Ligament Transection Research Articles

Effect of Different Collagen on Anterior Cruciate Ligament Transection and Medial Meniscectomy-Induced Osteoarthritis Male Rats.

Osteoarthritis (OA) is a common type of arthritis characterized by degeneration of the articular cartilage and joint dysfunction. Various pharmacological and non-pharmacological techniques have been used to manage these diseases. Due to the diverse therapeutic properties of marine collagen, it has received considerable attention in its pharmacological application. Thus, the purpose of this study was to compare the efficacy of jellyfish collagen, collagen peptide, other sources of marine collagen, and glycine in treating OA. In the OA rat model, an anterior cruciate ligament transection combined with medial meniscectomy surgery (ACLT + MMx) was used to induce osteoarthritis in rats. Two weeks before surgery, male Sprague–Dawley rats were fed a chow-fat diet. After 6 weeks of treatment with collagen, collagen peptide, and glycine, the results show that they could inhibit the production of proinflammatory cytokines and their derivatives, such as COX-2, MMP-13, and CTX-II levels; therefore, it can attenuate cartilage degradation. Moreover, collagen peptides can promote the synthesis of collagen type II in cartilage. These results demonstrate that collagen and glycine have been shown to have protective properties against OA cartilage degradation. In contrast, collagen peptides have been shown to show cartilage regeneration but less protective properties. Jellyfish collagen peptide at a dose of 5 mg/kg b. w. has the most significant potential for treating OA because it protects and regenerates cartilage in the knee.

VNOTES Hysterectomy, Adnexectomy, and Uterosacral Ligament Suspension: A Walk-Through Guide

To provide a stepwise guide to performing vNOTES hysterectomy, adnexectomy, and vault suspension, using 2 access platform methods. Narrated surgical video based on 2 cases of vNOTES for abnormal uterine bleeding and endometrial intraepithelial neoplasia. A single tertiary-care academic center. Step-by-step walk-through is shown to demonstrate the successful completion of a hysterectomy, adnexectomy, and vault suspension. Use of a traditional glove platform and that of an advanced access system, the GelPOINT Access System (Applied Medical), are illustrated. The surgical steps are summarized as follows: (1) colpotomy and abdominal entry, (2) transection of the uterosacral ligaments, (3) placement of an access platform, (4) upper abdominal survey, (5) transection of the uterine and cornual pedicles, (6) identification of the ureters, (7) bilateral salpingo-oophorectomy, (8) uterosacral ligament suspension, (9) cystoscopy, and (10) vaginal vault closure and tying of the suspension sutures. This video demonstrates the steps to safely reproduce a vNOTES hysterectomy, adnexectomy, and uterosacral ligament suspension with 2 access techniques. vNOTES offers scar-free surgery, improved access to high pedicles and surgical fields, and a favorable recovery profile, making it an attractive surgical route in appropriate candidates.

Establishment of a New Qualitative Evaluation Method for Articular Cartilage by Dynamic T2w MRI Using a Novel Contrast Medium as a Water Tracer.

ObjectiveIn the early stages of cartilage damage, diagnostic methods focusing on the mechanism of maintaining the hydrostatic pressure of cartilage are thought to be useful. 17O-labeled water, which is a stable isotope of oxygen, has the advantage of no radiation exposure or allergic reactions and can be detected by magnetic resonance imaging (MRI). This study aimed to evaluate MRI images using 17O-labeled water in a rabbit model.DesignContrast MRI with 17O-labeled water and macroscopic and histological evaluations were performed 4 and 8 weeks after anterior cruciate ligament transection surgery in rabbits. A total of 18 T2-weighted images were acquired, and 17O-labeled water was manually administered on the third scan. The 17O concentration in each phase was calculated from the signal intensity at the articular cartilage. Macroscopic and histological grades were evaluated and compared with the 17O concentration.ResultsAn increase in 17O concentration in the macroscopic and histologically injured areas was observed by MRI. Macroscopic evaluation showed that the 17O concentration significantly increased in the damaged site group. Histological evaluations also showed that 17O concentrations significantly increased at 36 minutes 30 seconds after initiating MRI scanning in the Osteoarthritis Research Society International (OARSI) grade 3 (0.493 in grade 0, 0.659 in grade 1, 0.4651 in grade 2, and 0.9964 in grade 3, P < 0.05).Conclusion17O-labeled water could visualize earlier articular cartilage damage, which is difficult to detect by conventional methods.

Evaluation of the Anti-Inflammatory and Chondroprotective Effect of Celecoxib on Cartilage Ex Vivo and in a Rat Osteoarthritis Model.

ObjectiveThe potential chondroprotective effect of celecoxib, a nonsteroidal anti-inflammatory drug and selective cyclooxygenase-2 inhibitor used to reduce pain and inflammation in knee osteoarthritis patients, is disputed. This study aimed at investigating the chondroprotective effects of celecoxib on (1) human articular cartilage explants and (2) in an in vivo osteoarthritis rat model.DesignArticular cartilage explants from 16 osteoarthritis patients were cultured for 24 hours with celecoxib or vehicle. Secreted prostaglandins (prostaglandin E2, prostaglandin F2α, prostaglandin D2) and thromboxane B2 (TXB2) concentrations were determined in medium by ELISA, and protein regulation was measured with label-free proteomics. Cartilage samples from 7 of these patients were analyzed for gene expression using real-time quantitative polymerase chain reaction. To investigate the chondroprotective effect of celecoxib in vivo, 14 rats received an intra-articular injection of celecoxib or 0.9% NaCl after osteoarthritis induction by anterior cruciate ligament transection and partial medial meniscectomy (ACLT/pMMx model). Histopathological scoring was used to evaluate osteoarthritis severity 12 weeks after injection.ResultsSecretion of prostaglandins, target of Nesh-SH3 (ABI3BP), and osteonectin proteins decreased, whereas tissue inhibitor of metalloproteinase 2 (TIMP-2) increased significantly after celecoxib treatment in the human (ex vivo) explant culture. Gene expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5 (ADAMTS4/5) and metalloproteinase 13 (MMP13) was significantly reduced after celecoxib treatment in human cartilage explants. Cartilage degeneration was reduced significantly in an in vivo osteoarthritis knee rat model.ConclusionsOur data demonstrated that celecoxib acts chondroprotective on cartilage ex vivo and a single intra-articular bolus injection has a chondroprotective effect in vivo.

Dehydrocorydaline Accelerates Cell Proliferation and Extracellular Matrix Synthesis of TNFα-Treated Human Chondrocytes by Targeting Cox2 through JAK1-STAT3 Signaling Pathway.

Osteoarthritis (OA) causes severe degeneration of the meniscus and cartilage layer in the knee and endangers joint integrity and function. In this study, we utilized tumor necrosis factor α (TNFα) to establish in vitro OA models and analyzed the effects of dehydrocorydaline (DHC) on cell proliferation and extracellular matrix (ECM) synthesis in human chondrocytes with TNFα treatment. We found that TNFα treatment significantly reduced cell proliferation and mRNA and protein expression levels of aggrecan and type II collagen, but caused an increase in mRNA and protein expression levels of type I collagen, matrix metalloproteinase 1/13 (MMP1/13), and prostaglandin-endoperoxide synthase 2 (PTGS2, also known as Cox2) in human chondrocytes. DHC significantly promoted the cell activity of normal human chondrocytes without showing cytotoxity. Moreover, 10 and 20 μM DHC clearly restored cell proliferation, inhibited mRNA and protein expression levels of type I collagen, MMP 1/13, and Cox2, and further increased those of aggrecan and type II collagen in the TNFα-treated human chondrocytes. RNA transcriptome sequencing indicated that DHC could improve TNFα-induced metabolic abnormalities and inflammation reactions and inhibit the expression of TNFα-induced inflammatory factors. Furthermore, we found that the JAK1-STAT3 signaling pathway was confirmed to be involved in the regulatory effects of DHC on cell proliferation and ECM metabolism of the TNFα-treated human chondrocytes. Lastly, to explore the effects of DHC in vivo, we established an anterior cruciate ligament transection (ACLT)-stimulated rat OA model and found that DHC administration significantly attenuated OA development, inhibited the enzymatic hydrolysis of ECM, and reduced phosphorylated JAK1 and STAT3 protein expression in vivo after ACLT for 6 weeks. These results suggest that DHC can effectively relieve OA progression, and it has a potential to be utilized for the clinical prevention and therapy of OA as a natural small molecular drug.

Activation of adenosine A3 receptor attenuates progression of osteoarthritis through inhibiting the NLRP3/caspase‐1/GSDMD induced signalling

The specific adenosine A3 receptor (A3AR) agonist (CF101) has potential for inflammation and pain in various disease, such as arthritis, cancer and neuropathic pain, while the role of A3AR in post‐traumatic OA and the underlying mechanism is largely unknown. CF101 was orally administrated in OA rats induced by anterior cruciate ligament transection (ACLT) surgery, and the rat primary chondrocytes were stimulated by hydrogen peroxide (H2O2, 300 μM). Histologic grading system was performed for detecting cartilage degeneration and immunohistochemistry for determining pyroptosis. The moleculars associated with cartilage homeostasis and inflammatory cytokines were analysed; moreover, the activation of NLRP3 inflammasome was determined. CF101 treatment significantly attenuated OA cartilage damage, OA‐related pain and cartilage pyroptosis. Chondrocytes stimulated by H2O2 evoked ROS release, thereby promoting the activation of NLRP3 inflammasome and facilitating the cleavage of GSDMD, which ultimately resulted in the mass release of pro‐inflammatory cytokines including IL‐1β and IL‐18, and production of matrix hydrolase. The pre‐treatment with CF101 powerfully inhibited the above process both in vivo and in vitro. Our findings demonstrated that activation of A3AR attenuates OA progression and relieves pain perception through suppression of cartilage degradation and inhibition of ROS/NLRP3/GSDMD signalling, indicating pyroptosis is a potential candidate for OA treatment.

Hericium erinaceus Mycelium Ameliorates In Vivo Progression of Osteoarthritis.

Osteoarthritis (OA) is an age-related disorder that affects the joints and causes functional disability. Hericium erinaceus is a large edible mushroom with several known medicinal functions. However, the therapeutic effects of H. erinaceus in OA are unknown. In this study, data from Sprague-Dawley rats with knee OA induced by anterior cruciate ligament transection (ACLT) indicated that H. erinaceus mycelium improves ACLT-induced weight-bearing asymmetry and minimizes pain. ACLT-induced increases in articular cartilage degradation and bone erosion were significantly reduced by treatment with H. erinaceus mycelium. In addition, H. erinaceus mycelium reduced the synthesis of proinflammatory cytokines interleukin-1β and tumor necrosis factor-α in OA cartilage and synovium. H. erinaceus mycelium shows promise as a functional food in the treatment of OA.

Carnosine Alleviates Knee Osteoarthritis and Promotes Synoviocyte Protection via Activating the Nrf2/HO-1 Signaling Pathway: An In-Vivo and In-Vitro Study.

The most common joint disease in the elderly is knee osteoarthritis (OA). It is distinguished by cartilage degradation, subchondral bone loss, and a decrease in joint space. We studied the effects of carnosine (CA) on knee OA in male Wistar rats. OA is induced by anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) method and in vitro studies are conducted in fibroblast-like synoviocyte cells (FLS). The pain was assessed using weight-bearing and paw-withdrawal tests. CA supplementation significantly reduced pain. The enzyme-linked immunosorbent assay (ELISA) method was used to detect inflammatory proteins in the blood and intra-articular synovial fluid (IASF), and CA reduced the levels of inflammatory proteins. Histopathological studies were performed on knee-tissue samples using toluidine blue and hematoxylin and eosin (H and E) assays. CA treatment improved synovial protection and decreased cartilage degradation while decreasing zonal depth lesions. Furthermore, Western blotting studies revealed that the CA-treated group activated nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase (HO-1) and reduced the expression of cyclooxygenase-2 (COX-2). FLS cells were isolated from the knee joints and treated with IL-1β to stimulate the inflammatory response and increase reactive oxygen species (ROS). The matrix metalloproteinase protein (MMP’s) levels (MMP-3, and MMP-13) were determined using the reverse transcription-polymerase chain reaction (RT-PCR), and CA treatment reduced the MMP’s expression levels. When tested using the 2′,7′-dicholorodihydrofluroscene diacetate (DCFDA) assay and the 5,5′,6,6′-tetracholoro-1,1′,3,3′-tertraethylbenzimidazolcarboc janine iodide (JC-1) assay in augmented ROS FLS cells, CA reduced the ROS levels and improved the mitochondrial membrane permeability. This study’s investigation suggests that CA significantly alleviates knee OA both in vitro and in vivo.

Zinc finger protein 521 attenuates osteoarthritis via the histone deacetylases 4 in the nucleus

ABSTRACT To determine whether zinc finger protein 521 (Zfp521) has a chondroprotective effect by maintaining extracellular matrix (ECM) homeostasis to attenuate osteoarthritis (OA). In chondrocytes, Zfp521 was overexpressed or silenced to detect its effects on proliferation, apoptosis, and ECM homeostasis. Adenovirus encoding Zfp521 was injected into the knee joints of anterior cruciate ligament transection rats to test its efficacy against OA. Combined with proteomic analysis, the molecular mechanism of Zfp521 in cartilage degeneration was further explored. An intra-articular injection of adenovirus carrying a Zfp521 sequence showed a chondroprotective effect against OA. The molecular mechanism around Zfp521 was classified at the molecular, cellular, histological, and functional levels. It was reported that Zfp521 could effectively promote cartilage proliferation, inhibit apoptosis, and maintain the balance of anabolism and catabolism of ECM. Moreover, it was confirmed that Zfp521 exerted its effect better by upregulating histone deacetylases 4 (HDAC4) in the nucleus and was significantly weakened in the absence of HDAC4 in the nucleus. Overall, Zfp521 better exerts its efficacy against OA by increasing the HDAC4 content in the nucleus, making it a promising strategy for OA treatment.

Improved Joint Health Following Oral Administration of Glycosaminoglycans with Native Type II Collagen in a Rabbit Model of Osteoarthritis.

Simple SummaryOsteoarthritis is an incurable chronic disease. For this reason, new therapies are constantly emerging to improve clinical signs and the quality of life of our pets. Chondroitin sulfate, glucosamine and hyaluronic acid have been proven effective and are the most widely used in many formulations. In the present study, adding native type II collagen to the combination of chondroitin sulfate, glucosamine and hyaluronic acid showed improvements on osteoarthritis progression in an experimental model of osteoarthritis induced by transection of the cranial cruciate ligament of the knee in New Zealand white rabbits. Disease progression was monitored at different time points using magnetic resonance imaging biomarkers, measurement of hyaluronic acid in synovial fluid, and macroscopic and microscopic evaluations of cartilage, synovial membrane and subchondral bone. Overall, our results showed that adding native type II collagen to a combination of glycosaminoglycans allows a significantly slower osteoarthritis progression, compared to glycosaminoglycans alone.A prospective, experimental, randomized, double blinded study was designed to evaluate the effects of glycosaminoglycans, with or without native type II collagen (NC), in an osteoarthritis model induced by cranial cruciate ligament transection. The following compounds were tested: chondroitin sulfate (CS), glucosamine hydrochloride (GlHCl), hyaluronic acid (HA) and NC. Fifty-four female 12-week-old New Zealand rabbits were classified into three groups: CTR (control–no treatment), CGH (CS + GlHCl + HA) and CGH-NC (CS + GlHCl + HA + NC). Each group was subdivided into three subgroups according to survival times of 24, 56 and 84 days. Over time, all rabbits developed degenerative changes associated with osteoarthritis. CGH-NC showed significantly improved values on macroscopic evaluation, compared to CTR and CGH. Microscopically, significantly better results were seen with CGH and CGH-NC, compared to CTR, and synovial membrane values were significantly better with CGH-NC compared to CGH. A significant improvement in magnetic resonance imaging biomarkers was also observed with CGH-NC in cartilage transversal relaxation time (T2) and subchondral bone D2D fractal dimension in the lateral condyle. In conclusion, our results show beneficial effects on joint health of CGH and CGH-NC and also supports that adding NC to CGH results in even greater efficacy.

Experimental study on the regulation of subchondral bone plate osteoprotegerin/receptor activator of nuclear factor kappa-B ligand system by berberine to retard the development of osteoarthritis in rabbits

To investigate the effect of intra-articular berberine injection on the structural remodeling of subchondral bone plate and osteoprotegerin/receptor activator of nuclear factor kappa-B ligand(OPG/RANKL) system expression in rabbits with osteoarthritis(OA). Forty 12-month-old male rabbits with an average of(2.73±0.18) kg of body weight, underwent left anterior cruciate ligament transection(ACLT), and were divided into berberine group and placebo groups after operation, 20 rabbits in each group. The berberine group received intra-articular injection of 100 μmol/L berberine 0.3 ml every week for 6 weeks. In placebo group, the same dose of 0.9% sodium chloride injection was injected into the left knee joint cavity every week for 6 weeks. Another 20 12-month-old male rabbits, weighing (2.68±0.18) kg, underwent sham operation on the left knee joint without intra-articular injection intervention (sham operation group). On the last day of the sixth week after operation, three groups of animals were sacrificed to obtain knee joint specimens. The femoral medial condyle samples were obtained for histological evaluation of cartilage and subchondral bone, Mankin scoring system was used to evaluate articular cartilage structure. Image-Pro Plus(IPP) software was used to evaluate subchondral bone plate bone volume(BV), bone volume/total volume(BV/TV), trabecular circumference(TC), mean trabecular thickness (Tb.Th). Real-time quantitative reverse transcription polymerization Enzyme chain reaction(reverse transcription-polymerase chain reaction, RT-PCR) was used to detect the mRNA expression levels of OPG and RANKL in subchondral bone tissue at 6 weeks after operation. The cartilage structure evaluation showed that the surface of cartilage tissue in the sham operation group was smooth and flat, and the safranin coloration was full in the full thickness of the cartilage;the cartilage tissue in the berberine group showed uneven surface layer, and the staining of safranin O was mildly decreased;the surface layer fibrosis was seen in placebo group, Safranin O faded significantly. The Mankin score in the berberine group was lower than that in placebo group(P<0.01), but higher than that in sham operation group(P<0.01). The structural evaluation of subchondral bone plate showed that the trabecular bone in sham-operated group was densely arranged;after berberine intervention, the trabeculae were closely arranged;the subchondral bone trabeculae in placebo group were relatively sparse, and the distance between trabeculae was wider. Subchondral bone plate IPP software evaluation showed that BV, BV/TV, TC, Tb.Th in berberine group were higher than those in placebo group(P<0.01), BV, BV/TV, TC, Tb.Th in berberine group were higher than those in placebo group(P<0.01), while lower than the sham operation group (P<0.01). PCR test results showed that the expression of OPG mRNA in the berberine group was significantly higher than that in placebo group(P<0.01), and OPG mRNA in the berberine group was lower than that in sham operation group (P<0.01). There was no significant difference in mRNA expression of RANKL among three groups(P>0.05);the ratio of OPG/RANKL in berberine group was higher than that in placebo group(P<0.01), but lower than that in sham operation group(P<0.01). Intra-articular injection of berberine can effectively inhibit the resorption of subchondral bone in the early stage of OA and delay the development of the disease. The specific mechanism may be that berberine maintains the balance of OPG/RANKL system by up-regulating the expression of OPG gene in subchondral bone.

The Effect of Progressive Lateral Column Lengthening in a Novel Stage II-B Flatfoot Cadaveric Model Evaluated Using Software-Guided Radiographic Measurements of Foot Alignment.

This work used software-guided radiographic measurement to assess the effects of progressive lateral column lengthening (LCL) on restoring alignment in a novel cadaveric model of stage II-B flatfoot deformity. A stage II-B flatfoot was created in 8 cadaveric specimens by transecting the spring ligament complex, anterior deltoid, and interosseous talocalcaneal and cervical ligaments. Weightbearing computed tomographic (WBCT) scans were performed with specimens under 450 N of compressive load in the intact, flat, and 6-, 8-, and 10-mm lateral column-lengthening conditions. Custom software-guided radiographic measurements of the lateral talo-first metatarsal (Meary) angle, anteroposterior talo-first metatarsal angle, naviculocuneiform overlap, and 2 new measures (plantar fascia [PF] distance and angle) were recorded on digitally reconstructed radiographs. Four anonymized analysts performed measurements twice. Intra- and interobserver agreement was assessed using intraclass correlation coefficients (ICCs). Six-millimeter LCL restored alignment closest to the intact foot in this new cadaveric model, whereas 10-mm lengthening tended toward overcorrection. The PF line displaced laterally in the flatfoot condition, and LCL restored the PF line to a location beneath the talonavicular joint. Interobserver agreement was excellent for PF distance (ICC = 0.99) and naviculocuboid overlap (ICC = 0.91), good for Meary angle (ICC = 0.81) and PF angle (ICC = 0.69), and acceptable for the talonavicular coverage angle (ICC = 0.65). In this stage II-B cadaveric flatfoot model, cervical ligament transection was essential to create deformity after the medial hindfoot ligaments were transected. Software-guided radiographic measurement proved reliable; standardized implementation should improve comparability between studies of flatfoot deformity. The novel PF distance performed most consistently (ICC = 0.99) and warrants further study. With this model, we found that a 6-mm LCL restored alignment closest to the intact foot, whereas 10-mm lengthening tended toward overcorrection. Future joint-sparing flatfoot corrections may consider using a relatively small LCL combined with other bony and/or anatomic ligament/tendon reconstructions.

Rutin Inhibits the Progression of Osteoarthritis Through CBS-Mediated RhoA/ROCK Signaling.

Osteoarthritis (OA) is a chronic joint disease characterized by the deterioration of cartilage and subchondral bone in the joints. Currently, there is no complete cure for OA, only treatments designed to temporarily relieve pain and improve function. Compared with the high cost of surgical treatment, medical treatment of OA is more acceptable and cost-effective. Rutin, as a flavonoid, has been shown to have anti-OA properties. We evaluated the effects of rutin on chondrocytes in lipopolysaccharide (LPS)-induced OA and on OA in rats induced by anterior cruciate ligament transection. We found that rutin effectively reduced the expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase 13 (MMP-13) and increased the expression of Col II and aggrecan (p < 0.001). In addition, we also found that rutin increased the expression of cystathionine-β-synthase (CBS) and inhibited the expression of Rho-related coiled-coil protein kinase (ROCK) in chondrocytes (p < 0.05), thereby effectively inhibiting the inflammatory progression of OA. We concluded that rutin inhibits the inflammatory progression of OA through the CBS-mediated RhoA/ROCK signaling pathway.

Isolated injuries to the lateral ankle ligaments have no direct effect on syndesmotic stability.

This study aim was to detect the impact of lateral ankle ligaments injury on syndesmotic laxity when evaluated arthroscopically in a cadaveric model. The null hypothesis was that lateral ankle ligament injury does not affect the stability of syndesmosis. Sixteen fresh-frozen above-knee amputated cadaveric specimens were divided into two groups of eight specimens that underwent arthroscopic evaluation of the distal tibiofibular joint. In both the groups, the assessment was first done with all syndesmotic and ankle ligaments intact. Thereafter, Group 1 underwent sequential transection of the three lateral ankle ligaments first to identify the effects of lateral ligament injury: (1) anterior talofibular ligament (ATFL), (2) calcaneofibular ligament (CFL), (3) posterior talofibular ligament (PTFL), then followed by the syndesmotic ligaments, (4) AITFL, (5) Interosseous ligament (IOL), and (6) PITFL. Group 2 underwent sequential transection of the (1) AITFL, (2) ATFL, (3) CFL, (4) IOL, (5) PTFL, and (6) PITFL, which represent the most commonly injured pattern in ankle sprain. In all scenarios, four loading conditions were considered under 100N of direct force: (1) unstressed, (2) a lateral fibular hook test, (3) anterior to posterior (AP) fibular translation test, and (4) posterior to anterior (PA) fibular translation test. Distal tibiofibular coronal plane diastasis at the anterior and posterior third of syndesmosis, as well as AP and PA sagittal plane translation, were arthroscopically measured. The distal tibiofibular joint remained stable after transection of all lateral ankle ligaments (ATFL, CFL, and PTFL) as well as the AITFL. However, after additional transection of the IOL, the syndesmosis became unstable in both the coronal and sagittal plane. Syndesmosis laxity in the coronal plane was also observed after transection of the ATFL, CFL, AITFL, and IOL. Subsequent transection of the PITFL precipitated syndesmosis laxity in the sagittal plane, as well. The findings from the present study suggest that lateral ankle ligament injuries itself do not directly affect the stability of syndesmosis. However, if it combines with IOL injuries, even partial injuries cause syndesmotic laxity. As a clinical relevance, accurate diagnosis is the key for surgeons to determine syndesmosis fixation whether there is only AITFL injury or combined IOL injury in concomitant acute syndesmotic and lateral ligament injury.

A Triple-Strand Anatomic Medial Collateral Ligament Reconstruction Restores Knee Stability More Completely Than a Double-Strand Reconstruction: A Biomechanical Study In Vitro

Background: There are many descriptions of medial collateral ligament (MCL) reconstruction, but they may not reproduce the anatomic structures and there is little evidence of their biomechanical performance. Purpose: To investigate the ability of “anatomic” MCL reconstruction to restore native stability after grade III MCL plus posteromedial capsule/posterior oblique ligament injuries in vitro. Study Design: Controlled laboratory study. Methods: Twelve cadaveric knees were mounted in a kinematic testing rig to impose tibial displacing loads while the knee was flexed-extended: 88-N anteroposterior translation, 5-N·m internal-external rotation, 8-N·m valgus-varus, and combined anterior translation plus external rotation (anteromedial rotatory instability). Joint motion was measured via optical trackers with the knee intact; after superficial MCL (sMCL), deep MCL (dMCL), and posterior oblique ligament transection; and then after MCL double- and triple-strand reconstructions. Double strands reproduced the sMCL and posterior oblique ligament and triple-strands the sMCL, dMCL, and posterior oblique ligament. The sMCL was placed 5 mm posterior to the epicondyle in the double-strand technique and at the epicondyle in the triple-strand technique. Kinematic changes were examined by repeated measures 2-way analysis of variance with posttesting. Results: Transection of the sMCL, dMCL, and posterior oblique ligament increased valgus rotation (5° mean) and external rotation (9° mean). The double-strand reconstruction controlled valgus in extension but allowed 5° excess valgus in flexion and did not restore external rotation (7° excess). The triple-strand reconstruction restored both external rotation and valgus throughout flexion. Conclusion: In a cadaveric model, a triple-strand reconstruction including a dMCL graft restored native external rotation, while a double-strand reconstruction without a dMCL graft did not. A reconstruction with the sMCL graft placed isometrically on the medial epicondyle restored valgus rotation across the arc of knee flexion, whereas a reconstruction with a more posteriorly placed sMCL graft slackened with knee flexion. Clinical Relevance: An MCL injury may rupture the anteromedial capsule and dMCL, causing anteromedial rotatory instability. Persistent MCL instability increases the likelihood of ACL graft failure after combined injury. A reconstruction with an anteromedial dMCL graft restored native external rotation, which may help to unload/protect an ACL graft. It is important to locate the sMCL graft isometrically at the femoral epicondyle to restore valgus across flexion.

Sex-Dependent Mechanical Allodynia in Co-Morbid Hypertension and Osteoarthritis

Despite the common comorbid presentation of hypertension and osteoarthritis (OA), the relationship between these two diseases is often over-simplified as a result of limited physical activity in these populations. However, in the clinical population, there is a significant relationship between hypertension and both symptomatic and radiographic knee OA. Interestingly, aged spontaneously hypertensive rats (SHR) have spontaneous joint damage shown through micro-CT and histopathology compared to age matched non-hypertensive controls; however, the pain phenotype in these animals is unknown. Thus, the purpose of this study was to characterize the 50% withdrawal threshold in SHR animals to explore the pathophysiological interactions between hypertension and OA. OA was induced in female and male SHR animals via medial collateral ligament transection and medial meniscus transection (MCLT+MMT), with skin incision used as a sham control (n=7-8/group/sex). Mechanical allodynia was assessed at the ipsilateral hind paw at baseline, then every other week for 8 weeks post-op. The 50% withdrawal threshold was calculated using Chaplan's up-down application method of von Frey filaments. In female MCLT+MMT animals, 50% withdrawal threshold decreased from baseline to weeks 2 and 4 (p's<0.05). In female sham animals, this decrease was only seen at week 4 (p<0.05). No week-to-week differences were observed in male animals of either group. In the MCLT+MMT group, sex differences were observed at weeks 2, 4 and 6 (p's<0.05) while in the sham group, sex differences were only seen at week 4 (p<0.05). Finally, at this sample size, no effects due to OA were observed for either sex. Female hypertensive animals experience lower withdrawal thresholds compared to males, regardless of joint pathophysiology. Interestingly, sex differences were more prevalent in the MCLT+MMT group, indicating a possible sex-dependent interaction between hypertension and OA progression; however, further research should implement more sensitive pain-assessment techniques to determine these interactions. Supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Numbers R01AR071431 and F31 AR077996.

Seahorse Protein Hydrolysate Ameliorates Proinflammatory Mediators and Cartilage Degradation on Posttraumatic Osteoarthritis with an Obesity Rat Model.

Osteoarthritis (OA) is one of the age-related diseases and is highly present on the knees. Obesity and mechanical injuries as a risk factor of OA are attributed to cartilage disintegration, joint loading, and inflammation. This study is aimed at investigating the effects of seahorse protein hydrolysate (SH) on posttraumatic osteoarthritis in an obesity rat. The OA model was developed by anterior cruciate ligament transection with medial meniscectomy in a high-fat diet- (HFD-) induced obesity rat model. The male Sprague-Dawley rats were fed a HFD for 6 weeks before OA surgery. The OA rats were treated with oral gavage by 4, 8, or 20 mg/kg of body weight of SH for 6 weeks of treatment. The expressions of plasma proinflammatory factors, C-telopeptide of type II collagen, and matrix metalloproteinase- (MMP-) 3 and MMP-13 were reduced by SH treatment. Plasma superoxide dismutase and glutathione peroxidase activities were enhanced by SH. SH also relieved the pain of the knee joint and swelling as well as decreased proteoglycan loss in the knee articular cartilage caused by osteoarthritis. Based on these results, SH suppressed proinflammatory factors and attenuated cartilage degradation and pain in the OA model. Therefore, seahorse protein hydrolysate might be a potential opportunity for improving the development of osteoarthritis.

Monoamine oxidase A attenuates chondrocyte loss and extracellular matrix degradation in osteoarthritis by inducing autophagy

ObjectivesOsteoarthritis (OA) is a prevalent degenerative joint disorder characterized by cartilage destruction and extracellular matrix (ECM) degeneration. Here, we studied the potential function of monoamine oxidase A (MAOA) in OA pathogenesis. MethodsCartilage tissue samples were collected from 33 patients with knee OA and nine normal healthy controls. Sprague-Dawley rats with anterior cruciate ligament transection (ACLT) and primary chondrocytes treated with interleukin (IL)-1β were used as OA animal and cell models, respectively. The effects of adenovirus-mediated MAOA overexpression in OA models were studied using Safranin-O staining, immunohistochemistry, CCK-8 assay, EdU assay, flow cytometry, qRT-PCR, western blotting, and immunofluorescence. ResultsMAOA was identified as an overlapping downregulating gene in the GSE82107, GSE1919, GSE169077, and GSE29746 datasets. MAOA expression was negatively correlated with OA severity. MAOA downregulation was confirmed in ACLT rats and IL-1β-treated chondrocytes. Notably, MAOA overexpression significantly inhibited ACLT-induced OA pathogenesis in rats, as was evidenced by the reduced Osteoarthritis Research Society International (OARSI) score and serum crosslinked C-telopeptides of type II collagen (CTX-II) and cartilage oligomeric matrix protein (COMP) levels. These findings show that MAOA overexpression inhibits extracellular matrix (ECM) degradation and promotes ACLT-induced autophagy. The effects of MAOA on ECM degradation and autophagy were also confirmed in IL-1β-treated primary chondrocytes. Additionally, MAOA protects chondrocytes against IL-1β-induced apoptosis. Furthermore, treating chondrocytes with 3-MA significantly attenuated the protective effects of MAOA. ConclusionMAOA was identified as a downregulated gene in OA. Restoring MAOA expression protects against chondrocyte loss and ECM degradation through autophagy regulation.

Network Pharmacology-Based Prediction and Verification of the Potential Targets of Pinoresinol Diglucoside for OA Treatment.

Objective This study aimed to explore the effects and related mechanisms of pinoresinol diglucoside (PDG) on osteoarthritis (OA) via a combination of pharmacology and animal experiments. Methods Traditional Chinese Medicine Database and Analysis Platform (TCMSP) Drugbank, Online Mendelian Inheritance in Man, and GeneCards databases were used to predict the putative targets of PGD against OA. A protein protein interaction (PPI) network was constructed in STING database to analyze the interaction network of these targets. Enrichment analysis was performed with DAVID database. The OA model was built by anterior cruciate ligament transection and then injected with PDG for 5 weeks. Hematoxylin and eosin (HE) staining and safranin-fixed green staining were used to evaluate the pathological change. ELISA was applied to measure the serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Immunohistochemistry was employed to detect the protein levels of kinase B (AKT), BAX, Bcl2, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinases 1 (TIMP-1), and phosphatidylinositol 3 kinase (PI3K) in knee cartilage tissues. Results Seventy-one key targets were identified, including AKT1, epidermal growth factor receptor, SRC, estrogen receptor 1 (ESR1), and MMP9. Enrichment analysis revealed a series of pathway related to cancer, PI3K-Akt signaling pathway, and proteoglycans in cancer. Animal experiments showed that PDG alleviated the abnormal histomorphological changes of OA; suppressed TIPM, serum IL-1β, IL-6, and TNF-α levels, and PI3K and AKT activation; and increased MMP-1 expression and Bcl2/Bax ratio. Conclusion PDG has a cartilage-protecting effect associated with PI3K/AKT signaling pathway in rabbit with OA and therefore might serve as a potential agent for the treatment of this disease.

USP7 Attenuates Endoplasmic Reticulum Stress and NF-κB Signaling to Modulate Chondrocyte Proliferation, Apoptosis, and Inflammatory Response under Inflammation.

The purpose of this research was to observe the functions and mechanisms of ubiquitin-specific peptidase 7 (USP7) on chondrocytes under tumor necrosis factor alpha- (TNF-α-) induced inflammation. Knee osteoarthritis (OA) models of mice were constructed by anterior cruciate ligament transection. The knee joint of mice was observed by histological staining, and the expression of USP7 was measured by immunohistochemistry staining. After knocking down or inhibiting USP7, chondrocyte proliferation was measured by histological staining and the CCK-8 assay; apoptosis was measured by western blot, flow cytometry, Caspase-3 activity, and TUNEL staining; and inflammatory response was measured by qRT-PCR and ELISA. The 4-phenylbutyric acid (4-PBA), siRNA of CHOP (si-CHOP), and QNZ were used to verify the signaling pathways. It was found that USP7 was reduced in the knee joint cartilage of OA mice. The knockdown of USP7 or its inhibitor decreased chondrocyte proliferation and accelerated apoptosis and inflammatory response under inflammation. The USP7 inhibitor exacerbated cartilage destruction in mice with OA. The knockdown of USP7 or its inhibitor activated the BiP-eIF2α-ATF4-CHOP signaling of endoplasmic reticulum stress (ERS) and NF-κB/p65 signaling. 4-PBA, si-CHOP, and QNZ partly reversed chondrocyte proliferation, apoptosis, and inflammatory response caused by USP7 knockdown. In conclusion, through inhibiting the BiP-eIF2α-ATF4-CHOP signaling of ERS and NF-κB/p65 signaling, USP7 promotes chondrocyte proliferation and suppresses the apoptosis and inflammatory response under TNF-α-induced inflammation.