A Factor-Free Hydrogel with ROS Scavenging and Responsive Degradation for Enhanced Diabetic Bone Healing.

In view of the increased levels of reactive oxygen species (ROS) that disturb the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), the repair of diabetic bone defects remains a great challenge. Herein, a factor-free hydrogel is reported with ROS scavenging and responsive degradation properties for enhanced diabetic bone healing. These hydrogels contain ROS-cleavable thioketal (TK) linkers and ultraviolet (UV)-responsive norbornene (NB) groups conjugated with 8-arm PEG macromers, which are formed via UV crosslinking-mediated gelation. Upon reacting with high levels of ROS in the bone defect microenvironment, ROS-cleavable TK linkers are destroyed, allowing the responsive degradation of hydrogels, which promotes the migration of BMSCs. Moreover, ROS levels are reduced through hydrogel-mediated ROS scavenging to reverse BMSC differentiation from adipogenic to osteogenic phenotype. As such, a favorable microenvironment is created after simultaneous ROS scavenging and hydrogel degradation, leading to the effective repair of bone defects in diabetic mouse models, even without the addition of growth factors. Thus, this study presents a responsive hydrogel platform that regulates ROS scavenging and stromal degradation in bone engineering.

Macrophage Polarization Modulated by NF-κB in Polylactide Membranes-Treated Peritendinous Adhesion.

Foreign body reactions (FBR) to implants seriously impair tissue-implant integration and postoperative adhesion. The macrophage, owing to its phenotypic plasticity, is a major regulator in the formation of the inflammatory microenvironment; NF-κB signaling also plays a vital role in the process. It is hypothesized that NF-κB phosphorylation exerts a proinflammatory regulator in FBR to polylactide membranes (PLA-M) and adhesion. First, in vitro and in vivo experiments show that PLA-M induces NF-κB phosphorylation in macrophages, leading to M1 polarization and release of inflammatory factors. The inflammatory microenvironment formed due to PLA-M accelerates myofibroblast differentiation and release of collagen III and MMP2, jointly resulting in peritendinous adhesion. Therefore, JSH-23 (a selective NF-κB inhibitor)-loaded PLA membrane (JSH-23/PLA-M) is fabricated by blend electrospinning to regulate the associated M1 polarization for peritendinous anti-adhesion. JSH-23/PLA-M specifically inhibits NF-κB phosphorylation in macrophages and exhibits anti-inflammatory and anti-adhesion properties. The findings demonstrate that NF-κB phosphorylation has a critical role in PLA-induced M1 polarization and aggravating FBR to PLA-M. Additionally, JSH-23/PLA-M precisely targets modulation of NF-κB phosphorylation in FBR to break the vicious cycle in peritendinous adhesion therapy.

MicroRNA-199-3p up-regulation enhances chondrocyte proliferation and inhibits apoptosis in knee osteoarthritis via DNMT3A repression.

AIM: Studies have pivoted on the position of microRNAs (miRNAs) in knee osteoarthritis (KOA) but not the more specific function of miR-199-3p. Thus, this study is to uncover the mechanism of miR-199-3p in KOA. METHODS: Rats KOA models were established by modified Hulth method. miR-199-3p expression was observed in cartilage of KOA rats. The binding sites of miR-199-3p were predicted by bioinformatics analysis and the potential interaction between DNA methyltransferase 3A (DNMT3A) and miR-199-3p was verified by dual-luciferase reporter gene assay. Rats were injected with miR-199-3p agomir or antagomir and DNMT3A siRNA into the knee joint. Inflammatory response factors in serum and cartilage tissues, cell apoptosis, and pathological status of cartilage tissues were detected. Chondrocytes were isolated from KOA cartilages and treated with miR-199-3p mimic or inhibitor and DNMT3A siRNA. Chondrocyte proliferation and apoptosis were detected. RESULTS: miR-199-3p expression was suppressed in cartilage of KOA rats. Dual-luciferase reporter gene assay proved that a miR-199-3p-binding site was located in the 3'UTR of DNMT3A mRNA. Inflammation, chondrocyte apoptosis and cartilage pathological changes were improved by miR-199-3p agomir but aggravated by miR-199-3p antagomir. The effects of miR-199-3p antagomir on KOA rats were partially reversed by DNMT3A siRNA. miR-199-3p mimic or DNMT3A siRNA decreased KOA chondrocytes apoptosis and promoted proliferation. miR-199-3p inhibitor showed the opposite functions to miR-199-3p mimic. The effects of miR-199-3p inhibitor on chondrocytes were reversed by DNMT3A siRNA. CONCLUSION: This study highlights that miR-199-3p up-regulation or down-regulation of DNMT3A induces chondrocyte proliferation and inhibits apoptosis in KOA, which may widen our eyes to treat patients with KOA.

A Preliminary Study of Ankle Single Photon Emission Computed Tomography/Computed Tomography in Patients With Bony Impingement Syndrome: Association With the Visual Analogue Scale Pain Score.

Both osteoarthritis and impingement syndrome are the disorders commonly observed in sports medicine. However, failure in pain alleviation by surgical intervention introduces challenges in the diagnosis and decision-making for orthopedists. Hybrid single photon emission computed tomography/computed tomography (SPECT/CT) provides both functional and structural information of ankle pathology. The purpose of this retrospective study was to evaluate whether bone tracer uptake by ankle SPECT/CT is related to the lesion type and visual analog scale (VAS) pain score for patients with osteoarthritis and bony impingement. Fifty individuals with chronic ankle pain who underwent pretreatment ankle SPECT/CT were included in the current study. The median follow-up period was 2.5 (range 1.8 to 3.2) years. The lesion types were categorized by the positions of anatomical changes and bone tracer uptake. The VAS pain score was recorded 2 weeks before and 1.5 year after surgical intervention. Twenty-nine (58%) of 50 patients had osseous impingement. Among them, 16 (55.2%), 4 (13.8%), and 9 (31%) patients had anterior, posterior, and both types of ankle impingement, respectively. The uptake grade of bone tracer was significantly related to the lesion type of ankle impingement (p < .001). The VAS pain score was significantly correlated with bone tracer uptake before treatment (p < .001). Bone tracer uptake was related to the lesion type of impingement detected by SPECT/CT and was confirmed by surgical findings. The VAS pain score was significantly correlated with the bone tracer uptake. Preoperative ankle SPECT/CT may be helpful to clinically correlate the VAS pain score in the pre- and postsurgical periods for patients with osteoarthritis and bony impingement syndrome.

Effects of C-myc gene silencing on interleukin-1ß-induced rat chondrocyte cell proliferation, apoptosis and cytokine expression.

This study explores the effects of C-myc gene silencing on cell proliferation, apoptosis and cytokine expression in interleukin (IL)-1ß-induced rat chondrocytes. Primary chondrocytes were obtained from 40 Sprague-Dawley rats. For in vitro C-myc3-shRNA transfection, chondrocytes were assigned to a blank 1, model 1, IL-1ß + C-myc3-shRNA, C-myc3-shRNA, (IL-1ß + C-myc3-shRNA) + C-myc overexpression, C-myc3-shRNA + C-myc overexpression or IL-1ß + C-myc-Con group. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to detect C-myc, PCNA and cyclin D1 mRNA and protein expression. Cell proliferation was analyzed via CCK-8 assay and cell cycle while apoptosis was measured through flow cytometry. ELISA was utilized to assess the levels of metallopeptidase 13 (MMP-13), IL-6 and tumor necrosis factor-α (TNF-α). Both the qRT-PCR and Western blotting results demonstrated that C-myc3-shRNA transfection inhibits C-myc expression and promotes PCNA and cyclin D1 expression. In comparison to the model 1 group, all groups except the (IL-1ß + C-myc3-shRNA) + C-myc overexpression and IL-1ß + C-myc-Con groups showed increases in cell proliferation and S phase cell count and decreases in G0/G1 phase cell count, cell apoptosis and MMP-13, IL-6 and TNF-α levels. The model 1, C-myc3-shRNA and C-myc3-shRNA + C-myc overexpression groups displayed higher cell proliferation and S phase cell count and reduced G0/G1 phase cell count, cell apoptosis and MMP-13, IL-6 and TNF-α levels than the IL-1ß + C-myc3-shRNA group. In comparison to the model 1 and C-myc3-shRNA + C-myc overexpression groups, the C-myc3-shRNA group promoted cell proliferation and S phase cell counts but suppressed G0/G1 phase cell count, cell apoptosis and MMP-13, IL-6 and TNF-α levels. In conclusion, the study demonstrates that C-myc gene silencing can promote cell proliferation and inhibit cell apoptosis and cytokine expression in IL-1ß-induced rat chondrocytes.

Clinical characteristics and surgical experience of Type III Wagstaffe fractures: Pay attention to concomitant chondral injury of the talus.

BACKGROUND: The purpose of this study was to investigate clinical characteristics and surgical management of Type III Wagstaffe fracture. METHODS: From August 2012 to July 2015, 13 patients with Type III Wagstaffe fractures were surgically treated. During operation, the cartilage of joint surface was explored. Wagstaffe fragment was fixed with cannulated screw or suture, Chaput fragment was fixed with cannulated screw or plate, and Cotton test was performed to evaluate the stability of syndesmosis during the operation. All the patients were followed up for 14.3 months in average. Clinical outcome was assessed with Olerud-Molander score and American Orthopedic Foot and Ankle Society (AOFAS) score. The traumatic arthritis was evaluated with osteoarthritis-score (OA-score). RESULTS: During the operation, chondral injury was found on the lateral top of the talus in 8 cases, as "kissing lesion" of Chaput fragment. The fractures healed uneventfully and all the patients recovered satisfactorily except two had moderate restriction in ankle movement. The average Olerud-Molander score and AOFAS score were 82.3 and 86.1, respectively. CONCLUSION: Type III Wagstaffe is a rare and often missed fracture. 61% are associated with a chondral lesion on the lateral top of the talus. Anatomical reduction and rigid fixation of both fragments are mandatory to obtain ankle stability and good results.

Diets intervene osteoporosis via gut-bone axis.

Osteoporosis is a systemic skeletal disease that seriously endangers the health of middle-aged and older adults. Recently, with the continuous deepening of research, an increasing number of studies have revealed gut microbiota as a potential target for osteoporosis, and the research concept of the gut-bone axis has gradually emerged. Additionally, the intake of dietary nutrients and the adoption of dietary patterns may affect the gut microbiota, and alterations in the gut microbiota might also influence the metabolic status of the host, thus adjusting bone metabolism. Based on the gut-bone axis, dietary intake can also participate in the modulation of bone metabolism by altering abundance, diversity, and composition of gut microbiota. Herein, combined with emerging literatures and relevant studies, this review is aimed to summarize the impacts of different dietary components and patterns on osteoporosis by acting on gut microbiota, as well as underlying mechanisms and proper dietary recommendations.

Engineering Large-Scale Self-Mineralizing Bone Organoids with Bone Matrix-Inspired Hydroxyapatite Hybrid Bioinks.

Addressing large bone defects remains a significant challenge owing to the inherent limitations in self-healing capabilities, resulting in prolonged recovery and suboptimal regeneration. Although current clinical solutions are available, they have notable shortcomings, necessitating more efficacious approaches to bone regeneration. Organoids derived from stem cells show great potential in this field; however, the development of bone organoids has been hindered by specific demands, including the need for robust mechanical support provided by scaffolds and hybrid extracellular matrices (ECM). In this context, bioprinting technologies have emerged as powerful means of replicating the complex architecture of bone tissue. The research focused on the fabrication of a highly intricate bone ECM analog using a novel bioink composed of gelatin methacrylate/alginate methacrylate/hydroxyapatite (GelMA/AlgMA/HAP). Bioprinted scaffolds facilitate the long-term cultivation and progressive maturation of extensive bioprinted bone organoids, foster multicellular differentiation, and offer valuable insights into the initial stages of bone formation. The intrinsic self-mineralizing quality of the bioink closely emulates the properties of natural bone, empowering organoids with enhanced bone repair for both in vitro and in vivo applications. This trailblazing investigation propels the field of bone tissue engineering and holds significant promise for its translation into practical applications.

MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis.

Posttraumatic osteoarthritis (PTOA) patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective. Early PTOA is characterized by overexpressed matrix metalloprotease 13 (MMP13). Herein, we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable, cyanine 5 (Cy5)-containing PEG, black hole quencher-3 (BHQ3), and cRGD ligands and loaded with siRNA silencing MMP13 (siM13), namely ERMs@siM13. ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell, causing cRGD exposure. Accordingly, the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surface αvß3 integrin, increasing intracellular siM13 delivery for on-demand MMP13 downregulation. Meanwhile, the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle, precisely reflecting the diseased cartilage state. In particular, the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity, enabling the physicians to adjust the therapeutic regimen. Finally, in the murine PTOA model, ERMs@siM13 could diagnose the early-stage PTOA, perform timely interventions, and monitor the OA progression level during treatment through a real-time detection of MMP13. Therefore, ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.

Clinical guideline on the third generation minimally invasive surgery for hallux valgus.

Minimally invasive surgery for hallux valgus correction, has been attracting great interests in the recent decades, due to the potential benefits of less pain, decreased recovery times, smaller scars with better cosmesis, and improved early post-operative range of motion. The most recent developments in minimally invasive surgery have evolved into the third generation with modifications of the chevron-type osteotomy. This evidence-based clinical guideline of the third generation minimally invasive surgery for hallux valgus is initiated and developed collectively by the Foot and Ankle Committee of Orthopedic Branch of Chinese Medical Doctor Association, Foot and Ankle Committee of Sports Medicine Branch of Chinese Medical Doctor Association, and Foot and Ankle Expert Committee of Orthopedic Branch of the Chinese Association of the Integrative Medicine. This clinical guideline provides recommendations for indications, contraindications, operative planning and techniques, post-operative management, management of complications, and prognosis of the third generation minimally invasive surgery for hallux valgus. The Translational Potential of this Article This comprehensive guideline aims to establish standardized recommendations for the indications, contraindications, operative techniques, and post-operative management of the third generation minimally invasive surgery for hallux valgus. By adhering to this guideline, the success rate of the procedure could be maximized. This comprehensive guideline serves as a valuable reference for practitioners interested in or preparing to perform minimally invasive surgery for hallux valgus.

Heterogeneous DNA hydrogel loaded with Apt02 modified tetrahedral framework nucleic acid accelerated critical-size bone defect repair.

Segmental bone defects, stemming from trauma, infection, and tumors, pose formidable clinical challenges. Traditional bone repair materials, such as autologous and allogeneic bone grafts, grapple with limitations including source scarcity and immune rejection risks. The advent of nucleic acid nanotechnology, particularly the use of DNA hydrogels in tissue engineering, presents a promising solution, attributed to their biocompatibility, biodegradability, and programmability. However, these hydrogels, typically hindered by high gelation temperatures (∼46 °C) and high construction costs, limit cell encapsulation and broader application. Our research introduces a novel polymer-modified DNA hydrogel, developed using nucleic acid nanotechnology, which gels at a more biocompatible temperature of 37 °C and is cost-effective. This hydrogel then incorporates tetrahedral Framework Nucleic Acid (tFNA) to enhance osteogenic mineralization. Furthermore, considering the modifiability of tFNA, we modified its chains with Aptamer02 (Apt02), an aptamer known to foster angiogenesis. This dual approach significantly accelerates osteogenic differentiation in bone marrow stromal cells (BMSCs) and angiogenesis in human umbilical vein endothelial cells (HUVECs), with cell sequencing confirming their targeting efficacy, respectively. In vivo experiments in rats with critical-size cranial bone defects demonstrate their effectiveness in enhancing new bone formation. This innovation not only offers a viable solution for repairing segmental bone defects but also opens avenues for future advancements in bone organoids construction, marking a significant advancement in tissue engineering and regenerative medicine.

Advanced glycation end products mediate biomineralization disorder in diabetic bone disease.

Patients with diabetes often experience fragile fractures despite normal or higher bone mineral density (BMD), a phenomenon termed the diabetic bone paradox (DBP). The pathogenesis and therapeutics opinions for diabetic bone disease (DBD) are not fully explored. In this study, we utilize two preclinical diabetic models, the leptin receptor-deficient db/db mice (DB) mouse model and the streptozotocin-induced diabetes (STZ) mouse model. These models demonstrate higher BMD and lower mechanical strength, mirroring clinical observations in diabetic patients. Advanced glycation end products (AGEs) accumulate in diabetic bones, causing higher non-enzymatic crosslinking within collagen fibrils. This inhibits intrafibrillar mineralization and leads to disordered mineral deposition on collagen fibrils, ultimately reducing bone strength. Guanidines, inhibiting AGE formation, significantly improve the microstructure and biomechanical strength of diabetic bone and enhance bone fracture healing. Therefore, targeting AGEs may offer a strategy to regulate bone mineralization and microstructure, potentially preventing the onset of DBD.

Expert consensus on Prospective Precision Diagnosis and Treatment Strategies for Osteoporotic Fractures.

Osteoporotic fractures are the most severe complications of osteoporosis, characterized by poor bone quality, difficult realignment and fixation, slow fracture healing, and a high risk of recurrence. Clinically managing these fractures is relatively challenging, and in the context of rapid aging, they pose significant social hazards. The rapid advancement of disciplines such as biophysics and biochemistry brings new opportunities for future medical diagnosis and treatment. However, there has been limited attention to precision diagnosis and treatment strategies for osteoporotic fractures both domestically and internationally. In response to this, the Chinese Medical Association Orthopaedic Branch Youth Osteoporosis Group, Chinese Geriatrics Society Geriatric Orthopaedics Committee, Chinese Medical Doctor Association Orthopaedic Physicians Branch Youth Committee Osteoporosis Group, and Shanghai Association of Integrated Traditional Chinese and Western Medicine Osteoporosis Professional Committee have collaborated to develop this consensus. It aims to elucidate emerging technologies that may play a pivotal role in both diagnosis and treatment, advocating for clinicians to embrace interdisciplinary approaches and incorporate these new technologies into their practice. Ultimately, the goal is to improve the prognosis and quality of life for elderly patients with osteoporotic fractures.

Intra-articular Osteoid Osteoma of the Intermediate Cuneiform Bone Causing Articular Degeneration: A Rare Case and Literature Review.

Osteoid osteoma of the cuneiform bone is an exceedingly rare and easily missed cause of foot pain. The uncharacteristic and nonspecific radiographs of such intra-articular osteoid osteoma further increase difficulty in making the diagnosis. To date, there has been no description of intra-articular osteoid osteoma of the intermediate cuneiform bone causing articular degeneration in any published literatures. We present a case of intra-articular osteoid osteoma of the intermediate cuneiform bone causing articular degeneration, who underwent curettage, allograft bone graft, and navicular-cuneiform arthrodesis. The patient presented with radiographic bone union, full motor function recovery and pain-free at the 22-month follow-up. This report adds to the existing literature. Intra-articular osteoid osteoma of the intermediate cuneiform bone causing articular degeneration is an exceedingly rare and easily missed cause of foot pain. It proves a complicated and challenging task to identify intra-articular osteoid osteoma. Clinicians should be particularly careful not to exclude the possibility of arthritis and, thus, vigilant when choosing the surgical option.

Clinical significance of the anteromedial talus osteophyte in anteromedial ankle impingement in chronic lateral ankle instability.

PURPOSE: The aim of this study was to evaluate the relation between anteromedial ankle osteophytes (AMAO) and anteromedial ankle impingement (AMAI) in chronic lateral ankle instability (CLAI) through visualization and quantification. METHODS: Forty-three patients with unilateral CLAI between September 2018 and March 2020 accepted arthroscopic repair of an anterior talofibular ligament (ATFL) and were split into two groups: AMAI (AMAI including intraoperative AMAO resection) and pure CLAI (with AMAO but without AMAI, no AMAO resection). The AMAO protrusion lengths in each direction were measured and compared after all of the ankles were reconstructed. All patients were assessed preoperatively and at 2-year follow-up with ankle dorsiflexion, the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, and visual analog scale (VAS) score. RESULTS: Intelligent analysis showed that a large extent of osteophytes was found at the dorsomedial surface of the talar neck in AMAI group. The upper and inner bound protrusion distances of AMAO in AMAI group were greater than in the pure CLAI group. There was no significant difference in anterior bound protrusion distance of AMAO between the two groups. Preoperatively, the ankle dorsiflexion of AMAI group (7.6 ± 1.4°) was considerably lower than that of pure CLAI group (22.4 ± 1.9°) (p < 0.001). When compared to the pure CLAI group, the AMAI group had a substantially worse AOFAS score (62.2 ± 6.7 vs 71.1 ± 9.1; p < 0.001) and VAS score (6.0 ± 1.0 vs 4.9 ± 0.8; p < 0.05). However, there was no significant difference in postoperative ankle dorsiflexion, AOFAS score, or VAS score between the two groups. CONCLUSION: AMAO is formed mostly on the dorsomedial surface of the talar neck in CLAI with AMAI, and the upper and inner bound protrusion lengths of AMAO were shown to be significantly correlated with the existence of AMAI in CLAI.

Is the diagnostic validity of conventional radiography for Lisfranc injury acceptable?

BACKGROUND: Lisfranc injuries mainly involve the tarsometatarsal joint complex and are commonly misdiagnosed or missed in clinical settings. Most medical institutions prefer to use conventional radiography. However, existing studies on conventional radiographs in Lisfranc injury lack a large population-based sample, influencing the validity of the results. We aimed to determine the diagnostic validity and reliability of conventional radiography for Lisfranc injury and whether computed tomography can alter clinical decision-making. METHODS: This retrospective study included 307 patients with, and 100 patients without, Lisfranc injury from January 2017 to December 2019. Diagnosis was confirmed using computed tomography. A senior and junior surgeon independently completed two assessments of the same set of anonymised conventional radiographs at least 3 months apart. The surgeons were then asked to suggest one of two treatment options (surgery or conservative treatment) for each case based on the radiographs and subsequently on the CT images. RESULTS: All inter- and intra-observer reliabilities were moderate to very good (all κ coefficients > 0.4). The mean (range) true positive rate was 81.8% (73.9%-87.0%), true negative rate was 90.0% (85.0%-94.0%), false positive rate was 10.0% (6.0%-15.0%), false negative rate was 18.2% (13.0%-26.1%), positive predictive value was 96.1% (93.8%-97.8%), negative predictive value was 62.4% (51.5%-69.7%), classification accuracy was 83.8% (76.7%-88.2%), and balanced error rate was 14.1% (10.2%-20.5%). Three-column injuries were most likely to be recognized (mean rate, 92.1%), followed by intermediate-lateral-column injuries (mean rate, 81.5%). Medial-column injuries were relatively difficult to identify (mean rate, 60.7%). The diagnostic rate for non-displaced injuries (mean rate, 76.7%) was lower than that for displaced injuries (mean rate, 95.5%). The typical examples are given. A significant difference between the two surgeons was found in the recognition rate of non-displaced injuries (p = 0.005). The mean alteration rate was 21.9%; the senior surgeon tended to a lower rate (15.6%) than the junior one (28.3%) (p < 0.001). CONCLUSIONS: The sensitivity, specificity, and classification accuracy of conventional radiographs for Lisfranc injury were 81.8%, 90.0%, and 83.8%, respectively. Three-column or displaced injuries were most likely to be recognized. The possibility of changing the initial treatment decision after subsequently evaluating computed tomography images was 21.9%. The diagnostic and clinical decision-making of surgeons with different experience levels demonstrated some degree of variability. Protected weight-bearing and a further CT scan should be considered if a Lisfranc injury is suspected and conventional radiography is negative.

Ubiquitin-Specific Peptidase 8 Is Critical for the Onset of Infectious Osteomyelitis by Targeting RIPK2 Ubiquitination.

Receptor-interacting serine/threonine kinase (RIPK) is associated with cellular inflammation and immune regulation. The current study explored the role of RIPK2 in osteomyelitis and the potential upstream targets of RIPK2. A Staphylococcus aureus-induced osteomyelitis mouse model was established using wild-type (WT) and ubiquitin-specific peptidase 8 (USP8)-deficient (USP-/-) mice, and the osteomyelitis-related symptoms were evaluated. Bone marrow-derived macrophages (BMDMs) were isolated from the WT and USP-/- mice. Enzyme-linked immunosorbent assays, quantitative polymerase chain reaction, and immunoblot analysis were used to determine the levels of target biomarkers, which were induced by lipopolysaccharide (LPS), CpG, or PAM3CSK4. USP8 promoted RIPK2-mediated NF-κB activation. USP8 is indispensable for RIPK2-mediated LPS-induced NF-κB activation in BMDMs. USP8 is required for the production of inflammatory cytokines induced by LPS, CpG, or PAM3CSK4 in BMDMs. In addition, USP-/- mice exhibited ameliorated symptoms, including less body weight and cortical bone loss, and reduced bacterial load and reactive bone formation in the S. aureus-induced osteomyelitis mouse model. USP8 is critical in the S. aureus-induced osteomyelitis mouse model by targeting RIPK2 ubiquitination.

Finite element analyses of three minimally invasive fixation techniques for treating Sanders type II intra-articular calcaneal fractures.

BACKGROUND AND OBJECTIVE: Calcaneal Sanders type II or III fractures are highly disabling with significant burden. Surgical treatment modalities include open reduction and internal fixation (ORIF) techniques and a variety of minimally invasive surgical (MIS) approaches. ORIF techniques are associated with complications and traditional MIS techniques need extensive intraoperative fluoroscopic procedures. The present study aims to investigate the effects of three different minimally invasive internal fixation (MIIF) techniques used to treat Sanders type II intra-articular calcaneal fractures using finite element analyses. METHODS: A 64-row spiral computed tomography scan was used to observe the calcaneus of a healthy adult. The scanning data were imported into Mimics in a DICOM format. Using a new model of a Sanders type II-B intra-articular calcaneal fracture, three minimally invasive techniques were simulated. Technique A involved fixation using an isolated minimally invasive locking plate; Technique B used a minimally invasive locking plate with one medial support screw; and Technique C simulated a screw fixation technique using four 4.0-mm screws. After simulating a 640-N load on the subtalar facet, the maximum displacement and von Mises stress of fragments and implants were recorded to evaluate the biomechanical stability of different fixation techniques using finite element analyses. RESULTS: After stress loading, the maximum displacements of the fragments and implants were located at the sustentaculum tali and the tip of sustentaculum tali screw, respectively, in the three techniques; however, among the three techniques, Technique B had better results for displacement of both. The maximum von Mises stress on the fragments was < 56 Mpa, and stress on the implants using the three techniques was less than the yield strength, with Technique C having the least stress. CONCLUSION: All three techniques were successful in providing a stable fixation for Sanders type II intra-articular calcaneal fractures, while the minimally invasive calcaneal locking plate with medial support screw fixation approach exhibited greater stability, leading to improved enhancement for the facet fragment; however, screw fixation dispersed the stress more effectively than the other two techniques.

The Ubiquitination of RIPK2 is Mediated by Peli3 and Negatively Regulates the Onset of Infectious Osteomyelitis.

Osteomyelitis is the infection and destruction of the bone. To date, there is no universal protocol for its treatment. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) has been implicated in osteomyelitis development. However, the detailed mechanism remains unknown. Here, 6-8w wild-type or Pellino E3 Ubiquitin Protein Ligase Family Member 3 (Peli3)-deficient mice were injected with Staphylococcus aureus to induce osteomyelitis. RAW264.7 cells or bone marrow-derived macrophages isolated from mice were treated with lipopolysaccharide (LPS). Knocking down Peli3 in RAW264.7 cells increased the expression of inflammatory cytokines (interleukin-1ß, interleukin-6, and tumor necrosis factor-α) after LPS stimulation. Inflammation was also activated in S. aureus-induced Peli3-deficient mice. Moreover, S. aureus-infected Peli3-deficient mice also displayed more severe symptoms of osteomyelitis than S. aureus-infected wild-type mice. Moreover, Peli3 targets and degrades RIPK2 through K48-linked ubiquitination, and negatively modulates osteomyelitis by degrading RIPK2. Our data further expands the current understanding of RIPK2 in osteomyelitis, and suggests that RIPK2 might serve as a novel therapeutic target for treating osteomyelitis.

Risk factors for chronic ankle instability after first episode of lateral ankle sprain: A retrospective analysis of 362 cases.

BACKGROUND: Chronic ankle instability (CAI) is a common sequela following an acute lateral ankle sprain (LAS). To treat an acute LAS more effectively and efficiently, it is important to identify patients at substantial risk for developing CAI. This study identifies magnetic resonance imaging (MRI) manifestations for predicting CAI development after a first episode of LAS and explores appropriate clinical indications for ordering MRI scans for these patients. METHODS: All patients with a first-episode LAS who received plain radiograph and MRI scanning within the first 2 weeks after LAS from December 1, 2017 to December 1, 2019 were identified. Data were collected using the Cumberland Ankle Instability Tool at final follow-up. Demographic and other related clinical variables, including age, sex, body mass index, and treatment were also recorded. Univariable and multivariable analyses were performed successively to identify risk factors for CAI after first-episode LAS. RESULTS: A total 131 out of 362 patients with a mean follow-up of 3.0 ± 0.6 years (mean ± SD; 2.0-4.1 years) developed CAI after first-episode LAS. According to multivariable regression, development of CAI after first-episode LAS was associated with 5 prognostic factors: age (odds ratio (OR) = 0.96, 95% confidence interval (95%CI): 0.93-1.00, p = 0.032); body mass index (OR = 1.09, 95%CI: 1.02-1.17, p = 0.009); posterior talofibular ligament injury (OR = 2.17, 95%CI: 1.05-4.48, p = 0.035); large bone marrow lesion of the talus (OR = 2.69, 95%CI: 1.30-5.58, p = 0.008), and Grade 2 effusion of the tibiotalar joint (OR = 2.61, 95%CI: 1.39-4.89, p = 0.003). When patients had at least 1 positive clinical finding in the 10-m walk test, anterior drawer test, or inversion tilt test, they had a 90.2% sensitivity and 77.4% specificity in terms of detecting at least 1 prognostic factor by MRI. CONCLUSION: MRI scanning is valuable in predicting CAI after first-episode LAS for those patients with at least 1 positive clinical finding in the 10-m walk test, anterior drawer test, and inversion tilt test. Further prospective and large-scale studies are necessary for validation.