Transplantation of Wnt5a-modified Bone Marrow Mesenchymal Stem Cells Promotes Recovery After Spinal Cord Injury via the PI3K/AKT Pathway.

Spinal cord injury (SCI) is a severe neurological condition that can lead to paralysis or even death. This study explored the potential benefits of bone marrow mesenchymal stem cell (BMSC) transplantation for repairing SCI. BMSCs also differentiate into astrocytes within damaged spinal cord tissues hindering the cell transplantation efficacy, therefore it is crucial to enhance their neuronal differentiation rate to facilitate spinal cord repair. Wnt5a, an upstream protein in the non-classical Wnt signaling pathway, has been implicated in stem cell migration, differentiation, and neurite formation but its role in the neuronal differentiation of BMSCs remains unclear. Thus, this study investigated the role and underlying mechanisms of Wnt5a in promoting neuronal differentiation of BMSCs both in vivo and in vitro. Wnt5a enhanced neuronal differentiation of BMSCs in vitro while reducing astrocyte differentiation. Additionally, high-throughput RNA sequencing revealed a correlation between Wnt5a and phosphoinositide 3-kinase (PI3K)/protein kinase B(AKT) signaling, which was confirmed by the use of the PI3K inhibitor LY294002 to reverse the effects of Wnt5a on BMSC neuronal differentiation. Furthermore, transplantation of Wnt5a-modified BMSCs into SCI rats effectively improved the histomorphology (Hematoxylin and eosin [H&E], Nissl and Luxol Fast Blue [LFB] staining), motor function scores (Footprint test and Basso-Beattie-Bresnahan [BBB]scores)and promoted neuron production, axonal formation, and remodeling of myelin sheaths (microtubule associated protein-2 [MAP-2], growth-associated protein 43 [GAP43], myelin basic protein [MBP]), while reducing astrocyte production (glial fibrillary acidic protein [GFAP]). Therefore, targeting the Wnt5a/PI3K/AKT pathway could enhance BMSC transplantation for SCI treatment.

Capsule closure has better hip function than non-closure in hip arthroscopy for femoracetabular impingement: A systematic review and meta-analysis.

Background: The impact of capsular closure vs non-closure in hip arthroscopy for femoracetabular impingement (FAI) was assessed by a meta-analysis. Methods: With the most recent search update occurring in August 2022, relevant studies were found by searching the Pubmed and EMBASE databases. A collection of studies was made that conducted hip arthroscopy for FAI. Review Manager 5.3 was used to carry out the meta-analysis. The dichotomous and continuous factors were compared using the odds ratios (OR) and mean differences (MD). A fixed-effect or random-effect model was chosen, depending on the degree of heterogeneity (I2). Forest plots were used to assess the results. A significance level of P < 0.05 was applied to the statistical analysis. Results: Ultimately, 15 studies were incorporated into the meta-analysis. The surgery time was longer for the capsular closure group (CC group) compared to the non-closure (NC group) group. (P < 0.001, SMD = 8.59, 95%CI [7.40, 9.77], I2 = 32 %). Following hip arthroscopy, the CC group's mHHS was superior to that of the NC group (P = 0.001, MD = 2.05, 95%CI [0.83, 3.27], I2 = 42 %), HOS-ADL (P < 0.001, MD = 4.29, 95%CI [3.08, 5.50], I2 = 0 %). The capsular closure group had a reduced rate of postoperative complications (P = 0.001, OR = 0.21, 95%CI [0.08, 0.54], I2 = 0 %) and conversion to THA (P = 0.01, OR = 0.42, 95%CI [0.21, 0.83], I2 = 0 %) following hip arthroscopy than the non-closure group. The revision rate, VAS, and postoperative HOS-SSS did not significantly differ between these two groups (P＞0.05). Conclusion: The current meta-analysis found that the closed group had a lower complication rate and considerably greater mHHS and HOS-ADL following surgery compared to the non-closed capsule group. Whether this is related to the continuous progress of biomechanical and clinical research techniques deserves our attention. Level of evidence: Level IV, systematic review of Level I through Level III studies.

Chronic ACLD Knees with Early Developmental Cartilage Lesions Exhibited Increased Posterior Tibial Translation during Level Walking.

OBJECTIVE: Early articular cartilage lesion (CL) is a vital sign in the onset of posttraumatic knee osteoarthritis (PTOA) in patients with anterior cruciate ligament deficiency (ACLD). Researchers have suggested that altered kinematics could accelerate CLs and, therefore, lead to the onset of PTOA. However, little is known about whether specific knee kinematics exist that lead to early CL in chronic ACLD knees. Level walking is the most frequent and relevant in vivo activity, which greatly impacts knee health. We hypothesized that the knee kinematics during level walking in chronic ACLD knees with early tibiofemoral CL would significantly differ from those of chronic ACLD knees without early tibiofemoral CL. METHODS: Thirty patients with a chronic ACLD history, including 18 subjects with CLs and 12 subjects without CLs, and 35 healthy control subjects were recruited for the study from July 2020 to August 2022. The knee kinematic data during level walking were collected using a three-dimensional motion analysis system. The kinematic differences between groups were compared using statistical parametric mapping with one dimension for One-Way ANOVA. The cartilage statuses of the ACLD knees were assessed via MRI examination. The CLs distribution of subjects was evaluated using a modified Noyes scale and analyzed by chi-square tests. RESULTS: ACLD knees with CLs had significantly greater posterior tibial translation (7.7-8.0mm, 12%-18% gait cycle GC, p = 0.014) compared to ACLD knees without CLs during level walking. ACLD knees with CLs had greater posterior tibial translation (4.6-5.5mm, 0%-23% GC, p < 0.001; 5.8-8.0mm, 86%-100% GC, p < 0.001) than healthy controls during level walking. In the group of ACLD knees with CLs, CL is mainly located in the back of the tibia plateau and front of load bearing area of the medial femoral condyle (p < 0.05). CONCLUSION: Chronic anterior cruciate ligament deficient knees with cartilage lesions have increased posterior tibial translation compared to anterior cruciate ligament deficient knees without cartilage lesions and healthy subjects. The posterior tibial translation may play an important role in knee cartilage degeneration in ACLD knees. The increased posterior tibial translation and cartilage lesion characteristics may improve our understanding of the role of knee kinematics in cartilage degeneration and could be a helpful potential reference for anterior cruciate ligament deficient therapy, such as physical training to improve abnormal kinematic behavior.

Injectable, Electroconductive, Free Radical Scavenging Silk Fibroin/Black Phosphorus/Glycyrrhizic Acid Nanocomposite Hydrogel for Enhancing Spinal Cord Repair.

Spinal cord injury (SCI) often leads to a severe permanent disability. A poor inflammatory microenvironment and nerve electric signal conduction block are the main reasons for difficulty in spinal cord nerve regeneration. In this study, black phosphorus (BP) and glycyrrhizic acid (GA) are integrated into methacrylate-modified silk fibroin (SF) to construct a bifunctional injectable hydrogel (SF/BP/GA) with appropriate conductivity and the ability to inhibit inflammation to promote neuronal regeneration after SCI. This work discovers that the SF/BP/GA hydrogel can reduce the oxidative damage mediated by oxygen free radicals, promote the polarization of macrophages toward the anti-inflammatory M2 phenotype, reduce the expression of inflammatory factors, and improve the inflammatory microenvironment. Moreover, it induces neural stem cell (NSC) differentiation and neurosphere formation, restores signal conduction at the SCI site in vivo, and ameliorates motor function in mice with spinal cord hemisection, revealing a significant neural repair effect. An injectable, electroconductive, free-radical-scavenging hydrogel is a promising therapeutic strategy for SCI repair.

Dual Cannula Combined With Modified Shoelace Continuous Capsular Closure Technique in Hip Arthroscopic Surgery.

The Technical Note aims to present an arthroscopic capsular closure technique at the end of the hip arthroscopy. The technology employs a dual-channel approach and modified shoelace suture technique to continuously suture the hip capsule. Recent studies have indicated that routine intraoperative repair of the articular capsule at the end of the hip arthroscopy is advocated. However, the majority of the hip capsular closure techniques are relatively complex, time-consuming, and bring many complications, which has hindered their widespread use in clinical practice. Herein, we provide an arthroscopic capsular closure technique using the modified shoelace continuous suture in combination with a dual cannula for correcting hip instability during hip arthroscopic surgery of femoroacetabular impingement.

Transplantation of MiR-28-5p-Modified BMSCs Promotes Functional Recovery After Spinal Cord Injury.

Traumatic spinal cord injury (TSCI) is a prevalent central nervous system condition that imposes a significant burden on both families and society, affecting more than 2 million people worldwide. Recently, there has been increasing interest in bone marrow mesenchymal stem cell (BMSC) transplantation as a promising treatment for spinal cord injury (SCI) due to their accessibility and low immunogenicity. However, the mere transplantation of BMSCs has limited capacity to directly participate in the repair of host spinal cord nerve function. MiR-28-5p, identified as a key differentially expressed miRNA in spinal cord ischemia-reperfusion injury, exhibits differential expression and regulation in various neurological diseases. Nevertheless, its involvement in this process and its specific regulatory mechanisms in SCI remain unclear. Therefore, this study aimed to investigate the potential mechanisms through which miR-28-5p promotes the neuronal differentiation of BMSCs both in vivo and in vitro. Our results indicate that miR-28-5p may directly target Notch1, thereby facilitating the neuronal differentiation of BMSCs in vitro. Furthermore, the transplantation of lentivirus-mediated miR-28-5p-overexpressed BMSCs into SCI rats effectively improved footprint tests and Basso, Beattie, and Bresnahan (BBB) scores, ameliorated histological morphology (hematoxylin-eosin [HE] and Nissl staining), promoted axonal regeneration (MAP2 and growth-associated protein 43 [GAP43]), and facilitated axonal remyelination (myelin basic protein [MBP]). These findings may suggest that miR-28-5p-modified BMSCs could serve as a therapeutic target to enhance the behavioral and neurological recovery of SCI rats.

Obacunone targets macrophage migration inhibitory factor (MIF) to impede osteoclastogenesis and alleviate ovariectomy-induced bone loss.

INTRODUCTION: Osteoporosis is the most common bone disorder where the hyperactive osteoclasts represent the leading role during the pathogenesis. Targeting hyperactive osteoclasts is currently the primary therapeutic strategy. However, concerns about the long-term efficacy and side effects of current frontline treatments persist. Alternative therapeutic agents are still needed. OBJECTIVES: Obacunone (OB) is a small molecule with a broad spectrum of biological activities, particularly antioxidant and anti-inflammatory effects. This study aims to examine OB's therapeutic potential on osteoporosis and explore the rudimentary mechanisms. METHODS: Osteoclast formation and osteoclastic resorption assays were carried out to examine OB's inhibitory effects in vitro, followed by the in-vivo studies of OB's therapeutic effects on ovariectomy-induced osteoporotic preclinical model. To further study the underlying mechanisms, mRNA sequencing and analysis were used to investigate the changes of downstream pathways. The molecular targets of OB were predicted, and in-silico docking analysis was performed. Ligand-target binding was verified by surface plasmon resonance (SPR) assay and Western Blotting assay. RESULTS: The results indicated that OB suppressed the formation of osteoclast and its resorptive function in vitro. Mechanistically, OB interacts with macrophage migration inhibitory factor (MIF) which attenuates receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced signaling pathways, including reactive oxygen species (ROS), NF-κB pathway, and mitogen-activated protein kinases (MAPKs). These effects eventually caused the diminished expression level of the master transcriptional factor of osteoclastogenesis, nuclear factor of activated T cells 1 (NFATc1), and its downstream osteoclast-specific proteins. Furthermore, our data revealed that OB alleviated estrogen deficiency-induced osteoporosis by targeting MIF and thus inhibiting hyperactive osteoclasts in vivo. CONCLUSION: These results together implicated that OB may represent as a therapeutic candidate for bone disorders caused by osteoclasts, such as osteoporosis.

Corrigendum: Inhibitory effects of Rhaponticin on osteoclast formation and resorption by targeting RANKL-induced NFATc1 and ROS activity.

[This corrects the article DOI: 10.3389/fphar.2021.645140.].

Polydatin administration attenuates the severe sublesional bone loss in mice with chronic spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is often accompanied by rapid and extensive bone mineral loss below the lesion level, and there is currently no gold standard for treatment. Evidence suggests that polydatin (PLD) may help promote osteogenic differentiation and exhibit anti-osteoporotic activity. However, whether PLD could reverse substantial bone loss in SCI patients, especially those with protracted injury, and the underlying regulatory mechanism have not been investigated. STUDY DESIGN: Male C57BL/6J mice were subjected to either contusion SCI or laminectomy at the T8-9 level. Eight weeks after SCI, PLD (40 mg/kg/day) or vehicle was administrated to the mice via the intragastric route for consecutive eight weeks. Blood was collected after the treatment regimen, and the tibiae and femora were removed. Bone marrow stromal cells were isolated from the long bones for ex vivo osteoblastogenesis and osteoclastogenesis assays. RESULTS: Chronic SCI led to a rapid and significant decrease in bone mineral density (BMD) of the distal femur and proximal tibia, resulting in structural deterioration of the bone tissues. Treatment with PLD largely restored BMD and bone structure. In addition, static histo-morphometric analysis revealed that PLD enhanced bone formation and inhibited bone resorption in vivo. PLD also promoted osteoblastogenesis and inhibited osteoclastogenesis ex vivo, which was accompanied by increased OPG/RANKL ratio, and reduced expression levels of CTR, TRAP, NFATc1 and c-Fos. However, PLD had no marked effect on serum 25(OH)D levels and VDR protein expression, although it did significantly lower serum and femoral malondialdehyde levels, inhibited expression level of matrix metallopeptidase 9 (MMP9), upregulated skeletal Wnt3a, Lrp5 and ctnnb1 mRNAs, and increased ß-catenin protein expression. CONCLUSIONS: PLD protected mice with chronic SCI against sublesional bone loss by modulating genes involved the differentiation and activity of osteoclasts and osteoblasts, abating oxidative stress and MMP activity, and restoring the Wnt/ß-catenin signaling pathway.

Biomechanical analysis of sacroiliac joint motion following oblique-pulling manipulation with or without pubic symphysis injury.

Background: Oblique-pulling manipulation has been widely applied in treating sacroiliac joint (SIJ) dysfunction. However, little is known about the biomechanical mechanism of the manipulation. This study aims to analyze the SIJ motion under oblique-pulling manipulation, in comparison with compression and traction loads. Methods/Study Design: A total of six specimens of embalmed human pelvis cadavers were dissected to expose the SIJ and surrounding ligaments. Through a servo-hydraulic testing system, biomechanical tests were performed on the stable pelvis and the unstable pelvis with pubic symphysis injury (PSI). A three-dimensional (3D) photogrammetry system was employed to determine the separation and nutation in three tests: axial compression (test A), axial traction (test B), and oblique-pulling manipulation (test C). Results: After applying the testing loads, the range of nutation was no more than 0.3° (without PSI) and 0.5°(with PSI), separately. Except for test B, a greater nutation was found with PSI (p < 0.05). Under both conditions, nutation following test A was significantly greater than that of other tests (p < 0.05). SIJ narrowed in test A and separated in tests B and C, where the range of motion did not exceed 0.1 mm (without PSI) or 0.3 mm (with PSI) separately. Under both conditions, the separation of SIJ in test C was not as apparent as the narrowness of SIJ in test A (p < 0.05). Compared to SIJ, a more significant increasing displacement was found at the site of the iliolumbar ligament (p < 0.05). Nevertheless, when the force was withdrawn in all tests, the range of nutation and separation of SIJ nearly decreased to the origin. Conclusion: Pubic symphysis is essential to restrict SIJ motion, and the oblique-pulling manipulation could cause a weak nutation and separation of SIJ. However, the resulting SIJ motion might be neutralized by regular standing and weight-bearing load. Also, the effect on SIJ seems to disappear at the end of manipulation. Therefore, the stretching and loosening of surrounding ligaments need to be paid more attention to.

Pain Management of Hallux Valgus Surgery Is Achieved by Cocktail Therapy.

Background: Hallux valgus is a relatively common forefoot disease in clinical practice. The aim of our study was to assess the role of local cocktail drugs and postoperative pain after hallux valgus surgery. Methods: A retrospective case-control study was conducted to analyze 75 moderate to severe hallux valgus patients from June 1, 2018 to December 1, 2019. All patients were divided into cocktail and control groups according to whether the cocktail therapy was used or not after the operation. The anesthesiologist did not provide analgesic treatment other than nerve block anesthesia and intravenous anesthesia, such as analgesic pumps. The operative region of the cocktail group received a mixture of 10 ml of 0.75% ropivacaine, 10 ml of flurbiprofen axetil injection, and 1 ml of compound betamethasone injection, whereas the control group received nothing in the surgical spot. We recorded patients' VAS scores preoperatively and at 6, 24 hours postoperatively; the length of hospital stay and the number of hospitalization expenses; the scores of Kolcaba comfort level; and the scores of Pittsburgh sleep quality. Result: There was no significant difference in age or sex between the two groups. The VAS scores at 6 and 24 hours postoperatively were significantly lower in the cocktail group. The average length of hospital stay was 8.24 days in the control group and 3.73 days in the cocktail group. The average total hospitalization cost of the control group was ¥28285.16, and that of the cocktail group was ¥22366.31. In expenses of total hospitalization costs, the cocktail group was lower than the control group. Kolcaba's comfort various scores and the total score of the cocktail group were higher than the control group. The total score of PSQI and all dimensions in the experimental group were lower than those in the control group. Conclusion: We found a significant difference in the results of postoperative pain management except for age, sex, and hospitalization expenses. After hallux valgus surgery, inject cocktail drugs around the first metatarsophalangeal joint did reduce postoperative pain level. Level of Evidence. Level III, case-control study.

Accuracy and Safety of Robot-Assisted versus Fluoroscopy-Guided Posterior C1 Lateral Mass and C2 Pedicle Screw Internal Fixation for Atlantoaxial Dislocation: A Preliminary Study.

Objective: To compare the accuracy, efficiency, and safety of robotic assistance (RA) and conventional fluoroscopy guidance for the placement of C1 lateral mass and C2 pedicle screws in posterior atlantoaxial fusion. Methods: The data of patients who underwent posterior C1-C2 screw fixation (Goel-Harm's technique) in our hospital from August 2014 to March 2021 were retrospectively evaluated, including 14 cases under fluoroscopic guidance and 11 cases under RA. The hospital records, radiographic results, surgical data, and follow-up records were reviewed. Accuracy of screw placement was assessed using the Gertzbein and Robbins scale, and clinical outcomes were evaluated by Japanese Orthopedic Association (JOA) score, visual analogue scale (VAS), modified MacNab criteria, and postoperative complications. Results: Baseline characteristics of both groups were similar. The mean estimated blood loss in the fluoroscopic guidance and RA groups was 205.7 ± 80.3 mL and 120.9 ± 31.9 mL, respectively (p = 0.03). The mean surgical duration was 34 min longer with RA compared to that performed with free-hand (FH) method (p = 0.15). In addition, lower intraoperative radiation exposure was detected in the RA group (12.4 ± 1.4 mGy/screw) versus the FH (19.9 ± 2.1 mGy/screw) group (p = 0.01). The proportion of "clinically acceptable" screws (graded 0 and I) was higher in the RA group (93.2%) than that in the FH group (87.5%, p = 0.04). There was no significant difference in the increase of JOA score and decrease of VAS score between the two surgical procedures. Furthermore, there were no significant differences in overall clinical outcome between the two groups and no neurovascular complications associated with screw insertion. Conclusions: RA is a safe and potentially more accurate alternative to the conventional fluoroscopic-guided FH technique for posterior atlantoaxial internal fixation.

Morphological Variations of the Posterior Superior Iliac Spine in Chinese Population: Potential Effects on the Reliability of Palpation.

Objectives: The posterior superior iliac spine (PSIS) is an important anatomical landmark often involved in spinal manipulation and surgical bone harvest. Hence, knowledge of variations in the PSIS may be predictive and valuable in clinical settings. Taking the complex morphology into account, the study is aimed at proposing a classification of PSIS in the Chinese population. Methods: An anatomical study was undertaken on 288 human ilia. First, the morphological features of variations in the PSIS were noted following visual inspection. Then, 12 variable anatomical parameters were measured in order to determine the differences based on morphology, side, and sex. Results: Overall, four types of PSIS were found among 288 bones, including type I "V-shape" (106, 36.8%), type II "U-shape" (121, 42.0%), type III "W-shape" (36, 12.5%), and type IV "ossification-shape" (25, 8.7%). There were no significant sex or bilateral differences in the morphological distribution of the PSIS (p > 0.05). Furthermore, the measurements showed that type I was the narrowest and type III the broadest (p < 0.05). Moreover, female specimens had an overall larger distance and width of surrounding landmarks (p < 0.05), and a significant difference was found in the width of the PSIS between the left and right sides (p < 0.05). Conclusion: The PSIS samples displayed multiple morphological variations and could be classified into four types. In addition, sex-based or bilateral differences existed in the size and relative positions. It is thus likely that differences in the morphology and asymmetry of the PSIS provide references for palpation, bone harvest, and other clinical settings.

Bu Shen Huo Xue decoction promotes functional recovery in spinal cord injury mice by improving the microenvironment to promote axonal regeneration.

BACKGROUND: Bu-Shen-Huo-Xue (BSHX) decoction has been used in the postoperative rehabilitation of patients with spinal cord injury in China. In the present study, we aim to reveal the bioactive compounds in BSHX decoction and comprehensively explore the effects of BSHX decoction and the underlying mechanism in spinal cord injury recovery. METHODS: The main chemical constituents in BSHX decoction were determined by UPLC-MS/MS. SCI mice were induced by a pneumatic impact device at T9-T10 level of the vertebra, and treated with BSHX decoction. Basso-Beattie-Bresnahan (BBB) score, footprint analysis, hematoxylin-eosin (H&E) staining, Nissl staining and a series of immunofluorescence staining were performed to investigate the functional recovery, glial scar formation and axon regeneration after BSHX treatment. Immunofluorescent staining of bromodeoxyuridine (BrdU), neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) was performed to evaluate the effect of BSHX decoction on neural stem cells (NSCs) proliferation and differentiation. RESULTS: We found that the main compounds in BSHX decoction were Gallic acid, 3,4-Dihydroxybenzaldehyde, (+)-Catechin, Paeoniflorin, Rosmarinic acid, and Diosmetin. BSHX decoction improved the pathological findings in SCI mice through invigorating blood circulation and cleaning blood stasis in the lesion site. In addition, it reduced tissue damage and neuron loss by inhibiting astrocytes activation, and promoting the polarization of microglia towards M2 phenotype. The functional recovery test revealed that BSHX treatment improved the motor function recovery post SCI. CONCLUSIONS: Our study provided evidence that BSHX treatment could improve the microenvironment of the injured spinal cord to promote axonal regeneration and functional recovery in SCI mice.

Sodium tanshinone IIA sulfonate promotes spinal cord injury repair by inhibiting blood spinal cord barrier disruption in vitro and in vivo.

Spinal cord injury (SCI) leads to microvascular damage and the destruction of the blood spinal cord barrier (BSCB), which can progress into secondary injuries, such as apoptosis and necrosis of neurons and glia, culminating in permanent neurological deficits. BSCB restoration is the primary goal of SCI therapy, although very few drugs can repair damaged barrier structure and permeability. Sodium tanshinone IIA sulfonate (STS) is commonly used to treat cardiovascular disease. However, the therapeutic effects of STS on damaged BSCB during the early stage of SCI remain uncertain. Therefore, we exposed spinal cord microvascular endothelial cells to H2 O2 and treated them with different doses of STS. In addition to protecting the cells from H2 O2 -induced apoptosis, STS also reduced cellular permeability. In the in vivo model of SCI, STS reduced BSCB permeability, relieved tissue edema and hemorrhage, suppressed MMP activation and prevented the loss of tight junction and adherens junction proteins. Our findings indicate that STS treatment promotes SCI recovery, and should be investigated further as a drug candidate against traumatic SCI.

Inhibitory Effects of Rhaponticin on Osteoclast Formation and Resorption by Targeting RANKL-Induced NFATc1 and ROS Activity.

The extravagant osteoclast formation and resorption is the main cause of osteoporosis. Inhibiting the hyperactive osteoclastic resorption is considered as an efficient treatment for osteoporosis. Rhaponticin (RH) is a small molecule that has been reported to possess anti-inflammatory, anti-allergic, anti-fibrotic, and anti-diabetic activities. However, the influence of RH on osteoclasts differentiation and function is still unclear. To this end, an array of assays including receptor activator of nuclear factor kappa-Β (NF-κB) ligand (RANKL) induced osteoclastogenesis, tartrate-resistant acidic phosphatase (TRAcP) staining, immunofluorescence, and hydroxyapatite resorption were performed in this study. It was found that RH had significant anti-catabolic effects by inhibiting osteoclastogenesis and bone resorption without cytotoxicity. Mechanistically, the expression of NADPH oxidase 1 (Nox1) was found to be suppressed and antioxidant enzymes including catalase, superoxide dismutase 2 (SOD-2), and heme oxygenase-1(HO-1) were enhanced following RH treatment, suggesting RH exhibited antioxidant activity by reducing the generation of reactive oxygen species (ROS) as well as enhancing the depletion of ROS. In addition, MAPKs, NF-κB, and intracellular Ca2+ oscillation pathways were significantly inhibited by RH. These changes led to the deactivation of osteoclast master transcriptional factor-nuclear factor of activated T cells 1 (NFATc1), as examined by qPCR and Western blot assay, which led to the decreased expression of downstream integrin ß3, c-Fos, cathepsin K, and Atp6v0d2. These results suggested that RH could effectively suppress RANKL-regulated osteoclast formation and bone resorption. Therefore, we propose that RH can represent a novel natural small molecule for the treatment of osteoporosis by inhibiting excessive osteoclast activity.

Would high-dose corticosteroid addition to multimodal cocktail periarticular injection contribute to prolonged pain control and better recovery following total knee arthroplasty?: study protocol for a randomized controlled trial.

BACKGROUND: Enhanced recovery following total knee arthroplasty (TKA) has been advocated to enhance postoperative recovery. Multimodal cocktail periarticular injection (MCPI) use for pain control in TKA has gained wide acceptance. MCPI-containing corticosteroids are believed to be an effective solution owing to their local anti-inflammatory effects and ability to reduce the local stress response postoperatively. However, there is conflicting evidence regarding its benefits. This trial aims to compare MCPI with a high dose of corticosteroid, normal dose of corticosteroid, and non-corticosteroid during TKA, to assess the effectiveness of MCPI containing corticosteroids in postoperative pain relief, functional improvement, rescue analgesia, and side effects and provide evidence that high-dose corticosteroids result in prolonged pain control and better recovery following TKA. METHODS: This is a double-blinded, randomized, placebo-controlled study. A total of 234 patients scheduled for TKA will be recruited. During surgery, before wound closure, 80 ml of the cocktail analgesic will be injected into the muscle and joint capsule for local infiltration analgesia; the participants will be randomly assigned to three groups to receive a high dose of betamethasone MCPI (group H), normal dose of betamethasone MCPI (group N), and non-betamethasone MCPI (group C). The following indices will be recorded and analyzed: the strongest knee pain experienced during 90° flexion at 6 h, 24 h, 48 h, 72 h, 5 days, 14 days, and 30 days after surgery; 1 min walking ability; and circumference around the patella at 2, 5, 14, and 30 days after surgery; Knee Society knee score at 14 days and 30 days after surgery; C-reactive protein and blood sedimentation; blood sugar 2, 5, 14, and 30 days following surgery; rescue analgesic consumption; and adverse events. If any participant withdraws from the trial, an intention-to-treat analysis will be performed. DISCUSSION: The results of this study will provide clinical evidence on the effectiveness of MCPI-containing corticosteroids in postoperative pain relief, functional improvement, rescue analgesia, and adverse events, as well as provide evidence on the efficacy of high-dose corticosteroids in prolonged pain control and better recovery following TKA. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000038671 . Registered on September 27, 2020.

Tauroursodeoxycholic acid alleviates secondary injury in spinal cord injury mice by reducing oxidative stress, apoptosis, and inflammatory response.

BACKGROUND: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid derivative, which has been demonstrated to have neuroprotective effects in different neurological disease models. However, the effect and underlying mechanism of TUDCA on spinal cord injury (SCI) have not been fully elucidated. This study aims to investigate the protective effects of TUDCA in the SCI mouse model and the related mechanism involved. METHODS: The primary cortical neurons were isolated from E16.5 C57BL/6 mouse embryos. To evaluate the effect of TUDCA on axon degeneration induced by oxidative stress in vitro, the cortical neurons were treated with H2O2 with or without TUDCA added and immunostained with Tuj1. Mice were randomly divided into sham, SCI, and SCI+TUDCA groups. SCI model was induced using a pneumatic impact device at T9-T10 level of the vertebra. TUDCA (200 mg/kg) or an equal volume of saline was intragastrically administrated daily post-injury for 14 days. RESULTS: We found that TUDCA attenuated axon degeneration induced by H2O2 treatment and protected primary cortical neurons from oxidative stress in vitro. In vivo, TUDCA treatment significantly reduced tissue injury, oxidative stress, inflammatory response, and apoptosis and promoted axon regeneration and remyelination in the lesion site of the spinal cord of SCI mice. The functional recovery test revealed that TUDCA treatment significantly ameliorated the recovery of limb function. CONCLUSIONS: TUDCA treatment can alleviate secondary injury and promote functional recovery by reducing oxidative stress, inflammatory response, and apoptosis induced by primary injury, and promote axon regeneration and remyelination, which could be used as a potential therapy for human SCI recovery.

Biomechanical testing of three coracoclavicular ligament reconstruction techniques with a 3D printing navigation template for clavicle-coracoid drilling.

BACKGROUND: The identification and precise clavicle-coracoid drilling during coracoclavicular (CC) ligament reconstruction for acromioclavicular (AC) joint dislocation require a high level of experience and surgical skills. Furthermore, the improvement of flexible fixation, such as Endobutton techniques for CC ligament reconstructions is ongoing. We have developed a 3D printing technique navigation template for clavicle-coracoid drilling and a novel implant for the reconstruction. This study aimed to determine the efficiency of the navigation template for clavicle-coracoid drilling and to evaluate the biomechanical performance of the novel CC ligament reconstruction technique. METHODS: A total of 24 fresh-frozen human cadaveric shoulders were randomly assigned to 1 of 3 reconstruction groups or a control group: TightRope, Triple Endobutton, and the Adjustable Closed-Loop Double Endobutton technique. Computed tomography scans, navigation template designs, and 3D printing were performed for the shoulders. Then, AC joint dislocation was simulated in the reconstruction groups, and 3 CC ligament reconstruction techniques were operated via the 3D printing template separately. Furthermore, biomechanical protocols including the translation test (load from 5 to 70 N) and the load-to-failure test were performed to characterize the behaviors and strengths. One-way ANOVA test analyzed differences in displacement under the translation load and the load at failure. RESULTS: CC ligament reconstructions were performed successfully along with the 3D printing navigation template in the 3 reconstruction groups. During the translation test, no significant difference was found in displacements among the 4 groups. Meanwhile, the mean load of all reconstruction groups at failure (Adjustable Closed-Loop Double Endobutton, 722.1620 N; TightRope, 680.4020 N; Triple Endobutton, 868.5762 N) was significantly larger than the control group (564.6264 N, P<0.05). The Triple Endobutton group had the maximum load at failure (P<0.05), however, no significant difference was noticed between the other 2 reconstruction groups (P>0.05). CONCLUSIONS: The 3D printing navigation template may become helpful and reliable for AC joint dislocation surgery. Among the 3 CC ligament reconstruction techniques, the Triple Endobutton technique has the best strength in terms of biomechanics, while the biomechanical strength of the Adjustable Closed-Loop Double Endobutton technique is reliable in comparison with the TightRope technique.

Polydatin Attenuates OGD/R-Induced Neuronal Injury and Spinal Cord Ischemia/Reperfusion Injury by Protecting Mitochondrial Function via Nrf2/ARE Signaling Pathway.

Spinal cord ischemia/reperfusion injury (SCII) is a devastating complication of spinal or thoracic surgical procedures and can lead to paraplegia or quadriplegia. Neuronal cell damage involving mitochondrial dysfunction plays an important role in the pathogenesis of SCII. Despite the availability of various treatment options, there are currently no mitochondria-targeting drugs that have proven effective against SCII. Polydatin (PD), a glucoside of resveratrol, is known to preserve mitochondrial function in central nervous system (CNS) diseases. The aim of the present study was to explore the neuro- and mito-protective functions of PD and its underlying mechanisms. An in vitro model of SCII was established by exposing spinal cord motor neurons (SMNs) to oxygen-glucose-deprivation/reperfusion (OGD/R), and the cells were treated with different dosages of PD for varying durations. PD improved neuronal viability and protected against OGD/R-induced apoptosis and mitochondrial injury in a dose-dependent manner. In addition, PD restored the activity of neuronal mitochondria in terms of mitochondrial membrane potential (MMP), intracellular calcium levels, mitochondrial permeability transition pore (mPTP) opening, generation of reactive oxygen species (ROS), and adenosine triphosphate (ATP) levels. Mechanistically, PD downregulated Keap1 and upregulated Nrf2, NQO-1, and HO-1 in the OGD/R-treated SMNs. Likewise, PD treatment also reversed the neuronal and mitochondrial damage induced by SCII in a mouse model. Furthermore, the protective effects of PD were partially blocked by the Nrf2 inhibitor. Taken together, PD relieves mitochondrial dysfunction-induced neuronal cell damage by activating the Nrf2/ARE pathway and is a suitable therapeutic option for SCII.