendon defect and, hence, its potential for the treatment of patellar tendinopathy. Study Design: Controlled laboratory study. Methods: After receiving a full-thickness patellar tendon defect, 24 New Zealand White rabbits were divided into a control group (without treatment) and an experimental group that received an atelocollagen injection into the defect. Six rabbits from each group were subsequently used for either histologic scoring or biomechanical testing. The Mann-Whitney U test was used to compare histologic evaluation scores and load to failure between the 2 groups. Statistical significance was set at P < .05. Results: The experimental group showed excellent repair of the damaged patellar tendon and good remodeling of the defective area. In contrast, the control group showed defective healing with loose, irregular matrix fibers and adipose tissue formation. A statistically significant difference was found between the 2 groups in both histologic scores and biomechanical tests at postoperative week 12. Conclusion: Injection of atelocollagen significantly improved the regeneration of damaged patellar tendons. Clinical Relevance: Atelocollagen gel injections could be used to treat patellar tendinopathy in outpatient clinic settings.

Tibial plateau fractures (TPFs) are a challenging type of fracture in orthopedic traumatology. We previously designed a plate (Patent Number: CN201520195596.5) for posterolateral TPF combined with posterior lateral collapse.. In this study, finite element analysis was used to compare the biomechanical characteristics of two internal fixation methods for posterolateral TPF. We investigated the support effect of the new steel plate on lateral TPFs combined with posterior TPFs.Two models of complex TPF were established. Model A was fixed with the new type of plate, and model B was fixed without the plate. Three axial loads of 500, 1,000, and 1,500 N were applied using FEA on the two fracture models (A and B) to analyze the data.In model A, the maximum displacement at 500, 1,000, and 1,500 N was 0.085797, 0.17043, and 0.25465 mm, respectively; the maximum stress of the bone block was 11.285, 20.648, and 29.227 MPa, respectively; and the maximum strain of the bone block was 0.0012474, 0.007435, and 0.0035769 mm, respectively. The maximum displacement of the internal fixation was 0.096932, 0.18682, and 0.27655 mm, respectively; the maximum stress was 69.54, 112.1, and 155.71 MPa, respectively; and the maximum strain was 0.00066228, 0.0010676, and 0.0014829 mm, respectively. In model B, the maximum displacement of fractures at 500, 1,000, and 1,500 N was 0.15675, 0.29868, and 0.44017 mm, respectively; the maximum stress of the bone block was 6.5519, 12.575, and 18.842 MPa, respectively; and the maximum strain of the bone block was 0.0032554, 0.0074357, and 0.012146 mm, respectively. The maximum displacement of the screw was 0.14177, 0.27109, and 0.39849 mm, respectively; the maximum stress was 48.916, 92.251, and 135.27 MPa, respectively; and the maximum strain was 0.00046608, 0.00087893, and 0.0012887 mm, respectively.The fixation method using this type of plates and screws can replace other methods using two plates to fix complex TPF.

BACKGROUND: High tibial osteotomy (HTO) is a well-established method for the treatment of medial compartment osteoarthritis of the knee with varus deformity. However, HTO alone cannot adequately repair the arthritic joint, necessitating cartilage regeneration therapy. Cartilage regeneration procedures with concomitant HTO are used to improve the clinical outcome in patients with varus deformity. AIM: To evaluate cartilage regeneration after implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) with concomitant HTO. METHODS: Data for patients who underwent implantation of hUCB-MSCs with concomitant HTO were evaluated. The patients included in this study were over 40 years old, had a varus deformity of more than 5°, and a full-thickness International Cartilage Repair Society (ICRS) grade IV articular cartilage lesion of more than 4 cm(2) in the medial compartment of the knee. All patients underwent second-look arthroscopy during hardware removal. Cartilage regeneration was evaluated macroscopically using the ICRS grading system in second-look arthroscopy. We also assessed the effects of patient characteristics, such as trochlear lesions, age, and lesion size, using patient medical records. RESULTS: A total of 125 patients were included in the study, with an average age of 58.3 ± 6.8 years (range: 43-74 years old); 95 (76%) were female and 30 (24%) were male. The average hip-knee-ankle (HKA) angle for measuring varus deformity was 7.6° ± 2.4° (range: 5.0-14.2°). In second-look arthroscopy, the status of medial femoral condyle (MFC) cartilage was as follows: 73 (58.4%) patients with ICRS grade I, 37 (29.6%) with ICRS grade II, and 15 (12%) with ICRS grade III. No patients were staged with ICRS grade IV. Additionally, the scores [except International Knee Documentation Committee (IKDC) at 1 year] of the ICRS grade I group improved more significantly than those of the ICRS grade II and III groups. CONCLUSION: Implantation of hUCB-MSCs with concomitant HTO is an effective treatment for patients with medial compartment osteoarthritis and varus deformity. Regeneration of cartilage improves the clinical outcomes for the patients.

Effective engineering approaches for cartilage regeneration involve a combination of cells and biomaterial scaffolds. Multipotent mesenchymal stem cells (MSCs) are important sources for cartilage regeneration. Atelocollagen provides a suitable substrate for MSC attachment and enhancing chondrogenic differentiation. Here, we assessed the chondrogenic potential of adipose tissue derived human MSCs (hMSCs) mixed with atelocollagen gel. We observed cell attachment, viability, and microstructures by electron microscopy over 21 days. The levels of Sox9, type II collagen, aggrecan, type I collagen, Runx2, type X collagen, ALP, Osterix, and MMP13 were measured by RT-qPCR. Cartilage matrix-related proteins were assessed by enzyme-linked immunosorbent assay (ELISA), histology, and immunohistochemistry. hMSCs of all groups exhibited well-maintained cell survival, distribution and morphology. Abundant type II collagen fibers developed on day 21; while Sox9, type II collagen, and aggrecan expression increased over time in the atelocollagen group. However, type I collagen, RUNX2, type X collagen (CoL10A1), Osterix, and ALP were not expressed. These results corroborated the protein expression detected by ELISA. Further, histological analysis revealed lacunae-like structures, while staining demonstrated glycosaminoglycan accumulation. Cumulatively, these results indicate that atelocollagen scaffolds improve hMSC chondrogenic differentiation and are a potential approach for cartilage regeneration.

Introduction: Clinical outcomes after the implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in osteoarthritic knees have been rarely reported. Our study aimed to investigate clinical outcomes of osteoarthritic patients who underwent hUCB-MSC implantation. Methods: In this case series (level of evidence: 4), from January 2014 to December 2015, 128 patients with full-thickness cartilage lesions (International Cartilage Repair Society grade 4 and Kellgren–Lawrence grade ≤3) who underwent hUCB-MSC implantation were retrospectively evaluated with a minimum of 2-year follow-up. After removing the sclerotic subchondral bone with an arthroscopic burr, 4-mm-diameter holes were created at 2-mm intervals, and hyaluronic acid and hUCB-MSCs were subsequently mixed and implanted in the holes and other articular defect sites.Clinical outcomes were evaluated preoperatively, 1 year postoperatively, and 2 years postoperatively (minimum) using visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) scores. To assess clinical outcomes, patients were divided into two or three groups according to the lesion size, lesion location, number of lesions, body mass index, and age; statistical analyses were performed using these data. Results: The mean (±standard deviation) VAS, WOMAC, and IKDC scores at 1 and 2 years after surgery including hUCB-MSC implantation improved significantly compared to the preoperative scores (P

BACKGROUND: Articular cartilage injury has a poor repair ability and limited regeneration capacity with therapy based on articular chondrocytes (ACs) implantation. Here, we validated the hypothesis that human nasal septum-derived chondrocytes (hNCs) are potent therapeutic agents for clinical use in cartilage tissue engineering using an injectable hydrogel, type I collagen (COL1). METHODS: We manufactured hNCs incorporated in clinical-grade soluble COL1 and investigated their clinical potential as agents in an articular defect model. RESULTS: The hNCs encapsulated in COL1 (hNC-collagen) were uniformly distributed throughout the collagen and showed much greater growth rate than hACs encapsulated in collagen for the 14 days of culture. Fluorescent staining of hNC-collagen showed high expression levels of chondrocyte-specific proteins under clinical conditions. Moreover, a negative mycoplasma screening result were obtained in culture of hNC-collagen. Notably, implantation of hNC-collagen increased the repair of osteochondral defects in rats compared with implantation of collagen only. Many human cells were detected within the cartilage defects. CONCLUSION: These results provide reliable evidences supporting for clinical applications of hNC-collagen in regenerative medicine for cartilage repair. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13770-020-00261-9) contains supplementary material, which is available to authorized users.

Interleukin-1β (IL-1β) 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-1β-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-1β activity by blocking IL-1β-IL-1R1 interaction in OA. In this study, we report the anti-IL-1β 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-1β-IL-1R1 interaction were identified. Among selected candidates, TA showed hindering IL-1β-IL-1R1 interaction by direct binding to IL-1β using surface plasmon resonance (SPR) assay. In addition, TA inhibited IL-1β bioactivity in HEK-Blue IL-1-dependent reporter cell line. TA also inhibited IL-1β-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-1β-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-1β-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-1β-mediated inflammation. Collectively, our results provide evidence that TA plays a potential role in OA and IL-1β-related diseases by hindering IL-1β-IL-1R1 interaction and suppressing IL-1β bioactivity.

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.

Chondrocytes secrete massive extracellular matrix (ECM) molecules that are produced, folded, and modified in the endoplasmic reticulum (ER). Thus, the ER-associated degradation (ERAD) complex—which removes misfolded and unfolded proteins to maintain proteostasis in the ER— plays an indispensable role in building and maintaining cartilage. Here, we examined the necessity of the ERAD complex in chondrocytes for cartilage formation and maintenance. We show that ERAD gene expression is exponentially increased during chondrogenesis, and disruption of ERAD function causes severe chondrodysplasia in developing embryos and loss of adult articular cartilage. ERAD complex malfunction also causes abnormal accumulation of cartilage ECM molecules and subsequent chondrodysplasia. ERAD gene expression is decreased in damaged cartilage from patients with osteoarthritis (OA), and disruption of ERAD function in articular cartilage leads to cartilage destruction in a mouse OA model., Description, Reduced secretory activity due to the unfolded protein accumulation in chondrocytes may worsen cartilage damage and loss in osteoa.

Osteoarthritis (OA) is the most common form of arthritis associated with ageing. Vitamin D has diverse biological effect on bone and cartilage, and observational studies have suggested it potential benefit in OA progression and inflammation process. However, the effect of vitamin D on OA is still contradictory. Here, we investigated the therapeutic potential of vitamin D in OA. Six-week-old male Wistar rats were injected with monosodium iodoacetate (MIA) to induce OA. Pain severity, cartilage destruction, and inflammation were measured in MIA-induced OA rats. Autophagy activity and mitochondrial function were also measured. Vitamin-D (1,25(OH)

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.

Osteonecrosis of femoral head (ONFH) is a disease of the femoral head and can cause femoral head collapse and arthritis. This can lead to pain and gait disorders. ONFH has various risk factors, it is often progressive, and if untreated results in secondary osteo-arthritis. Biological therapy makes use of bone marrow concentrate, cultured osteoblast and mesenchymal stem cell (MSC) obtained from various sources. These are often used in conjunction with core decompression surgery. In this review article, we discuss the current status of cell therapy and its limitations. We also present the future development of biological approach to treat ONFH.

Articular cartilage injuries are common. The diagnosis of these injuries is often delayed and may lead to early osteoarthritis. Treatment depends on many factors but mainly on the stage and size of the lesion. The anatomy of articular cartilage is complex, and it is an avascular, aneural, and alymphatic structure. Recently, more emphasis is laid on its anatomy and biomechanics to understand the regeneration process of articular cartilage.

Previously, most fractures have been treated through bone reduction and immobilization. With an increase in the patients' need for an early return to their normal function, development in surgical techniques and materials have accelerated. However, delayed union or non-union of the fracture site sometimes inhibits immediate return to normal life. To enhance fracture healing, diverse materials and methods have been developed. This is a review on the current modalities of fracture healing enhancement, which aims to provide a comprehensive knowledge regarding fracture healing for researchers and health practitioners.

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.

The autologous collagen-induced chondrogenesis technique is described, and the results of a 6-year follow-up clinical study using this technique are presented. 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. 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

BACKGROUND: Cell-based therapies have been studied for articular cartilage regeneration. Articular cartilage defects have little treatments because articular cartilage was limited regenerative capacity. Damaged articular cartilage is difficult to obtain a successful therapeutic effect. In additionally these articular cartilage defects often cause osteoarthritis. Chondrocyte implantation is a widely available therapy used for regeneration of articular cartilage because this tissue has poor repair capacity after injury. Human nasal septum-drived chondrocytes (hNCs) from the septum show greater proliferation ability and chondrogenic capacity than human articular chondrocytes (hACs), even across different donors with different ages. Moreover, the chondrogenic properties of hNCs can be maintained after extensive culture expansion. METHODS: In this study, 2 dimensional (2D) monolayer cultured hNCs (hNCs-2D) and 3 dimensional (3D) spheroids cultured hNCs (hNCs-3D) were examined for chondrogenic capacity in vitro by PCR and immunofluorescence staining for chondrogenic marker, cell survival during cultured and for cartilage regeneration ability in vivo in a rat osteochondral defect model. RESULTS: hNCs-3D showed higher viability and more uniform morphology than 3D spheroids cultured hACs (hACs-3D) in culture. hNCs-3D also showed greater expression levels of the chondrocyte-specific marker Type II collagen (COL2A1) and sex-determining region Y (SRY)-box 9 (SOX9) than hNCs-2D. hNCs-3D also expressed chondrogenic markers in collagen. Specially, in the osteochondral defect model, implantation of hNCs-3D led to greater chondrogenic repair of focal cartilage defects in rats than implantation of hNCs-2D. CONCLUSION: These data suggest that hNCs-3D are valuable therapeutic agents for repair and regeneration of cartilage defects.

Background To treat lateral compartment osteoarthritis caused by a valgus deformity, partial or total knee joint arthroplasty is recommended. However, for young patients, joint preservation surgery such as distal femoral osteotomy (DFO) can be an alternative treatment option. Combined cartilage defects of lateral compartment osteoarthritis can be restored by human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). This case report presents the results of DFO and hUCB-MSC implantation for treating two patients with valgus deformity who had lateral compartment osteoarthritis. Case presentation Two middle-aged patients with lateral compartment osteoarthritis and valgus deformity were treated using DFO and hUCB-MSC implantation. They recovered sufficiently to perform moderate exercise one year after surgery. The International Knee Documentation Committee, visual analog scale, and Western Ontario and McMaster Universities Osteoarthritis Index scores showed continuous improvement after surgery. Cartilage regeneration of International Cartilage Repair Society Grade 1, which was similar to normal, was observed in both patients through second-look arthroscopy. With time, the modified two-dimensional magnetic resonance observation of cartilage repair tissue scores also increased in both cases. Conclusion This is the first case report detailing the results of treating lateral compartment osteoarthritis using hUCB-MSCs and DFO. In conclusion, this can be considered a new treatment option for such cases.

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-1β, 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-1β–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-β 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.

Objective: Osteoarthritis (OA) is a common degenerative joint disease characterized by breakdown of joint cartilage. Mitochondrial dysfunction of the chondrocyte is a risk factor for OA progression. We examined the therapeutic potential of mitochondrial transplantation for OA.Methods: Mitochondria were injected into the knee joint of monosodium iodoacetate (MIA)-induced OA rats. Chondrocytes from OA rats or patients with OA were cultured to examine mitochondrial function in cellular pathophysiology.Results: Pain, cartilage destruction, and bone loss were improved in mitochondrial transplanted-OA rats. The transcript levels of interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), matrix metallopeptidase 13 (MMP13), and monocyte chemoattractant protein-1 (MCP-1) in cartilage were markedly decreased by mitochondrial transplantation. Mitochondrial function, as indicated by membrane potential and oxygen consumption rate, in chondrocytes from OA rats was improved by mitochondrial transplantation. Likewise, the mitochondrial function of chondrocytes from OA patients was improved by coculture with mitochondria. Furthermore, inflammatory cell death was significantly decreased by coculture with mitochondria.Conclusion: Mitochondrial transplantation ameliorated OA progression, which is caused by mitochondrial dysfunction. These results suggest the therapeutic potential of mitochondrial transplantation for OA.

The articular cartilage of the joint is the thin viscoelastic layer of the connective tissue. It has a unique anatomy and physiology, which makes the repair of the articular cartilage damage more difficult and challenging due to its limited healing capacity. Increasing knowledge regarding the importance of articular cartilage for joint preservation has led to increased attention on early identification of cartilage damage as well as degeneration in order to delay osteoarthritis. There are various treatment modalities ranging from preventive management, physical therapy, pharmacological, non-pharmacological and surgical treatments exist in current literature. However most of the studies have limited long term follow up and mainly consists of small case series and case reports. This is an up to date concise review discussing the available management options for articular cartilage damage starting to lifestyle modification to pharmacotherapy, physiotherapy, and osteobiologics till various joint preservation techniques that have been in use currently.

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.

Osteoarthritis (OA) is the most common degenerative arthritis associated with pain and cartilage destruction in the elderly, it is known to be involved in inflammation as well. A drug called celecoxib is commonly used in patients with osteoarthritis to control pain. Metformin is used to treat type 2 diabetes but also exhibits regulation of the autophagy pathway. The purpose of this study is to investigate whether metformin can treat monosodium iodoacetate (MIA)-induced OA in rats. Metformin was administered orally every day to rats with OA. Paw-withdrawal latency and threshold were used to assess pain severity. Cartilage damage and pain mediators in dorsal root ganglia were evaluated by histological analysis and a scoring system. Relative mRNA expression was measured by real-time PCR. Metformin reduced the progression of experimental OA and showed both antinociceptive properties and cartilage protection. The combined administration of metformin and celecoxib controlled cartilage damage more effectively than metformin alone. In chondrocytes from OA patients, metformin reduced catabolic factor gene expression and inflammatory cell death factor expression, increased LC3Ⅱb, p62, and LAMP1 expression, and induced an autophagy–lysosome fusion phenotype. We investigated if metformin treatment reduces cartilage damage and inflammatory cell death of chondrocytes. The results suggest the potential for the therapeutic use of metformin in OA patients based on its ability to suppress pain and protect cartilage.

Autologous collagen induced chondrogenesis (ACIC) is a single-stage arthroscopic procedure and we developed this method using micro-drilling with atelocollagen injection to the articular cartilage defects. Atelocollagen can provide biocompatibility and a chondrogenic environment for functional cartilage regeneration. We introduce this ACIC techniques in the clinical aspect.

The green-lipped mussel (GLM) contains novel omega-3 polyunsaturated fatty acids, which exhibit anti-inflammatory and joint-protecting properties. Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive loss of cartilage; oxidative stress plays a role in the pathogenesis of OA. The objectives of this study were to investigate the in vivo effects of the GLM on pain severity and cartilage degeneration using an experimental rat OA model, and to explore the mode of action of GLM. OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) into the knee. Oral GLM was initiated on the day after 3dyas of MIA injection. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Samples were analyzed both macroscopically and histologically. Immunohistochemistry was used to investigate the expression of interleukin-1β (IL-1β), IL-6, nitrotyrosine, and inducible nitric oxide synthase (iNOS) in knee joints. Also, the GLM was applied to OA chondrocyte, and the expression on catabolic marker and necroptosis factor were evaluated by real-time polymerase chain reaction. Administration of the GLM improved pain levels by preventing cartilage damage and inflammation. GLM significantly attenuated the expression levels of mRNAs encoding matrix metalloproteinase-3 (MMP-3), MMP-13, and ADAMTS5 in IL-1β-stimulated human OA chondrocytes. GLM decreased the expression levels of the necroptosis mediators RIPK1, RIPK3, and the mixed lineage kinase domain-like protein (MLKL) in IL-1β-stimulated human OA chondrocytes. Thus, GLM reduced pain and cartilage degeneration in rats with experimentally induced OA. The chondroprotective properties of GLM included suppression of oxidative damage and inhibition of catabolic factors implicated in the pathogenesis of OA cartilage damage. We suggest that GLM may usefully treat human OA.

Background With increasing life expectancy, stem cell therapy is receiving increasing attention. However, its application is restricted by ethical concerns. Hence a need exists for design of safe procedures for stem cell procurement. Here, we investigated whether hemovac blood (HVB) is an appropriate stem cell source. Methods HVB concentrates (HVBCs) from 20 total knee arthroplasty (TKA) patients and bone marrow aspirate (BMA) concentrates (BMACs) from 15 patients who underwent knee cartilage repair were comparatively evaluated. A bone marrow aspiration needle was inserted into the anterior superior iliac spine. Aspiration was performed using a 50-mL syringe, including 4 mL of anticoagulant, followed by centrifugation to obtain BMACs. To obtain HVBCs, blood was aspirated from the hemovac immediately after TKA surgery. Different cell types were enumerated. Isolation of BMA and HVB mononuclear cells was performed using density gradient centrifugation. Non-hematopoietic fibroblast colonies were quantified by colony forming unit-fibroblast assay surface marker analysis of HVB, HVBC, BMA, and BMAC was performed via flow cytometry. Mesenchymal stem cells (MSCs) isolated from HVBCs and BMACs were examined for osteogenic, adipogenic, and chondrogenic differentiation potential. Gene expression analysis was performed by quantitative real-time polymerase chain reaction (qRT-PCR). Results The number of cells from HVB and HVBC was significantly lower than from BMA and BMAC; however, the number of colonies in HVBC and BMAC did not differ significantly (P>0.05). Isolated cells from both sources had a fibroblast-like appearance, adhered to culture flasks, and formed colonies. Under different culture conditions, MSC-specific surface markers (CD29, CD44, CD90, CD105), osteogenic markers [RUNX2, osteopontin, osteocalcin, and alkaline phosphatase (ALP)] and adipogenic markers (PPARγ and C/EBPα) were expressed. Moreover, SOX9, type II collagen, and aggrecan were significantly upregulated upon chondrogenic differentiation. Conclusions HVB from TKA patients is a useful source of stem cells for research.

Background and Purpose Osteoarthritis (OA) is a leading cause of disability and bears a large socioeconomic cost, but we lack an effective disease-modifying therapy. There is great need to identify novel target molecules in OA pathogenesis. Here, by asking why old cartilage appears to be more sensitive to OA pathogenic factors, we identified the importance and underlying mechanism of K-7174 as a blocker of the Zmiz1-GATA axis in age-related OA pathogenesis. Experimental Approach As a novel transcriptional regulator in OA pathogenesis, Zmiz1 was isolated as an up-regulated gene from aged cartilage, using microarray and Ingenuity Pathway Analysis (IPA). Infection and intra-articular injection of Ad-Zmiz1 were performed in vitro and in vivo. Cartilage-specific Col2a1-Zmiz1 TG mice with or without DMM (destabilization of the medial meniscus) surgery were evaluated by measurement of OA manifestations. To identify a specific Zmiz1-related transcription factor and a potential inhibitor, we performed transcription factor, in silico binding, and inhibition assays. Key Results The transcriptional regulator, Zmiz1, is up-regulated in old mouse cartilage and highly expressed in damaged cartilage of OA patients and DMM mice. Col2a1-Zmiz1 TG mice and DMM-induced Col2a1-Zmiz1 TG mice showed more severe cartilage destruction. Overexpression of Zmiz1 induced cartilage destruction by up-regulating Mmps and Cox2 through activation of the Zmiz1-GATA axis. Finally, we demonstrate that K-7174 interfered with the activation of the Zmiz1-GATA axis to crucially protect against OA pathogenesis and promote ECM synthesis. Conclusion and Implications The K-7174-mediated blockade of the Zmiz1-GATA axis could be a useful therapeutic strategy for blocking OA pathogenesis.

Osteoarthritis (OA), which is the most common degenerative joint disorder, has been considered a non-inflammatory disease with abnormal mechanics. Interleukin (IL)-17 is a pleiotropic cytokine involved in inflammatory diseases and their production is driven by the cytokine including IL-1 and IL-23. However, little is known about the mechanism of IL-17 in the development of OA. Here, we investigated the role of IL-17 in the pathogenesis of OA using monosodium iodoacetate (MIA)-injected IL-17 and IL-1 receptor antagonist (IL-1Ra) double-deficient mice. In MIA-injected IL-1Ra KO mice, nociceptive properties, degree of cartilage damage, and the level of inflammatory factors in articular cartilage were increased compared to MIA-injected wild-type mice. Interestingly, the intestinal architecture was impaired in IL-1Ra KO mice compared to wild-type mice and the damage was further exacerbated by MIA injection. Deficiency of IL-17 reduced nociceptive properties and cartilage destruction, as well as inflammation-related factors in MIA-injected IL-1Ra KO mice compared to MIA-injected wild-type mice. Furthermore, IL-17-treated chondrocytes from OA patients showed enhanced expression of catabolic factors that are involved in the destruction of cartilage in OA. IL-17 accelerates the destruction of cartilage and small intestine via regulation of several inflammatory mediators in an OA murine model. These results suggest that IL-17 plays a critical role in the development of OA.

Articular cartilage has unique biological and biomechanical characteristics. Damage to this tissue fails to heal spontaneously, leading to progressive arthritis. Cartilage repair techniques have been looked forward to in the treatment of significant cartilage injuries. Cell-based regenerative techniques like the two-staged cultured chondrocytes and single-stage mesenchymal cell transplantation have been tried with varying results and limitations. We study the outcomes of cultured bone marrow derived MSCs in the treatment of articular cartilage defects of the knee in comparison to autologous cultured chondrocyte implantation (ACI). Both cultured MSC and ACI treatment methods resulted in significant improvements in patient reported outcome measures (PROMs). There was no difference in the PROMs, MOCART scores, T2∗ mapping and dGEMRIC values between the groups. Use of cultured MSCs leads to good clinical outcomes similar to ACI and represents a promising treatment to restore the articular cartilage in the knee.

Osteoarthritis (OA) is a chronic and degenerative disease that causes pain, cartilage deformation, and joint inflammation. Lactobacillus species have been used as dietary supplements to induce the production of antimicrobial and anti-inflammatory factors. The goal of this study was to determine whether Lactobacillus acidophilus ameliorates monosodium iodoacetate-induced OA. L. acidophilus showed anti-nociceptive properties and protected against cartilage destruction. It also downregulated the levels of proinflammatory cytokines and increased the levels of anti-inflammatory cytokines in the joints of OA rats. L. acidophilus additionally restored the balance between anabolic and catabolic factors in chondrocytes from OA patients. These results suggest that L. acidophilus can alleviate OA-associated pain and delay the progression of the disease by inhibiting proinflammatory cytokine production and reducing cartilage damage.

Osteoarthritis (OA) is a major degenerative joint condition that causes articular cartilage destruction. It was recently found that enhancement of chondroclasts and suppression in Treg cell differentiation are involved in the pathogenesis of OA. Kartogenin (KGN) is a small drug-like molecule that induces chondrogenesis in mesenchymal stem cells (MSCs). This study aimed to identify whether KGN can enhance severe pain behavior and improve cartilage repair in OA rat model. Induction of OA model was loaded by IA-injection of MIA. In the OA rat model, treatment an intra-articular injection of KGN. Pain levels were evaluated by analyzing PWL and PWT response in animals. Histological analysis and micro-CT images of femurs were used to analyze cartilage destruction. Gene expression was measured by real-time PCR. Immunohistochemistry was analyzed to detect protein expression. KGN injection significantly decreased pain severity and joint destruction in the MIA-induced OA model. KGN also increased mRNA levels of the anti-inflammatory cytokine IL-10 in OA patients’ chondrocytes stimulated by IL-1β. Decreased chondroclast expression, and increased Treg cell expression. KGN revealed therapeutic activity with the potential to reduce pain and improve cartilage destruction. Thus, KGN could be a therapeutic molecule for OA that inhibits cartilage damage.