A natural agent, 5-deoxycajanin, mitigates estrogen-deficiency bone loss via modulating osteoclast-osteoblast homeostasis.

Hyperactive osteoclasts and hypoactive osteoblasts usually result in osteolytic conditions such as estrogen-deficiency bone loss. Few natural compounds that both attenuating bone resorption and enhancing bone formation could exert effects on this imbalance. 5-Deoxycajanin (5-D), an isoflavonoid extracted from Cajan leaf with estrogen-like properties, were found to have beneficial pharmacological effects on rebalancing the activities of osteoclasts and osteoblasts. This study revealed that 5-D at the same concentration could inhibit osteoclastogenesis of BMMs and promoted osteoblast differentiation of BMSCs. 5-D not only attenuated the fluorescent formation of RANKL-induced F-actin belts and NFATc1, but also activated ALP and RUNX2 expressions. As to downstream factor expressions, 5-D could block osteoclast-specific genes and proteins including NFATc1 and CTSK, while increased osteogenic genes and proteins including OPG and OCN, as confirmed by Real-time PCR and Western Blotting. Additionally, the network pharmacology and molecular docking identified the involvement of 5-D in the MIF and MAPK signaling pathways and the stable binding between 5-D and MAPK2K1. Further Western blot studies showed that 5-D decreased the phosphorylation of p38 and ERK in osteoclasts, but promoted these phosphorylations in osteoblasts. In a female C57BL/6J mouse model of estrogen deficiency-induced bone loss, 5-D demonstrated efficacy in enhancing BMD through attenuating osteoclast activities and promoting osteogenesis. These results underscore the potential application of 5-D on treating osteolysis resulting from hyperactive osteoclasts and hypoactive osteoblasts, shedding light on modulating osteoclast-osteoblast homeostasis.

Therapeutic potential of a prominent dihydroxyflavanone pinocembrin for osteolytic bone disease: In vitro and in vivo evidence.

Background/objective: As the pivotal cellular mediators of bone resorption and pathological bone remodeling, osteoclasts have emerged as a prominent target for anti-resorptive interventions. Pinocembrin (PIN), a predominant flavonoid found in damiana, honey, fingerroot, and propolis, has been recognized for its potential therapeutic effects in osteolysis. The purpose of our project is to investigate the potential of PIN to prevent bone resorption in ovariectomized (OVX) mice by suppressing osteoclast production through its underlying mechanisms. Methods: The study commenced by employing protein-ligand molecular docking to ascertain the specific interaction between PIN and nuclear factor-κB (NF-κB) ligand (RANKL). Subsequently, PIN was introduced to bone marrow macrophages (BMMs) under the stimulation of RANKL. The impact of PIN on osteoclastic activity was assessed through the utilization of a positive TRAcP staining kit and a hydroxyapatite resorption assay. Furthermore, the study investigated the generation of reactive oxygen species (ROS) in osteoclasts induced by RANKL using H2DCFDA. To delve deeper into the underlying mechanisms, molecular cascades triggered by RANKL, including NF-κB, ROS, calcium oscillations, and NFATc1-mediated signaling pathways, were explored using Luciferase gene report, western blot analysis, and quantitative real-time polymerase chain reaction. Moreover, an estrogen-deficient osteoporosis murine model was established to evaluate the therapeutic effects of PIN in vivo. Results: In this study, we elucidated the profound inhibitory effects of PIN on osteoclastogenesis and bone resorption, achieved through repression of NF-κB and NFATc1-mediated signaling pathways. Notably, PIN also exhibited potent anti-oxidative properties by mitigating RANKL-induced ROS generation and augmenting activities of ROS-scavenging enzymes, ultimately leading to a reduction in intracellular ROS levels. Moreover, PIN effectively abrogated the expression of osteoclast-specific marker genes (Acp5, Cathepsin K, Atp6v0d2, Nfatc1, c-fos, and Mmp9), further underscoring its inhibitory impact on osteoclast differentiation and function. Additionally, employing an in vivo mouse model, we demonstrated that PIN effectively prevented osteoclast-induced bone loss resultant from estrogen deficiency. Conclusion: Our findings highlight the potent inhibitory effects of PIN on osteoclastogenesis, bone resorption, and RANKL-induced signaling pathways, thereby establishing PIN as a promising therapeutic candidate for the prevention and management of osteolytic bone diseases. The translational potential of this article: PIN serves as a promising therapeutic agent for the prevention and management of osteolytic bone diseases and holds promise for future clinical applications in addressing conditions characterized by excessive bone resorption. PIN is a natural compound found in various sources, including damiana, honey, fingerroot, and propolis. Its widespread availability and potential for therapeutic use make it an attractive candidate for further investigation and development as a clinical intervention.

The Preserved Thickness Ratio of the Femoral Head Contributes to the Collapse Predictor of Osteonecrosis.

OBJECTIVES: The collapse of femoral head is a serious symptom of osteonecrosis of the femoral head (ONFH), resulting in hip pain and deformity. However, it is hardly possible to reestablish the femoral head nonoperatively once the collapse happens. Predicting femoral head collapse is of great value for the prognosis of ONFH. This study aimed to develop a new method to quantify the preserved thickness of femoral head and to assess its diagnostic contribution in predicting femoral head collapse on plain radiographs. METHODS: This was a single-center retrospective study. A total of 101 hips (85 patients) with ARCO stage II from January 2008 to December 2016 were included in this study. The preserved thickness was measured on standard anteroposterior (AP) and frog-leg (FL) radiographs. The anteroposterior view's preserved thickness ratio (APTR) and the frog-leg view's preserved thickness ratio (FPTR) were calculated to show the preserved thickness ratio of the femoral head anteriorly and laterally. Univariate and multivariate logistic regression was performed to determine the risk factors for collapse. Sensitivity, specificity, and cut-off values for APTR and FPTR were determined by the receiver operating characteristic (ROC) curve analysis. Kaplan-Meier (K-M) analysis was applied to determine femoral head survival in ONFH patients. RESULTS: The mean age of the 27 females and 58 males was 38.93 years old. The mean follow-up time was 74.62 (36-124) months in the non-collapse group and 18.66 (3-82) months in the collapse group. Femoral head collapse was observed in 62 hips during the follow-up period. Logistic regression analysis and ROC results showed that APTR <24.79% and FPTR <10.62% were significantly correlated with femoral head collapse. The Kaplan-Meier survival curve suggested that the overall survival rate of APTR ≥24.79% was 68.2% at 5 and 10 years and FPTR ≥10.62% was 71.63% at 5 and 10 years. At the last follow-up, 26 hips had collapse on the anterior side of the femoral head, 12 hips occurred on the lateral side, and 24 hips happened to collapse on both anterior and lateral sides. CONCLUSION: Femoral head collapse predominantly occurred anteriorly rather than laterally in ONFH patients. The measurements of APTR and FPTR have noticeable implications for the prediction of femoral head collapse, and contribute to the selection of treatment options for ONFH patients with types B and C1 according to the JIC classification.

A novel Glycyrrhiza glabra extract liquiritin targeting NFATc1 activity and ROS levels to counteract ovariectomy-induced osteoporosis and bone loss in murine model.

Osteoporosis, a prevalent osteolytic condition worldwide, necessitates effective strategies to inhibit excessive bone resorption by curbing osteoclast hyperactivation. Liquiritin (LIQ), an flavanone derivative employed in acute lung injury and rheumatoid arthritis treatment, possesses an unclear role in addressing excessive bone resorption. In this investigation, we found that LIQ demonstrates the ability to inhibit osteoclast formation and the bone-resorbing activity induced by RANKL. At a specific concentration, LIQ significantly attenuated NF-κB-Luc activity induced by RANKL and curtailed NF-κB activation in RANKL-stimulated RAW264.7 cells, resulting in reduced IκB-α breakdown and diminished nuclear NF-κB levels. Furthermore, LIQ markedly inhibited RANKL-induced NFATc1 activation, as evidenced by diminished NFATc1 luciferase activity, reduced NFATc1 mRNA levels, and decreased nuclear NFATc1 protein levels. Subsequent experiments demonstrated that LIQ effectively restrained the RANKL-induced elevation of intracellular calcium as well as reactive oxygen species. Additionally, LIQ exhibited a downregulating effect on the expression of osteoclast-specific genes, which include Acp5, Cathepsin K, Atp6v0d2, Nfatc1, c-Fos, and Mmp9. Notably, our findings revealed the potential of LIQ to counteract decreased bone density in mice that underwent ovariectomy. Collectively, the data indicate that LIQ impedes osteoclast formation triggered by RANKL and the subsequent reduction in bone mass by mitigating ROS levels and suppressing the Ca2+/MAPK-NFATc1 signaling pathway, suggesting its promising candidacy as a therapeutic agent for RANKL-mediated osteoporosis.

Dragon blood resin ameliorates steroid-induced osteonecrosis of femoral head through osteoclastic pathways.

Objective: Dragon's Blood resin (DBR) is a traditional medicinal substance renowned for its diverse pharmacological effects, which consists of potent anti-inflammatory, antioxidant and angiogenic properties. This study aimed to elucidate its therapeutic mechanism in alleviating steroid-induced osteonecrosis of the femoral head (SIONFH). Methods: Techniques such as SPR and LC-MS were employed to identify and analyze the target proteins of DBR in bone marrow macrophages (BMMs). In vitro, BMMs were treated with RANKL and DBR, and TRAcP staining and actin belt staining were utilized to assess osteoclast activity. The inhibitory effects and underlying mechanisms of DBR on osteoclastogenesis and reactive oxygen species (ROS) generation were determined using real-time PCR, western blotting and immunofluorescence staining. An in vivo SIONFH rat model was set up to assess the curative impacts of DBR using micro-CT scanning and pathological staining. Results: Bioinformatic tools revealed a pivotal role of osteoclast differentiation in SIONFH. Proteomic analysis identified 164 proteins binding in BMMs. In vitro assessments demonstrated that DBR hindered osteoclastogenesis by modulating the expression of specific genes and proteins, along with antioxidant proteins including TRX1 and Glutathione Reductase. Notably, the resin effectively inhibited the expression of crucial proteins, such as the phosphorylation of JNK and the nuclear localization of p65 within the TRAF6/JNK and NFκB signaling pathways. In vivo experiments further confirmed that DBR mitigated the onset of SIONFH in rats by curbing osteoclast and ROS activities. Conclusion: These findings underscore the potential of Dragon's Blood as an effective administration for early-stage SIONFH, shedding light on its therapeutic influence on ROS-mediated osteoclastic signaling pathways.

Lateral classification system predicts the collapse of JIC type C1 nontraumatic osteonecrosis of the femoral head: a retrospective study.

PURPOSES: The aim of this study was to construct a lateral classification system for nontraumatic osteonecrosis of femoral head (NONFH) through three-dimensional reconstruction of the necrotic area to assist in evaluating the prognosis of patients with JIC type C1. METHODS: Retrospective analysis of patients with JIC type C1 NONFH from January 2018 to December 2020. All patients were followed up for more than 3.5 years. The patients were divided into collapse group and non-collapse group according to whether the femoral head collapsed during the follow-up.Lateral classification system for femoral head necrosis is constructed through three-dimensional reconstruction of the necrotic area.Comparison of lateral classification system,midsagittal necrosis angle(MNA)and general data between the two groups.Furthermore, ROC curve analysis and survival analysis were performed. RESULTS: 318 patients were included in this study.There was a significant difference between the two groups in the lateral classification system (P < 0.05). In addition, the MNA in the collapsed group was significantly greater than that in the non-collapse group(P < 0.05). As revealed by the results of ROC analysis, the cutoff point of MNA was 104.5° (P < 0.05).According to the survivorship analysis, the mean survival time of the hips of patients with MNA less than 104.5°was greater than that of patients with MNA over 104.5° (P < 0.05). The survival rates of 3.5 years femoral head were 45.8%, 33.7%, 14.8%, 93.0%, and 100% for lateral classification system 1, 2, 3, 4, and 5, respectively. CONCLUSION: Necrosis involving the anterior aspect of the femoral head is an important risk factor for collapse. The Lateral classification system can effectively predict the femoral head collapse in JIC C1 type NONFH patients, supplementing the deficiency of JIC classification in evaluating the front of the femoral head.

Identification and validation of ferroptosis-related biomarkers in steroid-induced osteonecrosis of the femoral head.

OBJECTIVES: Treatment of steroid-induced osteonecrosis of the femoral head (SIONFH) is challenging. Due to the limited understanding of its molecular mechanisms, investigating the potential mechanisms of ferroptosis will shed light on SIONFH and provide directions for treating this disease. METHODS: The GSE123568 dataset was utilized to apply various bioinformatics methodologies to identify ferroptosis-related hub genes (FRHGs). Subsequently, the importance of these genes and the reliability of the results were confirmed using protein data-independent acquisition (DIA) and cell experiments. Finally, we assessed the correlation between FRHG expression and immune cell infiltration. RESULTS: Thirty-one hub genes were identified and validated by constructing a protein-protein interaction network and subsequent screening using experimentally determined interactions. These 31 hub genes were enriched in immunity, the AMPK signaling pathway, and the Toll-like receptor signaling pathway. Next, we identified a diagnostic marker comprising two ferroptosis-related genes, NCF2 and SLC2A1. The differential expression of these two genes in healthy and necrotic regions was confirmed by protein DIA analysis. Cell experiments verified the link between FRHGs and ferroptosis and preliminarily explored the potential mechanism of the antioxidant vitexin in promoting osteogenic differentiation in cells. The diagnostic efficiency of these two markers was confirmed by receiver operating characteristic curve (ROC) curves, yielding an area under the curve of 1.0. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated enrichment of FRHGs in the superoxide anion and HIF-1 signaling pathways. A significant correlation was observed between FRHGs and various immune cell populations. CONCLUSION: NCF2 and SLC2A1 are promising ferroptosis-related diagnostic biomarkers of SIONFH. Concurrently, we embarked on a preliminary investigation to elucidate the potential mechanism underlying the promotion of osteogenic differentiation by the antioxidant vitexin. Moreover, these biomarkers are associated with distinct immune cell populations.

Dihydrotanshinone I attenuates estrogen-deficiency bone loss through RANKL-stimulated NF-κB, ERK and NFATc1 signaling pathways.

Postmenopausal osteoporosis, a chronic condition that predominantly affects postmenopausal women, presents a significant impediment to their overall well-being. The condition arises from estrogen deficiency, leading to enhanced osteoclast activity. Salvia miltiorrhiza, a well-established Chinese herbal medicine with a history of clinical use for osteoporosis treatment, contains diverse active constituents that have shown inhibitory effects on osteoclast formation and bone loss. Dihydrotanshinone I (DTI), a phenanthrenonequinone compound derived from the root of Salvia miltiorrhiza, has been identified as a potential therapeutic agent, although its mechanism of action on osteoclasts remains elusive. In this study, we aimed to elucidate the inhibitory potential of DTI on RANKL-induced osteoclastogenesis. We observed the ability of DTI to effectively impede the expression of key osteoclast-specific genes and proteins, as assessed by Real-time PCR and Western Blotting analyses. Mechanistically, DTI exerted its inhibitory effects on osteoclast formation by modulating critical signaling pathways including NF-κB, ERK, and calcium ion signaling. Notably, DTI intervention disrupted the nuclear translocation and subsequent transcriptional activity of the NFATc1, thus providing mechanistic insights into its inhibitory role in osteoclastogenesis. To further assess the therapeutic potential of DTI, we employed an ovariectomized osteoporosis animal model to examine its impact on bone loss. Encouragingly, DTI demonstrated efficacy in mitigating bone loss induced by estrogen deficiency. In conclusion, our investigation elucidates the ability of DTI to regulate multiple signaling pathways activated by RANKL, leading to the inhibition of osteoclast formation and prevention of estrogen-deficiency osteoporosis. Consequently, DTI emerges as a promising candidate for the treatment of osteoporosis.

Fibula allograft with cannulated screw fixation versus ordinary cannulated screw fixation for femoral neck fractures: a 10-year retrospective comparative study.

BACKGROUND: For femoral neck fractures in young and middle-aged patients, both fibula allograft with cannulated screw fixation and ordinary cannulated screw fixation are clinically effective treatments. However, for unstable femoral neck fractures, ordinary cannulated screw fixation is characterized by a high risk of postoperative complications and a high rate of mechanical failure after internal fixation. For this study, we systematically compared the long-term efficacy and postoperative complications of these two procedures. METHODS: A total of 156 subjects diagnosed as femoral neck fractures participated in our study. Subjects in the combination group underwent fibula allograft with cannulated screw fixation (n = 76), and those in the control group were treated with ordinary cannulated screw fixation (n = 80). Baseline characteristics, perioperative outcomes, Harris hip score (HHS) and EuroQoL five-dimension questionnaire (EQ-5D); and the incidence of postoperative and bone healing complications in the two groups were recorded and compared. RESULTS: The average follow-up time was more than 10 years. Intra-operative blood loss significantly increased in the combination group compared with the control group (P < 0.05). There were significantly improved performances in healing time, the time course of recovery of full-weight-bearing stepping, HHS and EQ-5D scores in the combination group compared with the control group (P < 0.05). Besides, the incidence rates of femoral head necrosis, nonunion, femoral neck shortening and total hip replacement were significantly lower in the combination group than those in the control group (P < 0.05). CONCLUSION: Fibula allograft with cannulated screw fixation shows a better long-term therapeutic effect than ordinary cannulated screw fixation for femoral neck fractures in young and middle-aged patients. Patients receiving the combination strategy have faster and high-quality functional recovery after femoral neck fractures and a lower incidence rate of postoperative complications.

Evaluation of the predictive values of collapse and necrotic lesion boundary for osteonecrosis of the femoral head prognosis.

Objective: Osteonecrosis of the femoral head (ONFH) is a disabling and intractable orthopedic disease largely affecting young and middle-aged groups. Current standard of treatment relies on the collapse of femoral head as a predictor for prognosis. However, a wide range of variability in repair potentials is observed in patients with femoral head collapse. Therefore, the present study aimed to evaluate the accuracy of femoral head collapse as a predictor and to propose the necrotic lesion boundary as a novel yet reliable measure for ONFH prognosis. Methods: A retrospective cross-sectional study was conducted at the First Affiliated Hospital of Guangzhou University of Chinese Medicine, 203 hips with ONFH from 134 patients were included. The occurrences and progression of femoral head collapse were recorded. Necrosis lesion boundary was quantified and classified for each case based on anteroposterior view intact ratio (APIR) and the frog-leg view intact ratio (FLIR) as independent variables. Dependent variables were defined as progressive collapse or terminal collapse for Association Research Circulation Osseous (ARCO) stage II and III respectively. Logistic regression analysis, Receiver Operating Characteristic (ROC) curve and Kaplan-Meier (K-M) survival analysis was performed and results were interpreted. Results: Out of the 106 hips in ARCO stage II, 31 hips collapsed with further progression, while 75 hips had no collapse or collapse with repair of the necrotic areas. Out of the 97 hips in ARCO stage IIIA, the collapse continued to progress in 58 hips while the necrotic areas were repaired in 39 hips. Logistic regression analysis demonstrated that both APIR and FLIR, were independent risk factors. Further ROC curve analysis indicated that the cutoff values of APIR and FLIR could be considered as indications for evaluating the prognosis of ONFH. Contrary to the traditional view of poor prognosis after femoral head collapse, K-M survival analysis demonstrated a high value of APIR and FLIR for ONFH prognosis. Conclusion: The present study found that the occurrence of collapse is an oversimplified predictor for ONFH prognosis. The collapse of the femoral head in ONFH does not predict a poor prognosis. The necrosis lesion boundary has a high value in predicting ONFH prognosis and informing clinical treatment strategies.

Supercritical fluid coating of flavonoids on excipients enhances drug release and antioxidant activity.

Supercritical anti-solvent fluidized bed (SAS-FB) technology can be applied to reduce particle size, prevent particle aggregation, and improve the dissolution and bioavailability of poorly soluble drugs. In this work, drug-loaded microparticles of three similar structures, the flavonoids luteolin (LUT), naringenin (NGR), and dihydromyricetin (DMY) were prepared using SAS-FB technology, to explore its effect on the coating of flavonoid particles. Operating temperature, pressure, carrier, solvent, and concentration of drug solution were investigated for their effects on the yield and dissolution of flavonoid particles. The results showed that temperature, pressure, carrier, and drug solution concentration have a large effect on yield. Within the study range, low supercritical CO2 density at higher temperature and lower pressure, a larger surface area carrier, and moderate drug solution concentration led to a higher yield. The effect of the solvent on the yield of flavonoids is a result of multiple factors. Scanning electron microscopy (SEM) images showed that the drug-loaded particles prepared from different carriers and solvents have different precipitations pattern on the carrier surface, and their particle sizes were smaller than unprocessed particles and those prepared by the SAS process. Fluorescence microscopy (FM) results showed that the flavonoids were uniformly coated on the carrier. X-ray powder diffraction (XRPD) results showed that the crystalline morphology of SAS-FB particles remained unchanged after the SAS-FB process, although the diffraction peak intensity decreased. The cumulative dissolution of SAS-FB particles was more than four times faster in the first 5 min than that of the unprocessed flavonoids. The antioxidant activity of SAS-FB processed LUT, NGR and DMY was 1.89-3.78 times, 4.92-10.68 times and 0.99-2.57 times higher than that of the untreated flavonoids, respectively. The approach provides a reference for the application of SAS-FB technology in flavonoids.

CircHIPK3 promotes bone microvascular endothelial cell proliferation, migration and angiogenesis by targeting miR-7 and KLF4/VEGF signaling in steroid-induced osteonecrosis of the femoral head.

BACKGROUND: Circular RNA homeodomain interacting protein kinase 3 (circHIPK3) has been implicated in facilitating angiogenesis in various conditions. However, its role in steroid-induced osteonecrosis of the femoral head (ONFH) remains unclear. OBJECTIVES: To investigate whether circHIPK3 promotes bone microvascular activity and angiogenesis by targeting miR-7 and Krüppel-like factor 4 (KLF4)/vascular endothelial growth factor (VEGF) signaling in ONFH. MATERIAL AND METHODS: Fifty patients with steroid-induced ONFH undergoing hip-preserving surgery or total hip arthroplasty were included in this study. The expression of circHIPK3, miR-7 and KLF4 was evaluated using reverse transcription polymerase chain reaction (RT-PCR) in necrotic and healthy samples of the femoral head. Bone microvascular endothelial cells (BMECs) were extracted and cultured with 0.1 mg/mL hydrocortisone to create a hormonally deficient cell model. These BMECs were then transfected with either circHIPK3 overexpressing or silencing plasmids with or without miR-7 mimics. The MTT assays were used to detect cell proliferation. Scratch assays were used to assess the migration ability of the BMECs. The tube formation was carried out using an in vitro Matrigel angiogenesis assay. Annexin V-FITC/PI and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used to assess the degree of apoptosis. Western blot assays were carried out to discern KLF4 and VEGF expression. The interactions of circHIPK3, miR-7 and KLF4 were confirmed using luciferase, RNA-binding protein immunoprecipitation (RIP), RNA pull-down, and fluorescence in situ hybridization (FISH) assays. RESULTS: The circHIPK3 and KLF4 expression was decreased, whereas miR-7 expression was increased in necrotic tissues compared to non-necrotic samples. Both circHIPK3 and KLF4 expression correlated negatively with miR-7. The overexpression of circHIPK3 promoted the proliferative, migratory and angiogenic capabilities of the BMECs, while adding an miR-7 mimic reversed these effects. At the same time, the overexpression of circHIPK3 reduced the apoptosis rate of the BMECs and increased KLF4 and VEGF protein expression, but adding an miR-7 mimic reversed these effects. The FISH, RNA pull-down, RIP, and luciferase assays revealed an interaction between circHIPK3, miR-7 and KLF4. CONCLUSIONS: The circHIPK3 promotes BMEC proliferation, migration and angiogenesis by targeting miR-7 and KLF4/VEGF signaling.

Multidisciplinary treatment of giant presacral solitary fibrous tumour: a case report and literature review.

Solitary fibrous tumours (SFTs) usually occur at the pleura. Extrapleural sites, particularly giant extrapleural solitary fibromas, are more rarely observed in the clinic, and the clinical diagnosis and treatment of this disease is a focus of attention. Herein, the case of a 43-year-old male patient with giant presacral SFT successfully treated by open surgery, and with a final diagnosis confirmed by postoperative pathology and immunohistochemistry, is reported. The patient was followed-up regularly during 5 years after surgery, with no obvious surgical complications, and no tumour recurrence noted on pelvic magnetic resonance imaging. This case provides clinical information that may help in the diagnosis and treatment of complex SFT.

Loureirin B downregulates osteoclast differentiation of bone marrow macrophages by targeting the MAPK signaling pathway.

Excessive absorption of osteoclasts will break the balance between osteoclasts and osteoblasts, leading to bone loss, decreased bone density, and increased bone fragility. We have shown that Loureirin B (LrB) can inhibit osteoclasts. In this study, we demonstrated the targeting-inhibitory mechanism of LrB acting on osteoclast precursor. Using SPR, HPLC and MALDI-TOF-MS to capture and analyze the target protein of Loureirin B in bone marrow macrophages (BMMs), we used this method to detect all target proteins that LrB acts on BMMs, and analyzed the distribution and enrichment rate of the target protein by DAVID enrichment analysis. Ledock molecular docking was used to detect the binding of LrB. We used Western Blot for verification. The target proteins of LrB acting on BMMs were Serpine1, Atp6ap1, Dvl1, Rhd, Fzd2, MAPK1, MAP2K2, MAPK3 and so on. MAPK1, MAP2K2 and MAPK3 were the most relevant. LrB treatment attenuated the expression of phosphorylated JNK and p38 kinases of the MAPK signaling pathway. Our research further confirmed that LrB affects the MAPK signaling pathway in BMMs, thereby inhibiting the differentiation of BMMs into osteoclasts. This discovery can confirm the mechanism by which LrB acts on BMMs.

Composite indices of femoral neck strength predicts the collapse of steroid-associated osteonecrosis of the femoral head: a retrospective study.

PURPOSES: The purpose of this study was to investigate the predictive effect exerted by composite indices of femoral neck strength (compressive strength index (CSI), bending strength index (BSI) and impact strength index (ISI) on the femoral head collapse in steroid-associated ONFH patients. METHODS: Nonoperative steroid-associated osteonecrosis of the femoral head (ONFH) patients from 2017 to 2019 were selected. The patients fell into the collapsed group and the non-collapsed group according to whether the femoral head collapsed. CSI, BSI and ISI were calculated. Moreover, bone turnover markers were measured. The statistical analysis was conducted on the predictive effects of composite indices of femoral neck strength and bone turnover index on ONFH collapse. RESULTS: A total of 62 patients were included. The mean CSI, BSI and ISI were significantly lower in the collapsed group than those in the non-collapsed group (P < 0.05). CSI, ISI,t-P1NP and ß-CTx were suggested as the protective risk factors for the femoral head collapse in ONFH patients. The ISI area under the curve values was 0. 878.The mean survival time of the hips of patients with ISI greater than 0.435 was greater (P < 0.05) than that of patients with ISI less than 0.435. CONCLUSION: The composite indices of femoral neck strength can predict steroid-associated ONFH femoral head collapse more effectively than the bone turnover markers. The ISI value of 0.435 is a potential cut-off value, lower than this value can predict the early collapse of steroid-associated ONFH.

Combining frog-leg lateral view may serve as a more sensitive X-ray position in monitoring collapse in osteonecrosis of the femoral head.

Load-bearing capacity of the bone structures of anterolateral weight-bearing area plays an important role in the progressive collapse in osteonecrosis of the femoral head (ONFH). The purpose of this study is to assess the efficacy of combined evaluation of anteroposterior (AP) and frog-leg lateral (FLL) view in diagnosing collapse. Between December 2016 and August 2018, a total of 478 hips from 372 patients with ONFH (268 male, 104 female; mean age 37.9 ± 11.4 years) were retrospectively evaluated. All patients received standard AP and FLL views of hip joints. Japanese Investigation Committee (JIC) classification system was used to classify necrotic lesion in AP view. Anterior necrotic lesion was evaluated by FLL view. All patients with pre-collapse ONFH underwent non-operative hip-preserving therapy. The collapse rates were calculated and compared with Kaplan-Meier survival analysis with radiological collapse as endpoints. Forty-four (44/478, 9.2%) hips were classified as type A, 65 (65/478, 13.6%) as type B, 232 (232/478, 48.5%) as type C1 and 137 (137/478, 28.7%) as type C2. Three hundred cases (300/478, 62.5%) were collapsed at the initial time point. Two hundred and twenty six (226/300, 75.3%) hips and 298 (298/300, 99.3%) hips collapse were identified with AP view and FLL view, respectively. An average follow-up of 37.0 ± 32.0 months was conducted to evaluate the occurrence of collapse in 178 pre-collapse hips. Collapses occurred in 89 hips (50.0%). Seventy-seven (77/89, 86.5%) hips were determined with AP view alone and 85 (85/89, 95.5%) hips were determined with the combination of AP and FLL views. The collapse rates at five years were reported as 0% and 0%, 16.2% and 24.3%, 58.3% and 68.1% and 100% and 100% according to AP view alone or combination of AP and FLL views for types A, B, C1 and C2, respectively. The collapse can be diagnosed more accurately by combination of AP and FLL views. Besides, JIC type A and type B ONFH can be treated with conservative hip preservation, but pre-collapse type C2 ONFH should be treated with joint-preserving surgery. Type C1 needs further study to determine which subtype has potential risk of collapse.

Efficacy of Rosuvastatin Combined with rt-PA Intravenous Thrombolytic Therapy for Elderly Acute Ischemic Stroke Patients.

Background: Acute ischemic stroke (AIS) is a fatal and disabling disease. Given the unsatisfactory results by current treatment strategies, optimizing the treatment of AIS is still an urgent problem to be solved. Objective: To determine the therapeutic efficacy of rosuvastatin (ROS) combined with thrombolytic therapy using recombinant tissue plasminogen activator (rt-PA) on senile AIS patients and analyze its effects on serum inflammatory responses and neurological function. Methods: A retrospective study was conducted on 150 senile AIS patients who visited the Longmen County People's Hospital between January 2019 and June 2021. Of them, 100 cases treated by ROS combined with rt-PA intravenous thrombolytic therapy (ivTT) were set as the observation group and the rest 50 cases receiving rt-PA alone were included in the control group. Intergroup comparisons were conducted with respect to the following parameters: neurological function (National Institutes of Health Stroke Scale, NIHSS; Scandinavian Stroke Scale, SSS), serum neuron-specific enolase (NSE) and high-sensitivity C-reactive protein (hs-CRP), therapeutic efficacy, incidence of adverse reactions, and patient satisfaction. Results: The observation group had lower NIHSS and SSS scores and serum NSE and hs-CRP than the control group. In addition, the observation group was found with a higher overall response rate, higher patient satisfaction, and fewer adverse reactions. Conclusion: ROS combined with rt-PA ivTT can better enhance the therapeutic efficacy of elderly patients with AIS, improve their neurological function, and reduce serum inflammatory responses.

Corrigendum: The Therapeutic Effect of Huo Xue Tong Luo Capsules in Association Research Circulation Osseous (ARCO) Stage II Osteonecrosis of the Femoral Head: A Clinical Study With an Average Follow-up Period of 7.95 Years.

[This corrects the article DOI: 10.3389/fphar.2021.773758.].

Clinical Outcome of Surgical Hip Dislocation Combined with Impacting Bone Grafts and Implanting Iliac Bone Flaps in the Treatment of Osteonecrosis of the Femoral Head: A Mid-term Retrospective Study.

OBJECTIVE: To report the medium-term outcomes of surgical hip dislocation (SHD) combined with impacting bone grafts and implanting iliac bone flaps in the treatment of osteonecrosis of the femoral head (ONFH) and to define the indications for this treatment. METHODS: This was a single-center retrospective study. In total, 64 patients (70 hips) with ONFH treated from January 2014 to December 2017 were included in this study. There were 51 males and 13 females aged 18-55 years with an average age of 32 years. All patients underwent surgery for SHD combined with impacting bone grafts and implanting iliac bone flaps. Preoperative and postoperative clinical outcomes were assessed. The clinical outcome was assessed using the Harris hip score (HHS) and the conversion rate of total hip arthroplasty (THA). Univariate and multivariate logistic regression analyses were performed to identify risk factors affecting the clinical outcome. Kaplan-Meier (K-M) analysis was applied to calculate the survival rate of the femoral head. RESULTS: At the last follow-up (60 ± 15.08 months), the HHS was excellent for 41 hips, good for 17 hips, fair for three hips, and poor for nine hips. All nine hips with poor HHS underwent THA, including five in the first 2 years following the index surgery and four between three and 5 years. The conversion rate of total hip arthroplasty was 12.86%. Univariate and multivariate logistic regression analyses showed that the duration of hip pain and JIC classification type were significantly associated with clinical outcomes. Elderly age and advanced ONFH stage tended to lead to worse surgical outcomes. The overall survival rate of JIC classification type C1 and duration of pain ≤6 months was 98.1% and 97.8% at 72 months, respectively, as estimated by the Kaplan-Meier method. CONCLUSION: Surgical hip dislocation combined with impacting bone grafts and implanting iliac bone flaps in the treatment of ONFH had a good mid-term clinical outcome, especially for patients with retention of the lateral column of the femoral head and hip pain less than 1 year.