Ligament Transection Research Articles

Quantitative high-resolution 7T MRI to assess longitudinal changes in articular cartilage after anterior cruciate ligament injury in a rabbit model of post-traumatic osteoarthritis

ObjectiveTo demonstrate an ultra-high field (UHF) 7 ​T delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) protocol for quantitative post-traumatic osteoarthritis (PTOA) detection and monitoring in a rabbit anterior cruciate ligament transection (ACLT) model. DesignACL transections were performed unilaterally in 5 rabbits (33-weeks-old, 3.5 ​± ​0.5 ​kg) to induce PTOA. MRI exams were performed at 7 ​T prior to and 2, 4, 7 and 10-weeks after ACLT using a modified dGEMRIC protocol. Voxel-based T1 and T2 maps were created over manually drawn femoral cartilage ROIs from the center of the tibial plateau to the posterior meniscus. Femoral, tibial, and patellar epiphyses were harvested 10-weeks post-surgery and processed for μCT imaging and histology. ResultsQuantitative analysis revealed a 35% and 39% decrease in dGEMRIC index in the medial ACLT knee compartment 7- and 10-weeks post-surgery, respectively (p ​= ​0.009 and p ​= ​0.006) when compared to baseline. There was no significant change in the lateral ACLT compartment or in either compartment of the control knees. Visual inspection of histology confirmed PTOA in the ACLT knees. Osteophytes were found only in ACLT knees (osteophyte volume in femur: 94.53 ​± ​44.08 ​mm3, tibia: 29.35 ​± ​13.79 ​mm3, and patella: 3.84 ​± ​0.92 ​mm3) and were significantly larger in the medial compartments of the femur than lateral (p ​= ​0.0312). ConclusionThe dGEMRIC technique quantitatively applied at 7 ​T UHF-MRI demonstrates site-specific cartilage degeneration in a large animal PTOA model. This should encourage further investigation, with potential applications in drug and therapeutic animal trials as well as human studies.

Marrow adipose tissue accumulation and dysgenesis of the trabecular bone after anterior cruciate ligament transection and reconstruction in the rat proximal tibial epiphysis

The accumulation of marrow adipose tissue (MAT) is frequently associated with bone loss. Although anterior cruciate ligament (ACL) injury induces bone loss, MAT accumulation after ACL injury has not been evaluated. In addition, no information about changes in MAT after ACL reconstruction is available. In this study, we aimed to examine (1) the effects of ACL transection on the amounts of trabecular bone and MAT present, and (2) whether ACL reconstruction inhibits the changes in the trabecular bone and MAT that are induced by ACL transection. ACL transection alone or with immediate reconstruction was performed on the right knees of rats. Untreated left knees were used as controls. Histomorphological changes in the trabecular bone and MAT in the proximal tibial epiphysis were examined prior to surgery and at one, four, and 12 weeks postsurgery. The trabecular bone area on the untreated side increased in a time-dependent manner. However, after ACL transection, the trabecular bone area did not increase during the experimental period, indicating dysgenesis of the bone (bone loss). Dysgenesis of the trabecular bone after ACL transection was attenuated by ACL reconstruction. MAT accumulation due to adipocyte hyperplasia and hypertrophy had been induced by ACL transection by four weeks postsurgery. This ACL transection-induced MAT accumulation was not prevented by ACL reconstruction. Based on these results, we conclude that (1) dysgenesis of the bone in the proximal tibia following ACL transection is accompanied by MAT accumulation, and (2) ACL reconstruction attenuates dysgenesis of the trabecular bone but cannot prevent MAT accumulation.

IMPACT OF EXERCISE ON POSTTRAUAMTIC OSTEOARTHRITIS AFTER KNEE JOINT INJURY: A SYSTEMATIC REVIEW OF ANIMALS WITH ANTERIOR CRUCIATE LIGAMENT OR MEDIAL MENISCUS

Purpose: A previous meta-anlysis of studies involving healthy animals demonstrated that a moderate daily dose of exercise may be chondroprotective. However, it remains unknown if exercise following joint injury may either accelerate posttraumatic changes or have a chondroprotective effect in animal models of posttraumatic osteoarthritis (PTOA). The purpose of the current systematic review and meta-analysis was to evaluate the role of exercise on knee cartilage changes in animals with either anterior cruciate ligament or medial meniscus transection.

SYNOVIAL FLUID INTERLEUKIN-1α CANNOT FULLY EXPLAIN PROTEOGLYCAN DEGRADATION IN RATS

Purpose: Osteoarthritis (OA) can result from joint injuries and biochemical perturbations. Proteoglycans (PGs) in cartilage are responsible for compressive stiffness and swelling and are severely affected by OA. The anterior cruciate ligament transection (ACLT) animal model is widely used for investigating the post-traumatic OA phenotype and high fat/sucrose diets (HFSD) are often used to induce obesity and the resultant metabolic OA and biochemical imbalance associated with metabolic syndrome. In rabbits, mechanical joint abnormalities caused by ACLT lead to PG degradation as early as 2 weeks post-surgery.

The protective effect of mangiferin on osteoarthritis: An in vitro and in vivo study.

Mangiferin is a kind of polyphenol chemical compound separated from these herbal medicines of Mangifera indica L., Anemarrhena asphodeloides Bge. and Belamcanda chinensis L., which has anti-inflammatory, anti-virus, and other physiological activities without toxic effects. Osteoarthritis (OA) is a chronic disease that is also a kind of arthritis disease in which articular cartilage or bones under the joint is damaged. In addition, artificial replacements are required in severe cases. At present, there are not too much researches on the potential biological activities of mangiferin that plays a protective role in the treatment of OA. In this study, we evaluated the protective effect of mangiferin on osteoarthritis (OA) in vitro and in vivo. First, the effect of different concentrations of mangiferin on rat chondrocytes was determined by MTT assay. Second, the effects of mangiferin on the expression levels of matrix metalloproteinase (MMP)-13, TNF alpha, Collagen II, Caspase-3, and cystatin-C in interleukin-1beta (IL-1beta)-induced rat chondrocytes were examined by the real-time polymerase chain reaction in vitro, meanwhile the effects of mangiferin on the nuclear factor kappa-B (NF-kappaB) signaling pathway were also investigated by Western Blot. Finally, the anti-osteoarthritic protective effect of mangiferin was evaluated in the rat model by anterior cruciate ligament transection (ACLT) combined with bilateral ovariectomy-induced OA in vivo. The results showed that the mangiferin was found to inhibit the expression of MMP-13, TNF-alpha, and Caspase-3 which also increased the expression of Collagen II and cystatin-C in IL 1beta induced rat chondrocytes. In addition, IL-1beta-induced activation of nuclear factor kappa-B (NF-kappaB) and the degradation of inhibitor of kappaB (IkappaB)-alpha were suppressed by mangiferin. For the in vivo study in a rat model of OA, 100 microl of mangiferin was administered by intra-articular injections for rats, the results showed that the cartilage degradation was suppressed by mangiferin through Micro CT and Histological Examination. According to both in vitro and in vivo results, mangiferin has a protective effect in the treatment of OA which may be a promising therapeutic agent for OA.

Improving the symptoms of post-traumatic osteoarthritis by α2-macroglobulin-rich serum

ABSTRACT Purpose Altered joint loading by trauma induces joint degeneration, eventually leading to the generation of post-traumaticosteoarthritis (PTOA). Recent studies have shown that α2-macroglobulin (A2M)inhibits PTOA, induced by anterior cruciate ligament transection (ACLT),pathogenesis by regulating proinflammatory cytokines and matrixmetalloproteinases. However, the application of A2M is limited due to highprices. Therefore, the aim of this study is to explore the novel preparation ofA2M. Materials and Methods The early change of A2M in synovial fluid and serum was measured by ELISA.Ultra-filtered centrifugation was performed to prepare α2-macroglobulin-richserum (A2MRS). The bioactivity of A2M in A2MRS was detected by improved Ellisand Gollas-Galvan method. The effects of A2MRS on PTOA were observed using immunohistochemistry,safranine O staining, micro X-ray, fluorescence molecular tomography etc. Results The concentration of A2M in PTOA group wassignificantly higher than that in Sham group in synovial fluid on the third dayafter ACLT in rat PTOA model. On the contrary, a significant downregulation ofA2M levels in PTOA group was observed compared to the Sham group in serum atthe seventh day after ACLT. Secondly, A2MRS was prepared successfully, and theconcentration and bioactivity of A2M in A2MRS was significantly higher thanthat in serum. Lastly, A2MRS not only reduced notably the production ofsecondary cartilage ossification, type 10 collagen and matrix metalloproteinase13, but also increased profoundly the generation of type 2 collagen, aggrecan,and chondrocytes’ number. Conclusion Our results indicate that A2MRS has protective effects on PTOA.

Efficacy and Safety of FX201, a Novel Intra-Articular IL-1Ra Gene Therapy for Osteoarthritis Treatment, in a Rat Model.

Osteoarthritis (OA) is a disabling, degenerative disease characterized by progressive cartilage and bone damage. There remains a need for local therapies that, following a single injection, can provide long-term pain relief and functional improvement and potentially delay disease progression. FX201 is a novel, intra-articular (IA), interleukin-1 receptor antagonist (IL-1Ra) gene therapy in development for the treatment of OA. In this study, we assessed the efficacy, biodistribution, and safety of helper-dependent adenovirus (HDAd)-ratIL-1Ra, the rat surrogate of FX201, and the biodistribution of FX201, in the anterior cruciate ligament transection (ACLT) rat OA model. A single IA injection of HDAd-ratIL-1Ra administered 7 days post-ACLT mitigated OA-related changes to cartilage, bone, and the synovial membrane at week 12 following surgery. Furthermore, FX201 and HDAd-ratIL-1Ra persisted for at least 92 days in the injected joint and proximal tissues with minimal evidence of vector spreading peripherally. Finally, HDAd-ratIL-1Ra showed a favorable safety profile without any local or systemic adverse effects. In conclusion, HDAd-ratIL-1Ra demonstrated local therapeutic and disease-modifying effects and was well tolerated, supporting further clinical development of FX201.

Effect of center of rotation of angulation-based leveling osteotomy on ex vivo stifle joint stability following cranial cruciate ligament transection and medial meniscal release with and without a hamstring load.

ObjectiveTo evaluate the effect of center of rotation of angulation (CORA)‐based leveling osteotomy (CBLO) and hamstring load on stifle stability following cranial cruciate ligament transection (CCLx) and medial meniscal release (MMR).Study designEx vivo experimental study.Sample populationCadaver hind limb preparations (n = 7).MethodsAfter instrumentation, constant quadriceps and gastrocnemius loads with an optional hamstring load in a 3:1:0.6 ratio were applied, and stifles were extended from fully flexed using an electrical motor during fluoroscopic recording. The recording process was repeated after each of CCLx, MMR and CBLO and the extracted landmark coordinates were used for calculation of cranial tibial translation (CTT) and patellar ligament angle (PTA).ResultsMean initial tibial plateau angle was 28.1°: post‐CBLO the mean was 9.7°. Cranial tibial translation developed from 50° and 75° with CCLx and MMR respectively (p < .04, < .02) without hamstring loading. Hamstring loading mitigated CTT due to CCLx and delayed CTT until 120° for MMR (P < .02) in this model. CBLO prevented CTT, except at 140° without hamstring loading (P = .01). Similar results were seen for PTA, but CBLO curves were parallel to and lower than intact values at all tested angles (P < .04), consistent with induced effective joint flexion.ConclusionCBLO to a target tibial plateau angle of 10° largely eliminated CTT induced by CCLx and MMR. Hamstring loads of 20% quadriceps load improved stifle stability in this model.ImpactStifle stability following CBLO appears to be multifactorial and depends on meniscal integrity, joint angle, and hamstring strength.

Age alters gait compensations following meniscal injury in male rats.

With age, susceptibility to osteoarthritis (OA) and OA-related pain and disability increases. Like in OA patients, gait patterns in rodent OA models shift to protect the injured limb during loading. However, unlike in OA patients, it is unknown how age affects gait changes in rodent OA models. In this study, gait compensations following meniscal injury in 3-, 6-, and 9-month-old rats were evaluated to examine age-effects of OA-related joint dysfunction. Rats 3, 6, and 9 months received medial collateral ligament transection plus medial meniscus transection (MCLT + MMT) surgery (n = 8/age group) or a skin incision (n = 8/age group). Postsurgery, rats underwent gait testing at 2, 4, 6, and 8 weeks. Postmortem, joints were processed for histology to assess cartilage damage. MCLT + MMT rats walked with reduced vertical loading in their injured limbs immediately after injury and throughout OA progression. Compared to sham-operated limbs, 6-and 9-month MCLT + MMT animals reduced loading in their injured limbs while 3-month MCLT + MMT animals did not. MCLT + MMT rats also increased stance time on the injured limb compared to the contralateral limb. Additionally, for the MCLT + MMT animals, 6-and 9-month animals had significantly worse cartilage damage compared to 3-month animals. These data indicated age at injury onset affects how animals load the OA-affected joint, with older animals developing gait compensations that more markedly reduce weight on the injured limb during walking.

The Gastrohepatic Ligament Approach in Robotic Spleen-Preserving Distal Pancreatectomy with Resection of the Splenic Vessels: The Superior Window Approach in the Warshaw Technique

BackgroundThere have been few studies reporting on the surgical approaches of minimally invasive spleen-preserving distal pancreatectomy (SPDP). Herein, we present two cases who underwent robotic SPDP with resection of the splenic vessels using our novel gastrohepatic ligament approach (the superior window approach in the Warshaw technique). MethodsOur gastrohepatic ligament approach in robotic SPDP consists of four steps: step 1, the gastrohepatic ligament transection; step 2, dissection around the pancreas; step 3, transection of the pancreas; and step 4, resection of the splenic vessels (the Warshaw technique). ResultsStarting with the gastrohepatic ligament transection, the pancreas was directly dissected with neither dissecting the gastrocolic ligament nor retracting the stomach. The mean operative time was 217 min with minimal estimated blood loss. Both of the patients had no postoperative morbidity. ConclusionsThe gastrohepatic ligament approach may be helpful and optional in robotic SPDP with the Warshaw technique.

Low-dose irradiation could mitigate osteoarthritis progression via anti-inflammatory action that modulates mitochondrial function

PurposeThe use of low-dose radiation therapy (LDRT) for osteoarthritis (OA) are rarely implemented, except in some European regions. Its clinical effects are controversial but little is known about how LDRT affects actual disease progression. We conducted a preclinical study to reveal the potential underlying mechanisms related to its disease modifying abilities. Methods and MaterialsUsing primary cultured human chondrocytes and synovium-derived cells obtained from OA patients, the effects of LDRT were measured by quantitative real-time PCR, western blotting, and mRNA sequencing. For in vivo validation, a surgically-induced isolated OA model was used after anterior cruciate ligament transection or surgical destabilization of the medial meniscus. ResultsLDRT decreased the expression of pro-inflammatory factor matrix metalloproteinase 13 (MMP13) in chondrocytes. By contrast, collagen type 2 (COL2) protein expression was increased. LDRT induced large transcriptomic changes in both chondrocytes/synoviocytes, especially in mitochondrial activities. Gene set variation analysis demonstrated inverted U-shaped response in several categories, such as mitochondrial unfolded protein responses and extracellular matrix interactions. Growth differentiation factor 15 (GDF15), which is a mitohormetic signaling factor, was increased after LDRT and mediated the anti-inflammatory effects. Aggrecan was increased in synoviocyte’s medium and TNF-α was decreased in chondrocyte’s medium after LDRT. Conversely, knockdown of GDF15 did not result in decreased MMP13 expression by LDRT. Next, OA rats treated with LDRT exhibited a decreased OA severity when compared with the no-irradiation group at 10 weeks post-surgery (mean OARSI score 3.7 in 0 Gy, 2.8 in 0.5 Gy, and 1.8 in 1 Gy; p = 0.003). Osteoclast activity was significantly reduced in the LDRT group. ConclusionsTaken together, these data show that LDRT could mitigate osteoarthritis progression by exerting its anti-inflammatory effects via mitochondrial function modulation.

Preclinical studies and clinical trials on mesenchymal stem cell therapy for knee osteoarthritis: A systematic review on models and cell doses.

To provide a systematic analysis of the study design in knee osteoarthritis (OA) preclinical studies, focusing on the characteristics of animal models and cell doses, and to compare these to the characteristics of clinical trials using mesenchymal stem cells (MSCs) for the treatment of knee OA. A systematic and comprehensive search was conducted using the PubMed, Web of Science, Ovid, and Embase electronic databases for research papers published in 2009-2020 on testing MSC treatment in OA animal models. The PubMed database and ClinicalTrials.gov website were used to search for published studies reporting clinical trials of MSC therapy for knee OA. In total, 9234 articles and two additional records were retrieved, of which 120 studies comprising preclinical and clinical studies were included for analysis. Among the preclinical studies, rats were the most commonly used species for modeling knee OA, and anterior cruciate ligament transection was the most commonly used method for inducing OA. There was a correlation between the cell dose and body weight of the animal. In clinical trials, there was large variation in the dose of MSCs used to treat knee OA, ranging from 1×106 to 200×106 cells with an average of 37.91×106 cells. Mesenchymal stem cells have shown great potential in improving pain relief and tissue protection in both preclinical and clinical studies of knee OA. Further high-quality preclinical and clinical studies are needed to explore the dose effectiveness relationship of MSC therapy and to translate the findings from preclinical studies to humans.

Establishment of a Surgery-Induced Osteoarthritis Rat Model

The degenerative arthritis has been a common knee joint disease in Taiwan. In mild cases of degenerative arthritis, it may just be a little uncomfortable to walk, but severe degenerative arthritis will cause difficulty in walking and even loss of basic mobility. The loss of articular cartilage in degenerative arthritis is irrecoverable. Currently, the degeneration of the knee joint can be easily divided into three levels based on its severity: primary, intermediate, and severe. The choice of treatments for degenerative arthritis will vary in according to different levels that is mainly divided into the non-surgical treatment and surgical treatment. Therefore, how to prevent knee joint degeneration is an important issue. In this study, anterior cruciate ligament transection (ACLT) plus medial meniscectomy (MMx) surgery were used to established a rat model with degenerative arthritis. According to all data, we have successfully established a rat model with degenerative arthritis via ACLT-MMx surgery. We wish this model will applied on the research of degenerative arthritis drugs and the design of therapeutic strategies for degenerative arthritis in the future.

Farnesoid X receptor agonist attenuates subchondral bone osteoclast fusion and osteochondral pathologies of osteoarthritis via suppressing JNK1/2/NFATc1 pathway.

Osteoarthritis (OA) is a prevalent degenerative disease of the joint, featured by articular cartilage destruction and subchondral bone marrow lesions. Articular cartilage and subchondral bone constitute an osteochondral unit that guarantees joint homeostasis. During OA initiation, activated osteoclasts in subchondral bone ultimately result in impaired capacities of the subchondral bone in response to mechanical stress, followed by the degradation of overlying articular cartilage. Thus, targeting osteoclasts could be a potential therapeutic option for treating OA. Here, we observed that farnesoid X receptor (FXR) expression and osteoclast fusion and activity in subchondral bone were concomitantly changed during early-stage OA in the OA mouse model established by anterior cruciate ligament transection (ACLT). Then, we explored the therapeutic effects of FXR agonist GW4064 on the osteochondral pathologies in ACLT mice. We showed that GW4064 obviously ameliorated subchondral bone deterioration, associated with reduction in tartrate-resistant acid phosphatase (TRAP) positive multinuclear osteoclast number, as well as articular cartilage degradation, which were blocked by the treatment with FXR antagonist Guggulsterone. Mechanistically, GW4064 impeded osteoclastogenesis through inhibiting subchondral bone osteoclast fusion via suppressing c-Jun N-terminal kinase (JNK) 1/2/nuclear factor of activated T-cells 1 (NFATc1) pathway. Taken together, our results present evidence for the protective effects of GW4064 against OA by blunting osteoclast-mediated aberrant subchondral bone loss and subsequent cartilage deterioration. Therefore, GW4064 demonstrates the potential as an alternative therapeutic option against OA for further drug development.

Synovial fluid proteome profile of surgical versus chemical induced osteoarthritis in rabbits.

BackgroundAnimal models are significant for understanding human osteoarthritis (OA). This study compared the synovial fluid proteomics changes in surgical and chemical induced OA models.MethodsThirty rabbits either had anterior cruciate ligament transection (ACLT) procedure or injected intra-articularly with monosodium iodoacetate (MIA, 8 mg) into the right knee. The joints were anatomically assessed, and the synovial fluid proteins analyzed using two-dimensional polyacrylamide gel electrophoresis (2DGE) and MALDI TOF/TOF mass spectrometry analysis at 4, 8 and 12 weeks. The proteins’ upregulation and downregulation were compared with control healthy knees.ResultsSeven proteins (histidine-rich glycoprotein, beta-actin-like protein 2 isoform X1, retinol-binding protein-4, alpha-1-antiproteinase, gelsolin isoform, serotransferrin, immunoglobulin kappa-b4 chain-C-region) were significantly expressed by the surgical induction. They characterized cellular process (27%), organization of cellular components or biogenesis (27%), localization (27%) and biological regulation (18%), which related to synovitis, increased cellularity, and subsequently cartilage damage. Three proteins (apolipoprotein I-IV precursor, serpin peptidase inhibitor and haptoglobin precursor) were significantly modified by the chemical induction. They characterized stimulus responses (23%), immune responses (15%), biological regulations (15%), metabolism (15%), organization of cellular components or biogenesis (8%), cellular process (8%), biological adhesions (8%) and localization (8%), which related to chondrocytes glycolysis/death, neovascularization, subchondral bone necrosis/collapse and inflammation.ConclusionsThe surgical induced OA model showed a wider range of protein changes, which were most upregulated at week 12. The biological process proteins expressions showed the chemical induced joints had slower OA progression compared to surgical induced joints. The chemical induced OA joints showed early inflammatory changes, which later decreased.

Bilobalide Exerts Anti-Inflammatory Effects on Chondrocytes Through the AMPK/SIRT1/mTOR Pathway to Attenuate ACLT-Induced Post-Traumatic Osteoarthritis in Rats.

Although osteoarthritis (OA) significantly affects the quality of life of the elderly, there is still no effective treatment strategy. The standardized Ginkgo biloba L. extract preparation has been shown to have a wide range of therapeutic effects. Bilobalide, a unique ingredient of Ginkgo biloba, has anti-inflammatory and antioxidant pharmacological properties, but its mechanism of action on OA remains unknown. In this study, we investigated the effects of bilobalide on the development of OA through in vivo and in vitro experiments, as well as its potential anti-inflammatory mechanisms. The in vitro experiments demonstrated that bilobalide significantly inhibited the production of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and matrix metalloproteinase 13 (MMP13) in ATDC5 chondrocytes induced by Interleukin-1β (IL-1β). At the molecular level, bilobalide induced chondrocyte autophagy by activating the AMPK/SIRT1/mTOR signaling pathway, which increased the expression of autophagy-related Atg genes, up-regulated the expression of LC3 protein, and reduced the expression of the p62 protein. In vivo, bilobalide exerted significant anti-inflammatory and anti-extracellular matrix (ECM) degradation effects in a rat model of post-traumatic OA (PTOA) induced by anterior cruciate ligament transection (ACLT). Bilobalide could relieve joint pain in PTOA rats, inhibit the expression of iNOS and COX-2 protein in cartilage via the AMPK/SIRT1/mTOR pathway, and reduce the level of ECM degradation biomarkers in serum. In conclusion, bilobalide exhibits vigorous anti-inflammatory activity, presenting it as an interesting potential therapeutic agent for OA.

Hierarchical functional nanoparticles boost osteoarthritis therapy by utilizing joint-resident mesenchymal stem cells

Utilization of joint-resident mesenchymal stem cells (MSC) to repair articular cartilage is a promising strategy in osteoarthritis (OA) therapy but remains a considerable research challenge. Here, hierarchical targeting and microenvironment responsive peptide functionalized nanoparticles (NPs) are used to achieve cartilage repair in situ. Ultrasmall copper oxide (CuO) NPs are conjugated with type 2 collagen and MSC dual-targeting peptide (designated WPV) with a matrix metalloproteinase 2 (MMP-2)-sensitive sequence as a spacer to achieve hierarchical targeting. Guided by this peptide, WPV-CuO NPs initially penetrate cartilage and subsequently expose the inner MSC-targeted peptide to attract MSCs through MMP-2 clearance. CuO further promotes chondrogenesis of MSCs. In an anterior cruciate ligament transection rat model, intraarticular injection of WPV-CuO NPs induces significant reduction of cartilage destruction. The therapeutic mechanism involves inhibition of the PI3K/AKT/mTOR pathway, as determined via transcriptome analysis. In conclusion, a novel therapeutic strategy for OA has been successfully developed based on localized MSC recruitment and cartilage repair without transplantation of exogenous cells or growth factors.Graphical

Exosomes Derived From Human Urine–Derived Stem Cells Overexpressing miR-140-5p Alleviate Knee Osteoarthritis Through Downregulation of VEGFA in a Rat Model

Background: Knee osteoarthritis (KOA) is one of the most common chronic musculoskeletal disorders worldwide, for which exosomes derived from stem cells may provide an effective treatment. Purpose: To assess the effect of exosomes derived from human urine–derived stem cells (hUSCs) overexpressing miR-140-5p (miR means microRNA) on KOA in an in vitro interleukin 1β (IL-1β)–induced osteoarthritis (OA) model and an in vivo rat KOA model. Study Design: Controlled laboratory study. Methods: Exosomes derived from hUSCs (hUSC-Exos) were isolated and validated. The hUSCs were transfected with miR-140s using lentivirus, and exosomes secreted from such cells (hUSC-140-Exos) were collected. The roles of hUSC-Exos and hUSC-140-Exos in protecting chondrocytes against IL-1β treatment were compared by analyzing the proliferation, migration, apoptosis, and secretion of extracellular matrix (ECM) in chondrocytes. After vascular endothelial growth factor A (VEGFA) was identified as a target of miR-140, the mechanism by which VEGFA can mediate the beneficial effect of miR-140 on OA was investigated using small interfering RNA transfection or chemical drugs. The expression of VEGFA in cartilage and synovial fluid from patients with KOA was measured and compared with that of healthy controls. Surgery for anterior cruciate ligament transection and destabilization of the medial meniscus were performed on the knee joints of Sprague-Dawley rats to establish an animal model of OA, and intra-articular (IA) injection of hUSC-Exos or hUSC-140-Exos was conducted at 4 to 8 weeks after the surgery. Cartilage regeneration and subchondral bone remodeling were evaluated through histological staining and micro–computed tomography analysis. Results: Proliferation and migration ability were enhanced and apoptosis was inhibited in chondrocytes treated with IL-1β via hUSC-Exos, with the side effect of decreased ECM secretion. hUSC-140-Exos not only retained the advantages of hUSC-Exos but also increased the secretion of ECM by targeting VEGFA, including collagen II and aggrecan. Increased expression of VEGFA during the progression of KOA was also confirmed in cartilage and synovial fluid samples obtained from patients with OA. In the rat OA model, IA injection of hUSC-140-Exos enhanced cartilage regeneration and subchondral bone remodeling. Conclusion: Our results demonstrated the superiority of hUSC-Exos overexpressing miR-140-5p for treating OA compared with the hUSC-Exos. The effect of hUSC-140-Exos for suppressing the progression of KOA is in part mediated by VEGFA. Clinical Relevance: Exosomes derived from stem cells may provide a promising treatment for KOA, and our study can advance the related basic research.

Comparison of Several Combinations of Suture Tape Reinforcement and Suture Button Constructs for Fixation of Unstable Syndesmosis.

The purpose of this study was to arthroscopically evaluate syndesmotic stability after fixation with several combinations of suture buttons (SBs) and suture tape reinforcement in a completely unstable cadaver model. Fifteen cadaver above-knee specimens underwent sequential ligament transection and fixation to create six experimental models: (1) intact model, (2) after complete disruption of the syndesmotic ligaments, and after repair with either suture tape reinforcement (3), suture tape reinforcement with a single SB (4), suture tape reinforcement with two diverging SBs (5), or two diverging SBs alone (6). Instability measurements included anterior and posterior tibiofibular spaces measured arthroscopically under 100 N coronal stress, tibiofibular anteroposterior and posteroanterior translation in sagittal plane measured arthroscopically under sagittal stress of 100 N, and anterior tibiofibular space measured directly with a caliper under external rotation torque of 7.5 N·m. Instability measurements taken after each fixation method were compared with the uninjured model and with the complete unstable model using the Wilcoxon signed-rank test. Fixation using a combination of one SB and singular suture tape reinforcement augmentation provided stability similar to the intact stage (coronal anterior space 1.24 versus 1.15, P = 0.887; coronal posterior space 1.63 versus 1.64, P = 0.8421; anteroposterior translation 0.91 versus 0.46, P = 0.003; posteroanterior translation 0.51 versus 0.57, P = 0.051; external rotation anterior tibiofibular space 1.08 versus 0.55, P = 0.069). Moreover, adding a second SB led to further gains in fixation stability. This study suggests that although a destabilizing syndesmotic injury that includes the anterior inferior tibiofibular ligament, interosseous ligament, and posterior inferior tibiofibular ligament is not adequately stabilized by either one or two SBs, the addition of a suture tape reinforcement to even one SB restores syndesmotic stability to the preinjury level.

The Traditional Chinese Medicine "Hu-Qian-Wan" Attenuates Osteoarthritis-Induced Signs and Symptoms in an Experimental Rat Model of Knee Osteoarthritis.

Background Knee osteoarthritis (KOA) is a chronic, low-grade inflammatory disease that affects knee joints and causes functional disability in the elderly. KOA is typically treated with oral NSAIDs, which are commonly associated with gastrointestinal side effects or cardiovascular complications. Traditional Chinese medicine (TCM) is widely used by patients with KOA in Taiwan; the Hu-Qian-Wan (HQW) formula is typically prescribed. We investigated the therapeutic role of a modified version of the HQW decoction in Sprague-Dawley rats with KOA induced by anterior cruciate ligament transection (ACLT) of the right knee. Materials and Methods Thirty rats were randomly assigned to five groups (six animals each): arthrotomy alone (sham surgery, controls), ACLT only, ACLT + low-dose (1,000 mg/kg) HQW, ACLT + high-dose (3,000 mg/kg) HQW, and ACLT + celecoxib (30 mg/kg). All study groups underwent weight-bearing behavioral testing, micro-computed tomography (CT), and histological examinations of the knee joint cartilage, as well as immunohistochemical analyses of levels of interleukin (IL) 1β and tumor necrosis factor (TNF) α expression in articular cartilage. Results At 6 weeks, compared with ACLT group only, ACLT rats administered high-dose HQW or celecoxib exhibited the fewest weight-bearing deficits, the greatest improvements from baseline in articular cartilage architecture, and the lowest amounts of TNF-α and IL-1β staining in cartilage and synovial sections (all values were significant compared with the ACLT-only group). The only values that were significantly increased by ACLT + low-dose HQW compared with ACLT alone were bone mineral density and trabecular numbers. Conclusion Our findings suggest that high-dose HQW improves weight-bearing asymmetry, decreases bone loss, and reduces levels of TNF-α and IL-1β in the affected joint in ACLT-induced KOA rats. More evidence is needed to support our findings.