Intra-articular Injection Research Articles

Can intra-articular daidzein injection reduce oxidative damage and early osteoarthritis in a rabbit temporomandibular joint model?

BackgroundOxidative damage and inflammatory cytokines in osteoarthritis (OA) exacerbate the disease course. Daidzein (DZ) has antioxidant and anti-inflammatory effects. This study evaluated the early histopathological effects of intra-articular daidzein injection on experimentally induced osteoarthritis in rabbit TMJs.MethodsThe predictor variable was intra-articular injection of DZ or a saline control. 50 µl of 3 mg/mL MIA solution was injected into the right TMJ of 16 New Zealand rabbits to induce experimental OA. One rabbit was sacrificed after 4 weeks to confirm the formation of the OA model and the OA model was obtained. The remaining 15 rabbits were randomly divided into 2 groups: an experimental group (9 rabbits) and a control group (6 rabbits). On days 1, 7, 14, and 21; 50 µl of saline solution was applied to the right TMJ of the control group and 50 µl daidzein solution (1.8 mg/ml) was applied to the right TMJ to the experimental group. After one week from the date of the last injection, the rabbits were sacrificed, and histopathological and biochemical evaluations were performed. The Shapiro-Wilk test was used to evaluate whether the variables in the study conformed to normal distribution. Mean ± SD (standard deviation) or median (interquartile range (IQR)) was used to show the descriptive statistics of the variables. T-test and Mann Whitney U test were used to compare the control and experimental groups for biochemical changes. The chi-square test was used to show the distribution of histopathological changes variables obtained within the scope of the study based on control and experimental groups. A P-value < 0.05 was considered significant for all evaluations.ResultsThere were 8 and 6 animate treated with DZ and saline, respectively. There was no statistically significant difference between groups in articular cartilage (p = 0.3), osteochondral junction (p = 0.3), subchondral bone structure (p = 1.0) or chondrocyte appearance (p = 0.4). The experimental group showed significantly lower mean values for Total Oxidant Status (TOS) (p = 0.002) and Oxidative Stress Index (OSI) (p = 0.007).ConclusionsAn intra-articular DZ injection appears to show limited reduction of oxidative damage and early OA in the rabbit TMJ. DZ might represent a promising natural compound with beneficial effects in the management of TMJ-OA.

An injectable self-lubricating supramolecular polymer hydrogel loaded with platelet lysate to boost osteoarthritis treatment

Globally, osteoarthritis (OA) is the most prevalent joint disease and is characterized by infiltration of M1 macrophages in the synovium, anabolic–catabolic imbalance of the extracellular matrix (ECM), increased articular shear force and overproduction of reactive oxygen species (ROS). Disease-modifying OA drugs are not yet available, and treatments for OA focus solely on reducing pain and inflammation and have limited therapeutic effect. Herein, we developed an injectable self-lubricating poly(N-acryloyl alaninamide) (PNAAA) hydrogel loaded with platelet lysate (PL) (termed “PNAAA@PL”) for treating OA. Tribological and drug release tests revealed suitable lubrication properties and sustained release of bioactive factors in PNAAA@PL. In vitro experiments showed that PNAAA@PL alleviated interleukin-1β (IL-1β)-induced anabolic–catabolic imbalance of chondrocytes and repolarized pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype via intracellular ROS scavenging. Additionally, the PNAAA@PL hydrogel enhanced the migratory capacity and chemotaxis ability of stem cells, which are essential for chondrogenesis. In vivo, the functionalized PNAAA@PL hydrogel acted like synovial fluid following intra-articular injection into a rat OA model with anterior cruciate ligament transection, ultimately attenuating cartilage degeneration and synovitis. According to molecular mechanism studies, PNAAA@PL repairs cartilage in the OA model by inhibiting the NF-ĸB pathway. Overall, this self-lubricating PNAAA@PL hydrogel offers a comprehensive strategy for preventing OA progression by engineering a biophysiochemical microenvironment to generate high-quality hyaline cartilage.

Immunotherapeutic potential of collagen V oral administration in mBSA/CFA-induced arthritis.

We hypothesized that after synovial injury, collagen V (Col V) expose occult antigens, and Col V autoantibodies develop, indicating the loss of immune tolerance against this molecule, thus leading to damage to mesenchymal-derived cells as well as the extracellular matrix in experimental arthritis. Thus, the present study investigated the effects of oral administration of Col V on the synovium after the development of inflammation in mBSA/CFA-induced arthritis. After fourteen days of intraarticular administration of mBSA, 10 male Lewis rats were orally administered Col V (500 μg/300 μL) diluted in 0.01 N acetic acid (IA-Col V group). The arthritic group (IA group, n = 10) received only intraarticular mBSA. An intra-articular saline injection (20 μL) was given to the control group (CT-Col V, n = 5). IA group presented damaged synovia, the expansion of the extracellular matrix by cellular infiltrate, which was characterized by T and B lymphocytes, and fibroblastic infiltration. In contrast, after Col V oral immunotherapy IA-Col V group showed a significant reduction in synovial inflammation and intense expression of IL-10+ and FoxP3+ cells, in addition to a reduction in Col V and an increase in Col I in the synovia compared to those in the IA group. Furthermore, an increase in IL-10 production was detected after IA-Col V group spleen cell stimulation with Col V in vitro. PET imaging did not differ between the groups. The evaluation of oral treatment with Col V, after mBSA/CFA-induced arthritis in rats, protects against inflammation and reduces synovial tissue damage, through modulation of the synovial matrix, showing an immunotherapeutic potential in inhibiting synovitis.

Activation of Heme Metabolism Promotes Tissue Health After Intraarticular Injury or Surgical Exposure.

Posttraumatic osteoarthritis (PTOA) is a well-recognized public health burden without any disease modifying treatment. This occurs despite noted advances in surgical care in the past 50 years. Mitochondrial oxidative damage pathways initiate PTOA after severe injuries like intraarticular fracture that often require surgery and contribute to PTOA after less severe injuries that may or may not require surgery like meniscal injuries. When considering the mitochondrial and redox environment of the injured joint, we hypothesized that activation of heme metabolism, previously associated with healing in many settings, would cause prototypic mitochondrial reprogramming effects in cartilage ideally suited for use at the time of injury repair. Activation of heme metabolism can be accomplished through the gasotransmitter carbon monoxide (CO), which activates hemeoxygenase-1 (HO1) and subsequent heme metabolism. In this study, we employed unique carbon monoxide (CO)-containing foam (COF) to stimulate heme metabolism and restore chondrocyte oxygen metabolism in vitro and in vivo . Doxycycline-inducible, chondrocyte-specific HO1 overexpressing transgenic mice show similar mitochondrial reprogramming after induction compared to COF. CO is retained at least 24 h after COF injection into stifle joints and induces sustained increases in heme metabolism. Lastly, intraarticular injection of COF causes key redox outcomes without any adverse safety outcomes in rabbit stifle joints ex vivo and in vivo . We propose that activation of heme metabolism is an ideal adjuvant to trauma care that replenishes chondrocyte mitochondrial metabolism and restores redox homeostasis.

New role of calcium-binding fluorescent dye alizarin complexone in detecting permeability from articular cartilage to subchondral bone.

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by the progressive deterioration of articular cartilage and concomitant alterations in subchondral bone architecture. However, the precise mechanisms underlying the initiation and progression of OA remains poorly understood. In the present study, we explored whether the calcification in the articular cartilage occurred in the early stage of mouse OA model, generated by the surgery destabilization of the medial meniscus (DMM), via the intra-articular injection of alizarin complexone due to its anionic nature for binding calcium-containing crystals. Although we did not observe the calcification in the articular cartilage of early stage of DMM mice, we unexpectedly identified alizarin complexone had the diffusion capacity for detecting the permeability from the articular cartilage to subchondral bone. Our data showed that the diffusion of alizarin complexone from the articular cartilage to calcified cartilage was greater in the early stage of DMM mice than that in sham controls. Additionally, we observed enhanced penetration of alizarin complexone through the periosteum in DMM mice compared to sham mice. In summary, we developed a novel imaging method that offers a valuable tool for further exploration of biochemical communication underlying OA development. Our findings provided new evidence that increased molecular interactions between the articular cartilage and subchondral bone is involved in the pathogenesis of OA progression.

Efficacy of intra-articular injection of combined platelet-rich-plasma (PRP) and hyaluronic acid (HA) in knee degenerative joint disease: a prospective, randomized, double-blind clinical trial.

Intra-articular injections of hyaluronic acid (HA) and platelet-rich plasma (PRP) represent promising options in the conservative treatment of early stages of knee osteoarthritis (OA). Although the combined use of these two compounds seems to have a synergistic effect in pre-clinical studies, few clinical trials compared the association of PRP and HA with PRP and HA alone. The aim of study is toevaluate the efficacy of combined intra-articular injections of PRP and HA in the treatment of mild to moderate knee OA, compared to PRP and HA alone. One hundred and seventy-four patients were prospectively enrolled and randomized to undergo three intra-articular injections of either HA or PRP or the combination of PRP and HA with a two-week interval period. Patients were evaluated before treatment and after 3, 6, and 12months using Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score, Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee subjective score, Visual Analogue Scale and TEGNER Activity Scores. All the treatments proved to be effective in reducing pain and improving joint function. The analysis of covariance did not show statistically significant differences among the three groups for any of the investigated outcome parameters after 6 and 12months (WOMAC: p = 0.45 and p = 0.64, respectively). No significant differences were found in terms of adverse events (p = 0.49) and painkiller use (p = 0.28 and p = 0.56, respectively) among the three groups. This multicenter, prospective, randomized, double-blind controlled trial revealed that intra-articular injections of PRP + HA, PRP, or HA represent a safe and viable treatment with comparable efficacy in terms of pain relief and functional outcomes in mild to moderate knee OA.

Intra-articular injection of chitosan combined with low-dose glucocorticoid for the treatment of knee osteoarthritis in early and middle stages.

This study explores the clinical efficacy of intra-articular injection of chitosan combined with low-dose glucocorticoid for the treatment of knee osteoarthritis in early and middle stages. The visual analog scale (VAS) score, Lysholm score, Hospital for Special Surgery (HSS) score, and changes in the levels of inflammatory cytokines IL-1, IL-6, and TNF-α in the joint fluid before and after treatment in the 3 groups were compared, and the clinical efficacy was evaluated. All cases were followed up, with a follow-up time of 7 to 12 months, and no lost cases. The horizontal comparison showed that the VAS score, Lysholm score, HSS score, and levels of inflammatory cytokines IL-1, IL-6, and TNF-α in the joint fluid after treatment in each group were better than before treatment, and the difference was statistically significant (P < .05). The longitudinal comparison showed that there was no significant difference in VAS score, Lysholm score, HSS score and levels of inflammatory cytokines IL-1, IL-6, and TNF-α in synovial fluid among the 3 groups before treatment (P > .05); However, after treatment, there were significant differences among the 3 groups (P < .05), group C was better than group A and group B, group B was better than group A, and the differences were statistically significant (P < .05). The difference in clinical efficacy among the 3 groups was statistically significant (P < .05). The clinical efficacy of chitosan combined with low-dose glucocorticoid intra-articular injection in the treatment of knee osteoarthritis in early and middle stages is significant, with the characteristics of small trauma, rapid onset, and lasting efficacy, and it avoids the adverse reactions of topical or oral nonsteroidal anti-inflammatory drugs. As a first-line treatment option, it is recommended for promotion and use in clinical practice.

Efficacy and safety of intra-articular-only meropenem after one-stage revision for treating Escherichia coli-induced periprosthetic joint infection in a rat model.

The optimum type of antibiotics and their administration route for treating Gram-negative (GN) periprosthetic joint infection (PJI) remain controversial. This study aimed to determine the GN bacterial species and antibacterial resistance rates related to clinical GN-PJI, and to determine the efficacy and safety of intra-articular (IA) antibiotic injection after one-stage revision in a GN pathogen-induced PJI rat model of total knee arthroplasty. A total of 36 consecutive PJI patients who had been infected with GN bacteria between February 2015 and December 2021 were retrospectively recruited in order to analyze the GN bacterial species involvement and antibacterial resistance rates. Antibiotic susceptibility assays of the GN bacterial species were performed to screen for the most sensitive antibiotic, which was then used to treat the most common GN pathogen-induced PJI rat model. The rats were randomized either to a PJI control group or to three meropenem groups (intraperitoneal (IP), IA, and IP + IA groups). After two weeks of treatment, infection control level, the side effects, and the volume of antibiotic use were evaluated. Escherichia coli was the most common pathogen in GN-PJI, and meropenem was the most sensitive antibiotic. Serum inflammatory markers, weightbearing activity, and Rissing score were significantly improved by meropenem, especially in the IA and IP + IA groups ( p < 0.05). Meropenem in the IA group eradicated E. coli from soft-tissue, bone, and prosthetic surfaces, with the same effect as in the IP + IA group. Radiological results revealed that IA and IP + IA meropenem were effective at relieving bone damage. Haematoxylin and eosin staining also showed that IA and IP + IA meropenem improved synovial inflammation and bone destruction. No pathological changes in the main organs or abnormal serum markers were observed in any of the meropenem-treated rats. The IA group required the lowest amount of meropenem, followed by the IP and IP + IA groups. IA-only meropenem with a two-week treatment course was effective and safe for PJI control following one-stage revision in a rat model, with less meropenem use.

Custo-Efetividade de Diferentes Tratamentos Minimamente Invasivos Para Disfunção Temporomandibular de Origem Articular sob a Perspectiva do Sistema Público de Saúde Brasileiro

ObjectiveThis study aimed to evaluate the cost-effectiveness (CE) of minimally invasive interventions for pain associated with articular temporomandibular dysfunction from the Brazilian Public Health System (SUS) perspective. MethodsThis is a CE study with a 1-year time horizon. Effectiveness data were extracted from a network meta-analysis, and 2 treatments with moderate levels of evidence certainty were evaluated: arthrocentesis (ARTRO) plus intra-articular corticosteroid (CO) injection and ARTRO plus intra-articular injection of sodium hyaluronate (SH). For CE analysis, the costs of 2 types of SH (low and high molecular weight) and 4 COs (betamethasone [B], dexamethasone acetate [D], methylprednisolone sodium succinate [M], or triamcinolone hexacetonide [T]) were considered. Modeling was conducted using TreeAge Pro Healthcare software, with the construction of a decision tree representing a hypothetical cohort of adults with articular temporomandibular dysfunction. Deterministic and probabilistic sensitivity analyses were performed. In addition, an acceptability curve was developed. ResultsThe total costs per joint for ARTRO plus low- and high-molecular-weight SH and ARTRO plus COs B, D, M, and T were, respectively, R$583.32, R$763.85, R$164.39, R$133.93, R$138.57, and R$159.86. ARTRO plus dexamethasone acetate was considered cost-effective, with lower cost and higher net monetary benefit than other technologies. In all sensitivity analysis scenarios, it remained cost-effective. It also showed greater acceptability. ConclusionARTRO plus dexamethasone acetate was considered the cost-effective technology, exhibiting higher net monetary benefit and higher acceptability from the SUS perspective.

Targeted Therapy of Osteoarthritis via Intra-Articular Delivery of Lipid-Nanoparticle-Encapsulated Recombinant Human FGF18 mRNA.

Fibroblast growth factor 18 (FGF18) emerges as a promising therapeutic target for osteoarthritis (OA). In this study, a novel articular cavity-localized lipid nanoparticle (LNP) named WG-PL14 is developed. This optimized formulation has a nearly 30-fold increase in mRNA expression as well as better articular cavity enrichment compared to commercial lipids MC3 when performing intra-articular injection. Then, a mRNA sequence encoding recombinant human FGF18 (rhFGF18) for potential mRNA therapy in OA is optimized. In vitro assays confirm the translation of rhFGF18 mRNA into functional proteins within rat and human chondrocytes, promoting cell proliferation and extracellular matrix (ECM) synthesis. Subsequently, the therapeutic efficacy of the LNP-rhFGF18 mRNA complex is systematically assessed in a mouse OA model. The administration exhibits several positive outcomes, including an improved pain response, upregulation of ECM-related genes (e.g., AGRN and HAS2), and remodeling of subchondral bone homeostasis compared to a control group. Taken together, these findings underscore the potential of localized LNP-rhFGF18 mRNA therapy in promoting the regeneration of cartilage tissue and mitigating the progression of OA.

Melatonin enhances therapeutic outcomes of adipose tissue-derived mesenchymal stem cell therapy in rat osteoarthritis by reducing TNF-α and IL-1β-induced injuries.

Although adipose tissue-derived mesenchymal stem cell (ADSC) transplantation has been effectively used to treat osteoarthritis (OA), the low cell survival rate induced by the inflammatory and oxidative stress, severely affects the therapeutic efficiency of ADSC transplantation in OA. This study was designed to evaluate whether melatonin pretreatment could improve ADSC survival and its therapeutic efficacy in OA. The papain-induced OA rats were pretreated with melatonin via intra-articular injection and then intra-articular injected with indocyanine green (ICG)-labeled ADSCs (3 × 106/rat). Afterward, ADSC retention was evaluated by NIR-II fluorescence imaging. The tibia and synovial fluid were collected for histopathological examination and ELISA assay, respectively. To confirm the anti-inflammatory effect of melatonin, a TNF-α and IL-1β-induced cell model was used to evaluate the protective effects of melatonin on ADSC viability, cell apoptosis, and migration. Our results showed that melatonin pretreatment enhanced ADSC survival and improved the therapeutic effects of ADSC transplantation on cartilage repair, and anti-inflammation by reducing TNF-α, IL-6, IL-1β, and IL-12 in vivo. In particular, we also found that melatonin promoted ADSC viability and migration, and reduced cell apoptosis in vitro. In conclusion, this study supports that melatonin pretreatment can effectively improve ADSC survival and therapeutic efficiency in OA by reducing inflammatory injuries, which provides a novel strategy for enhancing ADSC therapy.

Ultrasound-guided arthrocentesis and intra-articular injection of the hip and shoulder joints in the dog.

To provide a video tutorial on ultrasound-guided arthrocentesis and injection of the canine hip and shoulder joints. Dogs undergoing arthrocentesis or intra-articular injection for diagnostic or therapeutic purposes. The target joint is visualized in long axis with a 70% isopropyl alcohol medium and linear array probe with a frequency range of 2 to 14 MHz and footprint of 50 mm after clipping a window and preparing the region sterilely. The needle is inserted, bevel up, in long axis with the probe angled at the appropriate trajectory to enter the joint space. The needle is advanced until the tip is visualized entering the joint. Aspiration to obtain synovial fluid can further confirm needle placement or provide diagnostic sampling prior to injection. The aspirate syringe is exchanged for that containing the therapeutic agent, and injectate can then be visualized entering and/or expanding the joint upon injection. Ultrasound-guided arthrocentesis will help identify deep appendicular joints (hip and shoulder), avoid surrounding vasculature, confirm needle placement, and target joint fluid pocketing. Needle guidance into a joint can reduce iatrogenic tissue damage from inappropriate needle placement and/or by minimizing attempts. For arthrocentesis, ultrasound guidance can maximize joint fluid volume acquisition for diagnostic purposes (cytology, culture, and fluid analysis) while also avoiding blood contamination. For joint injections, ultrasound will help ensure real-time intra-articular delivery of the injectate (regardless of attaining synovial fluid feedback) to maximize the therapeutic effect. For either purpose, iatrogenic tissue damage and procedure time are minimized.

New Technologies in the Treatment of Base of Thumb Osteoarthritis.

Symptomatic osteoarthritis (OA) of the first carpometacarpal (CMC) joint is prevalent and debilitating, commonly affecting the elderly and postmenopausal population. This review highlights the latest advancements in the treatment of thumb CMC OA, which historically includes a range of nonsurgical and surgical options without a consensus benchmark. We will focus on innovative and emerging technologies. Nonsurgical treatments typically comprise custom braces and corticosteroid injections. In addition, this review explores advanced approaches such as 3D printed braces, which have improved patient satisfaction, and novel intra-articular injectables such as autologous fat, optimized by ultrasonography to enhance treatment precision and outcomes. Although standard surgical treatments include trapeziectomy, with or without ligament reconstruction and tendon interposition, more recent implant arthroplasty designs show promising long-term survival. Newer interventions include patient-specific instrumentation for metacarpal osteotomies, selective joint denervation, and innovative suspensionplasty devices, all marked by their increased precision and personalized care. However, it is important to note that these novel technologies are not yet established as superior to standard treatments of thumb CMC OA.

Comparison of Ultrasound-Guided Genicular Pulse Radiofrequency and Fluoroscopy-Guided Intra-Articular Pulse Radiofrequency for Knee Osteoarthritis-Related Pain.

To compare two different algological intervention technique outcomes with ultrasound-guided genicular pulse radiofrequency (PRF) and fluoroscopy-guided intra-articular pulse radiofrequency for knee osteoarthritis-related pain. Observational study. Place and Duration of the Study: Izmir Bakircay University, Cigli Training and Research Hospital and Health Science University Tepecik, Training and Research Hospital, Izmir, Turkiye, between March 2022 and May 2023. Patients aged 60 years and above with stage 3 and 4 knee osteoarthritis, experiencing knee pain for more than six months, and non-responsive to conservative treatments were included. Patients with recent knee surgery or intra-articular injections and those ineligible for radiofrequency application were excluded. Ultrasound-guided genicular nerve PRF and fluoroscopy-guided intra-articular PRF were administered to the included patients. Pain and quality of life were evaluated using the visual analogue scale (VAS) and Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) scores before and after the procedures. The study included 64 patients. Both ultrasound-guided genicular PRF and fluoroscopy-guided intra-articular PRF resulted in significant reductions in VAS and WOMAC scores at 1 and 3 months after the procedures. There was no significant difference in efficacy between the two techniques. Ultrasound-guided genicular PRF and fluoroscopy-guided intra-articular PRF are effective and safe options for managing knee osteoarthritis-related pain. Osteoarthritis, Pulse radiofrequency, Ultrasound, Fluoroscopy, Pain.

Effectiveness of hydrotherapy on pain and functional status of shoulder joint among individuals undergone intra-articular injections

BackgroundThe shoulder complex with its varied pathology responds differently from patient to patient and so, the best option for progression is a choice of rehabilitation. In the present post-COVID scenario, many patients are referred to acute and sub-acute shoulder pain and dysfunction. It is very difficult to predict the outcome of therapy. Some patients recover even without any modalities. Recurrent or adverse symptoms are also possible. Gender, other demographic features, physiological response, and progressive outcome need to be considered in rehabilitation. This study is intended to evaluate the short-term effects of hydrotherapy post-intra-articular injections of shoulder dysfunctions.Aims and objectivesTo evaluate the effectiveness of hydrotherapy during early rehabilitation of individuals who have undergone intra-articular injections of shoulder joint on pain and function.Materials and methodsIn this prospective study, we have studied a total of 59 cases within the age group of 40–70 years with idiopathic frozen shoulder, acromio-clavicular joint dysfunction, and grade-1 untreated rotator cuff injuries. Group A patients were treated with conventional shoulder exercises and group B patients were treated in a hydrotherapy pool. The chief aim was to obtain earlier pain relief with controlled movement patterns and earlier relief from functional disability. The Constant-Murley score (CMS–100 points scale) composing pain and functional parameters was the outcome measure.ResultsAfter confounding all the demographic factors, it was found that the experimental group B treated by hydrotherapy revealed a statistically extremely significant difference (p value < 0.0001) at the end of the first week as compared to the conventional group. The treatment protocol was continued for 5 weeks. More than 90% of patients in the hydrotherapy group felt it easier and exercise participation progression was best. Better progression and improvement of shoulder function were achieved in the hydrotherapy group compared to the conventional group.ConclusionFrom this study, we conclude that hydrotherapy during early management of shoulder dysfunctions post-intra-articular injections is safer and provides excellent relief from pain as early as the first week. Functional progression is better and avoids complications related to mobilization.

Nanozyme-enhanced injectable hyaluronic acid-based hydrogel for the treatment of osteoarthritis

The progression of osteoarthritis (OA) is dramatically accelerated by excessive reactive oxygen species (ROS)-induced apoptosis of chondrocytes and the inflammatory response of synovial macrophages. In this study, we developed an injectable hydrogel with a catalase-mimicking nanozyme activity as a therapeutic agent for OA. In vitro experiments confirmed that the HA and peroxide-mimetic nanoenzyme-enhanced hydrogel, containing ε-polylysine/Mn1.8Co1.2O4 (ε-PLE/MnCoO) nanoparticles, continuously eliminated ROS and inflammatory cytokines while promoting the polarization of inflammatory macrophages (M1 phenotype) towards anti-inflammatory macrophages (M2 phenotype) in dysfunctional microenvironments. When used for intraarticular injections in OA models, the nanoenzyme-enhanced hydrogel effectively reduced oxidative stress by scavenging ROS and regulating the immune microenvironment. It resulted in a subsequent reduction in the expression of inflammatory factors, including MMP-13, TNF-α, IL-1β, and iNOS in both the synovium and joint fluid. Moreover, cartilage repair was enhanced by the promotion of COL-2 and SOX-9 expression in the cartilage tissue, whereas osteophyte formation in OA was reduced. This study introduced an innovative treatment strategy for the clinical management of OA, demonstrating its significant potential for application in treating OA.

Efficacy of a single dose of cryopreserved human umbilical cord mesenchymal stromal cells for the treatment of knee osteoarthritis:a randomized, controlled, double-blind pilot study

BackgroundKnee osteoarthritis (OA) is the most prevalent degenerative musculoskeletal disorder, which is particularly common in older population. While conventional treatments have limited effectiveness, the development of more effective therapeutic strategies is necessary to address this primary source of pain and disability. Umbilical cord mesenchymal stromal cells (UC-MSCs) offer a promising therapeutic approach for treating knee OA. AimThis randomized, prospective, double-blind and controlled pilot study was carried out to evaluate and compare the safety and therapeutic efficacy of a single intra-articular injection of a standardized product CellistemOA (5 × 106 ± 5 × 105 UC-MSCs), vs. triamcinolone (a synthetic corticosteroid) (10 mg/mL) in thirty patients with symptomatic knee OA (Kellgren–Lawrence grade II or III). MethodsThe outcomes included changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores based on a Likert scale, numerical rating score (NRS) for pain, Magnetic Resonance Imaging (MRI), and quality of life (SF-36 questionnaire), from baseline and throughout 12-months of follow-up. ResultsPatients treated with CellistemOA showed significant improvement in WOMAC score (including the three subscale scores (pain, stiffness and function), NRS in pain, and SF-36 profile from baseline to 12 months (p < 0.05) compared to the triamcinolone group, and no severe adverse events were reported. There were no significant differences in MRI WORMS scores between the two groups. However, patients who received the cellular treatment experienced a significant improvement in their SF-36 profile (p < 0.05). ConclusionsThis pilot study revealed that a single dose of CellistemOA is safe and superior to the active comparator in knee OA at 1-year of follow-up, making it a compelling therapeutic alternative to treat symptomatic OA patients.

Panaxatriol exerts anti-senescence effects and alleviates osteoarthritis and cartilage repair fibrosis by targeting UFL1

IntroductionOsteoarthritis (OA), the most common degenerative joint disease, can eventually lead to disability. However, no safe or effective intervention is currently available. Therefore, there is an urgent need to develop effective drugs that reduce cartilage damage and treat OA. ObjectivesThis study aimed to ascertain the potential of panaxatriol, a natural small molecule, as a therapeutic drug for alleviating the progression of OA. MethodsAn in vitro culture of human cartilage explants and C28/I2 human chondrocytes and an in vivo surgically induced OA mouse model were used to evaluate the chondroprotective effect of panaxatriol. The Drug Affinity Responsive Target Stability assay, CRISPR-Cas9 assay, Whole-transcriptome RNA sequencing analysis and agonist or antagonist assays were used to identify the target and potential signaling pathways of panaxatriol. Poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) was used to construct the sustained-release system of panaxatriol. ResultsPanaxatriol protected against OA by regulating chondrocyte metabolism. Ubiquitin-fold modifier 1-specific E3 ligase 1 (UFL1) was identified as a novel target of panaxatriol. Whole transcriptome RNA sequencing showed that UFL1 was closely related to cell senescence. Panaxatriol inhibited chondrocyte senescence through UFL1/forkhead box O1 (FOXO1)/P21 and UFL1/NF-κB/SASPs signaling pathways. It also could inhibit fibrocartilage formation during cartilage repair via the UFL1/FOXO1/Collagen 1 signaling pathway. Finally, we constructed a sustained-release system for panaxatriol based on PLGA-PEG, which reduced the number of intra-articular injections, thereby alleviating joint swelling and injury. ConclusionsPanaxatriol exerts anti-senescence effects and has the potential to delay OA progression and reduce cartilage repair fibrosis by targeting UFL1.

M7G-modified mt-tRF3b-LeuTAA regulates mitophagy and metabolic reprogramming via SUMOylation of SIRT3 in chondrocytes

N7-methylguanosine (m7G) modification is one of the most prevalent RNA modifications, and methyltransferase-like protein-1 (METTL1) is a key component of the m7G methyltransferase complex. METTL1-catalyzed m7G as a new RNA modification pathway that regulates RNA structure, biogenesis, and cell migration. Increasing evidence indicates that m7G modification has been implicated in the pathophysiological process of osteoarthritis (OA). However, the underlying molecular mechanisms of m7G modification remains incompletely elucidated during the progression of OA. Here we found that METTL1 and m7G levels were markedly increased in OA chondrocytes. In addition, METTL1-mediated m7G modification upregulated mt-tRF3b-LeuTAA expression to exacerbate chondrocyte degeneration. Mechanistically, mt-tRF3b-LeuTAA decreased the SUMO-specific protease 1 (SENP1) protein expression and upregulated the level of sirtuin 3 (SIRT3) SUMOylation to inhibit PTEN induced kinase 1 (PINK1)/Parkin-mediated mitochondrial mitophagy. Intra-articular injection of PMC-tRF3b-LeuTAA inhibitor (Polyamidoamine-polyethylene glycol surface-modified with Minimal self-peptides and Chondrocyte-affinity peptides, PMC) attenuated destabilization of the medial meniscus (DMM) mouse cartilage degeneration in vivo. Our study demonstrates that METTL1/m7G/mt-tRF3b-LeuTAA axis accelerate cartilage degradation by inhibiting mitophagy and promoting mitochondrial dysfunction through SIRT3 SUMOylation, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for OA treatment.

Evaluation of serum biomarkers after intra-articular injection of rat bone marrow-derived mesenchymal stem cells in a rat model of knee osteoarthritis

Evaluation of serum biomarkers after intra-articular injection of rat bone marrow-derived mesenchymal stem cells in a rat model of knee osteoarthritis