Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a major global public health problem, and its occurrence is associated with adverse environmental exposures during development. In this study, we investigated the impact of the use of prednisone (a synthetic glucocorticoid drug) during pregnancy on susceptibility to MASLD in offspring and explored its potential therapeutic targets. Pregnant rodents were administered clinically equivalent doses of prednisone daily by oral gavage during gestation days (GDs) 0-20 in rats and GD0-18 mice, and their offspring were fed a high-fat diet from postnatal weeks 8-12. The results showed that prenatal prednisone exposure (PPE) led to reduced hepatic glucose uptake and fatty acid oxidation in offspring rats prenatally and postnatally and that the offspring developed more severe MASLD when fed a high-fat diet, with males exhibiting greater severity than females. Consistent findings were observed in PPE adult offspring mice. RNA-seq and experimental results revealed that hepatic Serpina3c expression was consistently reduced in PPE offspring before and after birth, which led to an increase in chymase-Ang II production and subsequent activation of its receptor AT1R, leading to MASLD susceptibility. In vivo and in vitro studies revealed that the programming of low Serpina3c expression was associated with reduced H3K27ac levels in the gene promoter region of Serpina3c caused by the activation of GR-HDAC3 signaling by the active metabolite prednisolone. Finally, postnatal high expression of hepatic Serpina3c reversed the activation of the chymase-Ang II-AT1R pathway and significantly ameliorated hepatic glucose and lipid metabolic dysfunction and MASLD susceptibility in PPE offspring. In summary, this study reveals MASLD susceptibility in offspring induced by PPE and identifies Serpina3c as a target for the prevention and treatment of MASLD susceptibility.

Acetaminophen is widely used during pregnancy but may cause developmental abnormalities in multiple systems in offspring. However, the effects of prenatal acetaminophen exposure (PAcE) on chondrodevelopment and long-term outcomes remain unclear. We administered 100 mg/kg per day of acetaminophen to rats on gestational days (GDs) 10-12 and treated fetal chondrocytes in vitro. In male PAcE offspring, cartilage matrix synthesis decreased and degradation increased at GD20 and postnatal week 12, with osteoarthritis (OA) susceptibility after running. Females exhibited only reduced matrix content at GD20. Mechanistically, acetaminophen inhibited the expression of hexokinase 1 (HK1) in chondrocytes under both normoxic and hypoxic conditions in vitro. However, HK1 inhibition induced feedback enhancement of the glycolytic only under hypoxic conditions, which increased lactic acid production and H3K18la lactylation levels in the Wnt5a promoter region, disrupting cartilage homeostasis. These effects were reversed by Wnt5a knockdown, HK1 overexpression, or LDHA knockdown. Finally, intra-articular adeno-associated virus-shWnt5a injection improved OA pathology in male PAcE offspring. In summary, PAcE upregulated H3K18la levels with Wnt5a through HK1-LDHA-mediated glycolytic feedback regulation, causing chondrodysplasia and increased OA susceptibility in male offspring, with sex differences. Our findings provide crucial insight into the hypoxia-dependent chondrotoxicity of PAcE, providing a reference for future research on fetal-derived OA. High H3K18la in the Wnt5a promoter region mediates PAcE-induced hypochondroplasia and susceptibility to adult OA in male offspring rats.

Aims:This investigation aimed to evaluate the efficacy and safety of intra-articular dimethyl itaconate (DI) combined with systemic vancomycin (Van) for the treatment of periprosthetic joint infections (PJI) induced by Staphylococcus aureus. Methods:The fifty rats were divided into five groups: Control (Con), PJI, PJI + DI, PJI + Van, and PJI + Van + DI. After three weeks, systemic and local inflammation, osteolysis, bone histomorphometry, bacterial load, and biofilm formation were analyzed. Tartrate-resistant acid phosphatase (TRAP) staining was used to evaluate osteoclast inhibition by DI and vancomycin, and Alizarin Red staining was used to assess its effect on osteogenic differentiation. Results:In vivo, the combination therapy demonstrated superior mitigation of bone loss and intra-articular synovial inflammation compared to Van monotherapy. Furthermore, the co-administration of DI and vancomycin effectively facilitated bacterial and biofilm clearance within the joint, further alleviating the dysregulation between bone resorption and remodelling. Compared to the DI and vancomycin monotherapy group, the Van + DI group showed reduced bacterial counts in implants, bone tissue, and soft-tissue. However, intra-articular DI alone was insufficient for complete eradication of S. aureus-induced PJI. Safety assessments indicated that neither DI monotherapy nor its combination with vancomycin elicited hepatic or renal toxicity in rats. In vitro, it was validated that DI exerts a promotive effect on osteoblast function while concurrently inhibiting osteoclast formation. Conclusion:Intra-articular injection of DI combined with systemic vancomycin appears to be a safe and effective therapeutic strategy for PJI in our current rat model.

Objective:To investigate the effectiveness of all-arthroscopic treatment for Pipkin type Ⅰ and Ⅱ femoral head fractures. Methods:A retrospective analysis was conducted on the clinical data of 13 patients with Pipkin type Ⅰ and Ⅱ femoral head fractures who underwent all-arthroscopic reduction and fixation between May 2015 and May 2024. The cohort included 10 males and 3 females, with an average age of 27.4 years (range, 14-40 years). The mechanisms of injury involved traffic accidents in 11 cases and falls from a height in 2 cases. According to the Pipkin classification, there were 7 type Ⅰ and 6 type Ⅱ fractures. Seven patients presented with concomitant posterior hip dislocation. The interval from injury to surgery ranged from 1 to 10 days, averaging 3.2 days. Fixation was achieved using bioabsorbable suture anchors in 7 cases, bioabsorbable screws in 4 cases, and Herbert screws in 2 cases. Key parameters including operation time, intraoperative blood loss, complications, and fracture healing time were recorded. At last follow-up, hip joint function was evaluated using the Harris hip score and the Thompson-Epstein evaluation criteria. Results:The operation time ranged from 100 to 140 minutes, with an average of 119.5 minutes. The intraoperative blood loss ranged from 20 to 65 mL, with an average of 40.8 mL. No postoperative complication such as neurovascular injuries occurred, and all incisions healed by primary intention. All 13 patients were successfully followed up 9-24 months, with an average of 16 months. The fracture healing time ranged from 10 to 18 weeks, averaging 14.1 weeks. During the follow-up, no complication such as traumatic osteoarthritis, osteonecrosis of the femoral head, heterotopic ossification, or internal fixation failure was observed. At last follow-up, the Harris hip score ranged from 91 to 97, averaging 94.6. Based on the Thompson-Epstein criteria, the clinical outcomes were graded as excellent in 9 cases and good in 4 cases, with an excellent and good rate of 100%. Conclusion:For Pipkin type Ⅰ and Ⅱ femoral head fractures, all-arthroscopic fixation represents a safe and effective therapeutic strategy. The individualized selection of Herbert screws, bioabsorbable screws, or suture anchors based on the specific characteristics of the fracture fragments offers significant clinical advantages. This approach ensures minimal invasiveness, minimal disruption of the femoral head blood supply, and a low complication rate.

Aims: A strong correlation has been observed between diabetes mellitus (DM) with the pathogenesis of osteoarthritis (OA). This study aimed to elucidate the cellular and molecular mechanisms by which DM exacerbates OA, through multiomics analysis of synovium and cartilage from OA patients with type 2 DM (T2DMOA). Methods: Single-cell RNA sequencing, bulk RNA sequencing, and metabolome profiling were performed on knee cartilage and synovium from 21 patients with OA or T2DMOA to investigate the differences in transcriptional landscape, intercellular signalling networks, transcription factor regulatory patterns, and alterations in metabolic pathways. Results: Single-cell profiling of synovium-cartilage tissues revealed distinct pathological alterations in T2DMOA patients compared to non-diabetic OA controls. In the T2DMOA synovium, we observed significantly enhanced differentiation of sublining fibroblasts into lining fibroblasts, along with enriched pathways governing energy metabolism, vasculogenesis, and cell proliferation. For cell-cell communication between cartilage and synovium, hepatocyte growth factor (HGF)-mesenchymal-epithelial transition factor (MET), fibroblast growth factors (FGF) 10-FGF receptor 1 (FGFR1), and nicotinamide phosphoribosyl transferase (NAMPT)-(integrin subunit alpha 5 (ITGA5) + integrin subunit beta 1 (ITGB1)) from synoviocytes to chondrocytes, as well as angiopoietin-like protein 2 (ANGPTL2)-toll-like receptor 4 (TLR4) and ANGPTL2-(ITGA5 + IGTB1) from chondrocytes to synoviocytes, showed a notable increase in T2DMOA patients. Conversely, T2DMOA cartilage exhibited a pronounced suppression of metabolic activity, particularly in amino acid transport and glycan biosynthesis. Additionally, transcription factors of synoviocytes and chondrocytes were clustered into five and four major modules, respectively, with various functions. Conclusion: Our findings define a diabetes-specific OA phenotype, characterized by aberrant synovial fibroblast activation, dysregulated synovium-cartilage crosstalk, and impaired cartilage metabolism. This integrated view establishes T2DMOA as a unique metabolic-subtype of OA, driven by disrupted intercellular communication and metabolic reprogramming. Cite this article: Bone Joint Res 2026;15(6):584–600.

Prednisone is commonly used to control autoimmune and inflammatory diseases during pregnancy, but its potential effects on fetal skeletal development remain incompletely characterized. This study investigated the dose- and exposure-period-related effects of prenatal prednisone exposure (PPE) on fetal long-bone development in mice and explored the cellular mechanism involving chondrocyte-to-osteoblast transdifferentiation. Pregnant mice received prednisone at 0.25 or 1.0 mg/kg/day throughout gestation or 1.0 mg/kg/day during defined gestational periods. Fetal femurs were collected on gestational day 18 (GD18) for histomorphometric, histochemical, and immunofluorescence analyses. PPE shortened fetal femurs, reduced the primary ossification center (POC), narrowed the proliferative zone (PZ), and expanded the hypertrophic zone (HZ), with generally greater changes after higher-dose or longer-duration exposure. Quantitative cellular analysis demonstrated fewer proliferative chondrocytes, accumulation of hypertrophic chondrocytes, and reduced osteoblast numbers within the POC. Consistently, PPE decreased SRY-box transcription factor 9 (SOX9) and runt-related transcription factor 2 (RUNX2) protein expression while increasing type X collagen (COL10) expression. The accumulation of hypertrophic chondrocytes, together with insufficient osteoblast formation, indicates that PPE impairs the cellular transition from hypertrophic chondrocytes to osteoblasts. Collectively, impaired chondrocyte-to-osteoblast transdifferentiation represents a cellular mechanism contributing to PPE-induced fetal long-bone dysplasia.

Integrative genetic approaches can combine Mendelian randomization, variant annotation, pathway-level interpretation, and exploratory cellular measurements to investigate complex disease mechanisms. However, the relationship between genetic liability to insulin medication use and osteoarthritis (OA) remains incompletely characterized GWAS summary statistics for insulin medication use were obtained from the UK Biobank insulin medication-use dataset. Insulin therapy-associated SNPs were selected using a suggestive significance threshold (p < 5 × 10-6) and clumped (r2 < 0.001, 10,000 kb). Two-sample Mendelian randomization (MR) was performed using the inverse-variance weighted (IVW) method as the primary analysis, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses included Cochran's Q test, MR-Egger intercept, MR-PRESSO global test, and leave-one-out analysis. Insulin-associated genetic variants were functionally annotated using Ensembl VEP, ANNOVAR, FUMA, and Open Targets Genetics, and mapped genes were subjected to exploratory GO biological process and KEGG pathway enrichment analysis. A separate exploratory cellular experiment was performed in the immortalized human chondrocyte cell line TC28a2 using insulin treatment followed by Safranin O staining, RT-qPCR, western blotting, and ELISA. After SNP selection and harmonization, 56 instrument-outcome associations were retained, comprising 29 SNPs in the ukb-a-106 OA dataset and 27 SNPs in the ukb-b-14,486 OA dataset. IVW analysis suggested an association between genetic liability to insulin medication use and increased OA susceptibility (ukb-a-106: OR = 1.195, 95% CI = 1.062-1.344, p = 0.003; ukb-b-14,486: OR = 1.179, 95% CI = 1.066-1.305, p = 0.001). Sensitivity tests did not detect statistically significant heterogeneity or directional horizontal pleiotropy; however, indication-related genetic liability, correlated pleiotropy, and biologically plausible alternative pathways remain important concerns. Seven mapped genes were used for exploratory enrichment analysis. In a separate exploratory cellular experiment, insulin-treated TC28a2 cells under high-glucose conditions showed reduced proteoglycan staining, increased matrix-degrading and inflammatory markers, and reduced NRF2 protein expression. This study suggests an association between genetic liability to insulin medication use and OA susceptibility and provides exploratory functional-annotation and cellular observations for further investigation.

Painful muscle spasms are characterized by sudden onset of involuntary muscle contractions accompanying severe pain. The occurrence of painful muscle spasms after total hip arthroplasty (THA) is extremely rare in clinical practice. We report a case in which a patient developed painful muscle spasms after THA, and symptoms were controlled by oxcarbazepine.

Background: Posterior cruciate ligament (PCL) injury is a relatively common musculoskeletal condition. However, there is currently a lack of consensus on decision-making, treatment and postoperative management for such injuries. Objectives: To use the modified Delphi method to reach expert consensus on the management of PCL injury. Methods: A literature search of PubMed, Cochrane Library, Embase, and Web of Science for articles up to 17 October 2024, to support the development of recommendation statements. An Expert Panel of 90 experienced clinicians from orthopaedics and sports medicine participated in a two-round Delphi process. Each statement was evaluated in two parts: the first part assessed content appropriateness (score of 7-9 indicating appropriateness and 4-6 indicating possible appropriateness), while the second part assessed agreement (score of 5-9 indicating agreement). Results: The panel members developed 11 statements using the Delphi process, addressing the following topics: (1) clinical decision-making, (2) treatment, and (3) postoperative management about PCL injuries. The final consensus was reached on 11 statements and we eventually translated these statements into a corresponding table of expert recommendations. Conclusion: Consensus was reached on 11 statements regarding three aspects of PCL injury management. These findings provide a foundation for developing evidence-based guidelines that can enhance clinical decision-making, improve treatment strategies, and optimize postoperative care for patients with PCL injuries.

BACKGROUND:Posterior cruciate ligament (PCL) injury is a relatively common musculoskeletal condition. However, there is currently a lack of consensus on decision-making, treatment and postoperative management for such injuries. OBJECTIVES:To use the modified Delphi method to reach expert consensus on the management of PCL injury. METHODS:A literature search of PubMed, Cochrane Library, Embase, and Web of Science for articles up to 17 October 2024, to support the development of recommendation statements. An Expert Panel of 90 experienced clinicians from orthopedics and sports medicine participated in a two-round Delphi process. Each statement was evaluated in two parts: the first part assessed content appropriateness (score of 7-9 indicating appropriateness and 4-6 indicating possible appropriateness), while the second part assessed agreement (score of 5-9 indicating agreement). RESULTS:The panel members developed 11 statements using the Delphi process, addressing the following topics: (1) clinical decision-making, (2) treatment, and (3) postoperative management about PCL injuries. The final consensus was reached on 11 statements and we eventually translated these statements into a corresponding table of expert recommendations. CONCLUSION:Consensus was reached on 11 statements regarding three aspects of PCL injury management. These findings provide a foundation for developing evidence-based guidelines that can enhance clinical decision-making, improve treatment strategies, and optimize postoperative care for patients with PCL injuries.

As a synthetic glucocorticoid, prednisone has been widely used in autoimmune diseases, recurrent abortion and asthma during pregnancy. Although studies suggested that glucocorticoid exposure during pregnancy have developmental toxicity, systematic research on the characteristics of the developmental toxicity of prednisone is lacking. This study intends to construct embryonic prednisone exposure (EPE) model to observe its bone developmental toxicity characteristics of prednisone and explore the mechanism. The results showed that EPE can shortened body and head length, reduced eye and head area, decreased operculum mineralization area, reduced mineralized vertebrae number, shortened ceratohyal and palatoquadrate cartilage length, and decreased expression of key osteogenic differentiation and cartilage development genes. The toxicity to osteogenesis is more severe than chondrogenesis. The toxicity caused by exposure in the middle and terminal stages of embryogenesis is more serious and shows a concentration-effect relationship. We confirmed that Gr/Hdac6 signaling activation mediates prednisone-induced inhibition of osteoblast differentiation by epigenetically regulating the Postnb/Wnt/β-catenin signaling pathway. The results of this study systematically demonstrate the characteristics of prednisone-induced systemic, bone, and cartilage developmental toxicity, and clarify the epigenetic mechanism of its osteogenic developmental toxicity. This provides theoretical and experimental evidence for the safe use of prednisone during pregnancy and the determination of early monitoring targets for bone developmental toxicity.

Amoxicillin, a beta-lactam antibiotic, is the preferred treatment for numerous common infections during pregnancy. However, it has been identified as an emerging environmental pollutant. Clinical and animal studies indicate that prenatal exposure to amoxicillin may pose fetal developmental toxicity risks. In view of the environmental exposure and clinical application status of amoxicillin, this study investigated the effects of amoxicillin exposure at different concentrations and embryonic stages on the overall development of zebrafish embryos, as well as the development of cartilage and bone, and their underlying mechanisms. Our findings revealed that embryonic exposure to amoxicillin inhibited the overall, cartilage, and bone development of zebrafish in a concentration (80-400 µmol/L) and stage (0-1.5 and 1.5-3.0 dpf) dependent manner. This inhibition was manifested as reduced head and body length, decreased head and eye area, shortened palatal and ceratohyal cartilage length, and diminished operculum bone area, with these effects persisting from the larval to the juvenile stage. Notably, early exposure to amoxicillin had a more pronounced impact on zebrafish embryonic cartilage development, attributed to the inhibition of the foxo3a signaling pathway. In contrast, late exposure to amoxicillin more significantly affected zebrafish embryonic bone development, associated with the inhibition of the jak2a/stat3 signaling pathway. This study has verified the toxicity of amoxicillin to cartilage and bone development and elucidated its potential mechanisms, providing a theoretical and experimental basis for evaluating the environmental exposure risk of amoxicillin and revealing its action patterns.

Aims:Osteoarthritis (OA) is a common degenerative disease that leads to pain, disability, and reduced quality of life. Orientin exhibits considerable anti-inflammatory and antioxidative properties, but its role in chondrocyte senescence and OA progress has not yet been fully characterized. The aim of this study was to evaluate the protective effects of orientin on OA. Methods:The role of orientin in extracellular matrix (ECM) degradation, mitochondrial homeostasis, and chondrocyte senescence was investigated in vitro. Meanwhile, we used molecular docking, small molecular inhibitors, and RNA interference to screen and validate candidate proteins regulated by orientin. In an anterior cruciate ligament transection (ACLT) rat model, radiograph, micro-CT, and various histological examinations were applied to evaluate the therapeutic effects of orientin on OA. Results:We found that orientin inhibited ECM degradation and senescence-associated secretory phenotype (SASP) factor expression in interleukin (IL)-1β-treated chondrocytes. Additionally, orientin reduced the level of reactive oxygen species (ROS) and improved mitochondrial homeostasis. Furthermore, orientin suppressed IL-1β-induced activation of the nuclear factor kappa B (NF-κB) signalling pathway. We also found that orientin bound to phosphoinositide 3-kinase (PI3K) and inhibited NF-κB cascades via the PI3K/AKT pathway. In vivo, we demonstrated that orientin improved cartilage wear and reduced synovial inflammation and osteophyte in an ACLT rat model. Conclusion:Orientin improves mitochondrial homeostasis, inhibits chondrocyte senescence, and alleviates OA progress via the PI3K/AKT/NF-κB axis, which suggests that orientin is a potential effective therapeutic agent for OA.

Nicotine, ethanol, and caffeine are the most common exogenous substances in the men's living environment, but their effects on the cartilage quality in the father and offspring have not been reported. According to the average daily intake of adult men, we constructed a male rat model of paternal mixed exposure (PME) to low-dose nicotine (0.1 mg/(kg·day)), ethanol (0.5 g/(kg·day)), and caffeine (7.5 mg/(kg·day)) for 8 weeks. Then, the male rats mated with normal female rats to obtain offspring. The results showed that PME reduced the cartilage quality of paternal and offspring rats. Among them, the paternal cartilage was damaged by enhancing matrix degradation, while the offspring cartilage was damaged by reducing matrix synthesis. The cartilage damage in male offspring rats was more evident than in female offspring. It was further confirmed that differential GC regulation mechanisms were the main reasons for the intergenerational differential damage of paternal/offspring cartilage quality caused by PME. In addition, the androgen receptor (AR) and estrogen receptor beta (ERβ) mediated the sex difference of PME-induced fetal cartilage dysplasia by affecting the binding degree of GR/P300. This study provided a theoretical and experimental basis for guiding male healthy lifestyle and exploring early prevention and treatment strategies for paternal diseases.

As life expectancy among patients infected with the human immunodeficiency virus (HIV) increases, a growing number of complications have been observed. This population displays an elevated risk of ischemic necrosis of the femoral head in comparison to the general population, which may be attributed to HIV infection, antiretroviral medication use, and hormone application. Patients infected with the human immunodeficiency virus (HIV) who also have necrosis of the femoral head tend to present at an earlier age, with a rapid disease progression and a high incidence of bilateral onset. Magnetic resonance imaging (MRI) facilitates the early diagnosis of the condition, and the recommended treatment is total hip arthroplasty. Currently, the most prevalent treatment modality is total hip arthroplasty. This can effectively prevent occupational exposure when the surgery is performed in accordance with the HIV infection control guidelines. Furthermore, the surgical procedure is more time-consuming than that performed on patients without HIV. The postoperative quality of life of patients is markedly enhanced, and there are no reports of surgical complications. The precise mechanism underlying femoral head necrosis in HIV-infected patients remains unclear. Potential contributing factors have been identified, including systemic immune response, inflammatory response, local microenvironmental changes in the femoral head, and the unique anatomical structure of the femoral head, among others. A more profound comprehension of the disease’s pathogenesis may facilitate the implementation of early prevention and treatment strategies, as well as the development of alternative conservative therapeutic options. This represents a promising avenue for future research. The present article reviews the epidemiological study of HIV-infected patients with osteonecrosis of the femoral head, local changes of the femoral head, possible mechanisms of osteonecrosis of the femoral head, occupational exposure during treatment, and surgical efficacy. The aim is to provide insights that can inform the diagnosis, prevention, treatment, and mechanism of this condition.

Prenatal exposure to glucocorticoids is linked to long-term health risks in offspring, but the role of maternal gut microbiota in mediating these effects remains unclear. Here, we demonstrate that prenatal prednisone therapy (PPT) in humans and prenatal prednisone exposure (PPE) in rats result in sex-specific long bone dysplasia in offspring, including reduced peak bone mass (PBM) and heightened osteoporosis risk in female offspring. Multi-omics profiling and fecal microbiota transplantation show that PPE alters maternal gut microbiota composition and depletes the microbial metabolite daidzein (DAI). DAI deficiency suppresses Hoxd12 expression, impairs osteogenesis, and leads to PBM decline in female offspring. In bone marrow-derived mesenchymal stem cells from PPE female offspring, DAI promoted Hoxd12 expression and osteogenic differentiation. Notably, DAI supplementation restored H3K9ac levels, enhanced Hoxd12 expression, and promoted osteogenic differentiation through the ERβ/KAT6A pathway. Furthermore, maternal DAI supplementation during pregnancy prevented osteoporosis susceptibility in PPE female offspring and alleviated functional abnormalities in multiple organs, including the liver, hippocampus, ovary, and adrenal gland. In conclusion, PPE induces multiorgan dysplasia and increases disease predisposition (e.g., osteoporosis) in female offspring by disrupting maternal gut microbiota and depleting DAI. Maternal DAI supplementation provides a promising preventive strategy to counteract these adverse outcomes.

Prednisone, a synthetic glucocorticoid, is widely used in the treatment of various maternal diseases during pregnancy, such as autoimmune disorders. However, epidemiological studies suggest that prenatal prednisone treatment may lead to fetal growth restriction. Preclinical research has shown that gestational prednisone exposure (PPE) exerts developmental toxicity on multiple organs in offspring. Nevertheless, the impacts of PPE at different doses and time windows on long bone development in offspring remain unclear. This study examined the effects of prednisone (PPE) on fetal long bone development using clinically relevant dosing regimens. pregnant mice received PPE at different doses (0.25, 0.5, or 1.0 mg/kg·d) throughout gestation or at 1.0 mg/kg·d during specific gestational periods: entire gestation (GD0-18), early pregnancy (GD0-9), or mid-to-late pregnancy (GD10-18). Results demonstrated that PPE induced femoral dysplasia in both male and female fetal mice, manifested as reduced femoral length, delayed growth plate differentiation, and impaired primary ossification center formation. These abnormalities were concurrent with suppressed development of osteoblasts, osteoclasts, and endothelial cells. Furthermore, PPE inhibited long bone development in a dose-dependent manner, with the most pronounced effects observed during mid-to-late gestation. In vitro experiments confirmed that prednisone, converted to prednisolone, suppresses the Sost/Wnt/β-catenin signaling pathway. In conclusion, PPE inhibits long bone development in male and female fetal mice, predominantly at high doses and during mid-late pregnancy, without significant sexual dimorphism. Mechanistically, suppression of the Sost/Wnt/β-catenin signaling pathway may mediate the long bone developmental toxicity of PPE. This study enhances our understanding of the risks associated with gestational prednisone exposure and provides theoretical and experimental evidence for guiding rational medication and effectively evaluating the long bone developmental toxicity of prednisone.

This Mendelian randomization (MR) study aimed to investigate the potential causal associations between modifiable lifestyle/metabolic factors and the risk of hallux valgus (HV), a common foot deformity characterized by lateral deviation of the great toe. We selected independent genetic variants strongly associated with five lifestyle factors (lifetime smoking index, smoking initiation, alcohol consumption, coffee intake, and vigorous physical activity) and ten metabolic traits (body mass index (BMI), waist-hip ratio, type 2 diabetes, systolic/diastolic blood pressure, high/low-density lipoprotein, apolipoprotein A-1/B, and triglycerides) as instrumental variables through rigorous quality control (R 2 < 0.001, p ≤ 5 × 10-8). Genetic association estimates were derived from large-scale genome-wide association studies (GWAS) in the UK Biobank, GSCAN consortium, and FinnGen cohorts. A two-sample MR approach was used to assess causal effects on HV risk. Genetically predicted smoking initiation (odds ratio (OR) 1.23, 95% confidence interval (CI) [1.06-1.43], p = 0.00784), lifetime smoking (OR 1.79, 95% CI [1.27-2.51] p = 0.000832), and higher BMI (OR 1.17, 95% CI [1.06-1.29] p = 0.00164) were significantly associated with increased HV risk. No significant associations were found for other tested factors. This study provides genetic evidence supporting a causal role of smoking and BMI in the development of HV. These findings highlight modifiable risk factors for targeted prevention strategies in HV management.

Abstract Background Rifaquizinone (RFQ, TNP-2092) is a novel multitargeting drug conjugate in development for the treatment of serious or life-threatening bacterial infections including those caused by gram-positive pathogens that have developed or acquired resistance to commonly used antibiotics and those associated with medical devices. RFQ exerts its antibacterial activity by inhibiting RNA polymerase, DNA gyrase, and topoisomerase IV. The current studies were conducted to evaluate the therapeutic efficacy of RFQ following intra-articular (IA) administration in two rodent prosthetic joint infections models with S. aureus. Methods Female C57BL/6 mice and male Wistar rats were used. Following surgical insertion of a metal wire into the femoral canal, the surgical site was inoculated with approximately 7 log10 CFU of an S. aureus strain. RFQ and control drugs were IA administered into mice and rats starting 7 days post-surgery once daily for 7 and 14 days, respectively. At 24 hours after the last dose, the wire and femur were aseptically removed and processed for bacterial titers. Results In the mice, mean wire and femur counts for the untreated controls at the end of the study were 4.77 and 6.88 log10 CFU, respectively. IA delivered RFQ resulted in mean wire and femur counts that were 2.50-2.72 log10 CFU and 1.71-3.42 log10 CFU lower than the untreated controls, respectively (p ≤ 0.0001). In the rats, mean wire and femur counts for the untreated controls at the end of the study were 6.02 and 5.06 log10 CFU, respectively. RFQ resulted in mean wire and femur counts that were 3.32-5.02 log10 CFU and 1.21-1.96 log10 CFU lower than the untreated controls, respectively (p ≤ 0.01). RFQ administration in the rats resulted in reduced knee swelling and expression of systemic inflammatory markers, a decrease in signs of femoral osteomyelitis and decreased biofilm formation. Doses of RFQ in both species were statistically more effective than vancomycin in reducing the bacterial burden. Conclusion The results of these studies indicate that IA injection of RFQ is effective in treating infections related to orthopedic implants. The studies serve as a basis for the use of RFQ in orthopedic practice and the treatment of serious implant-associated infections. Disclosures William J Weiss, MS, TenNor Therapeutics (Suzhou) Ltd: Investigator Mark E Pulse, MS, TenNor Therapeutics (Suzhou) Ltd: Investigator Phung Nguyen, BS, TenNor Therapeutics (Suzhou) Ltd: Investigator David Valtierra, Master, TenNor Therapeutics (Suzhou) Ltd: Investigator Kelly Peterson, PhD, TenNor Therapeutics (Suzhou) Ltd: Investigator Adaeze Ogbonna, Bachelor, TenNor Therapeutics (Suzhou) Ltd: Investigator Lane Beeman, Bachelor, TenNor Therapeutics (Suzhou) Ltd: Investigator Tianyu Dai, PhD, TenNor Therapeutics (Suzhou) Ltd: Investigator Liaobin Chen, PhD, TenNor Therapeutics (Suzhou) Ltd: Investigator Huan Wang, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee Zhenkun Ma, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee

Previous studies reported that preserving the anterior cruciate ligament (ACL) remnants following ACL rupture during reconstruction surgery could promote graft healing. However, the temporal proteomic expression of ACL remnants remains unclear. Based on previous reports, we have redefined the initial 6 weeks following ACL rupture as the acute phase and the subsequent 6 weeks to 6 months as the subacute phase. High-throughput proteomic sequencing on ACL remnants from the two groups was utilized. Our study unveiled a total of 381 differential expression proteins (DEPs), with 136 upregulated and 245 downregulated proteins in the acute phase. By intersecting these findings with secretory protein databases, we identified 26 upregulated secretory proteins and 19 downregulated in the acute phase. The upregulation of MMP9 and VTN and the downregulation of COL1A1 and POSTN in the acute phase were further confirmed by immunohistochemistry. These findings suggest that the elevated expression of secretory proteins in the acute phase may play crucial roles in promoting cell proliferation, angiogenesis, and tissue repair of the graft. This study not only enhances our understanding of repair mechanisms in ACL remnant preservation but also provides a theoretical foundation for guiding rational clinical surgical timing.