Crebanine mitigates glucocorticoid-induced osteonecrosis of the femoral head by restoring bone remodelling homeostasis via attenuating oxidative stress.

The onset of osteonecrosis of the femoral head (ONFH) is intimately associated with the extensive administration of glucocorticoids (GCs). Long-term stimulation of GCs can induce oxidative stress in both osteoclasts (OCs) and osteoblasts (OBs), resulting in the disturbance of bone remodelling. An alkaloid named crebanine (CN) demonstrates pharmacological properties including anti-inflammation and reactive oxygen species (ROS) modulation. Our objective is to assess the therapeutic potential of CN in treating ONFH and elucidate the associated underlying mechanisms. The network pharmacology analysis uncovered that CN played a role in regulating ROS metabolism. In vitro, CN demonstrated its ability to reduce the dexamethasone (DEX)-stimulated generation of OCs and suppress their resorptive function by downregulating the level of osteoclast marker genes. Concurrently, CN also mitigated DEX-induced damage to OBs, facilitating the restoration of osteoblast marker gene expression, cellular differentiation and function. These effects were achieved by CN augmenting the antioxidant system to reduce intracellular ROS levels. Furthermore, in vitro results were corroborated by micro-CT and histological data, which also showed that CN attenuated MPS-induced ONFH in mice. This study highlights the therapeutic potential of CN in counteracting GCs-induced ONFH.

Concerns with alumina bipolar hemiarthroplasties compared to metal bipolar hemiarthroplasties when performed for nontraumatic osteonecrosis of the femoral head.

PURPOSE: A nationwide multicenter follow-up cohort study of hip replacement arthroplasties performed for nontraumatic osteonecrosis of the femoral head (ONFH) aimed to answer the following questions: What factors were associated with need for reoperation? Although many modifications were made in bipolar hemiarthroplasties (BPs) to improve their durability, could we find any evidence of their efficacy? METHODS: Excluding 58 infected hips and 43 ABS THAs with very poor survivorship, we analyzed 7393 arthroplasties; 6284 total hip arthroplasties (THAs), 886 BPs, 188 total resurfacing arthroplasties, and 35 hemi-resurfacing arthroplasties (hRSs). In the 886 BPs, 440 hips had a smooth small-diameter prosthetic neck (nBPs), 667 hips had a smooth neck (sBPs), 116 hips had highly cross-linked polyethylene in the outer head (hBPs), and 238 hips had an outer head whose outer surface was alumina ceramic (aBPs) (648 hips had an outer head whose outer surface was metal [mBPs]). Multivariate analyses using a Cox proportional-hazard model analyzed risk factors. RESULTS: Follow-up ranged from 0.1 to 27 (average, 6.9) years, during which 265 hips (3.6%) needed reoperation. Combined systemic steroid use and excessive alcohol consumption and lateral approach were associated with higher risks, aBPs were less durable than THAs or mBPs, and hRSs were inferior to the others. Regarding BPs, the following divisions did not influence their survivorship; nBP or not, sBP or not, and hBP or not. CONCLUSIONS: Factors associated with reoperation risk were identified as described above. The modifications made in BPs did not improve their durability, but aBPs made it worse. LEVEL OF CLINICAL EVIDENCE: Level III, therapeutic cohort study.

Identification of key genes and pathways associated with gender difference in osteonecrosis of the femoral head based on bioinformatics analysis.

OBJECTIVE: To identify different key genes and pathways between males and females by studying differentially expressed genes (DEGs). METHODS: The gene expression data of GSE123568 were downloaded from GEO database, including osteonecrosis of the femoral head (ONFH) samples from 3 females and 7 males, and DEGs between different gender were identified with R software. Protein-protein interaction (PPI) network was constructed to further analyze the interactions between overlapping DEGs, and finally, GO, KEGG and gene set enrichment analysis (GSEA) were conducted for enrichment analysis. RESULTS: 131 DEGs were identified between ONFH females and ONFH males, including 76 up-regulated genes and 55 down-regulated genes. And 10 hub genes were identified in PPI network, including SLC4A1, GYPA, CXCL8, IFIT1, GBP5, IFI44, IFI44L, IFIT3, KEL and AHSP. Functional enrichment analysis revealed that these genes were mainly enriched in cGMP-PKG signaling pathway, Fatty acid degradation, Non-alcoholic fatty liver disease, Systemic lupus erythematosus, Hematopoietic cell lineage and NO-cGMP-PKG signaling. CONCLUSIONS: NO-cGMP-PKG signaling may play an important role in the occurrence and development of ONFH. SLC4A1, GYPA, CXCL8, GBP5 and AHSP may be key genes associated with gender difference in the progression of ONFH, which may be ideal targets or prognostic markers for the treatment of ONFH.

The use of extracorporeal shock wave therapy (ESWT) in treating osteonecrosis of the femoral head (AVNFH): a retrospective study.

PURPOSE: As most of the cases of avascular necrosis (AVN) in Saudi Arabia is seen in young population and as literature showed good effect of extracorporeal shock wave therapy (ESWT) in reducing pain and oedema in avascular necrosis and delaying the need of surgical intervention. Our purpose of this study is to assess the effectiveness of ESWT in reducing pain, improving range of motion (ROM) and delaying the surgical intervention in patient with AVN of femoral head and compare our results to published literature. MATERIAL AND METHODS: We have treated 24 patients, 13 males and 11 females with a mean age of 29 years (range 14-48) with 34 hips affected. There were 14 unilateral and ten bilateral lesions. In our series 11 out of 24 patients (45.8%) were due to sickle cell disease. Other causes included idiopathic in five patients (20.8%), corticosteroids use and systemic lupus erythematous in three patients each (12.5% each) and post-traumatic AVN in two patients (8.3%). Extracorporeal shock wave therapy was implanted in FICAT stage I, II and III. All patients had two sessions of extracorporeal shock wave therapy, four to six weeks apart, each with 4000 impulses divided into four points. Radiological and MRI assessment were performed at regular time intervals with a minimum follow-up of two years. Clinical assessment was based on Visual Analog Scale and Harris Hip Score (HHS). The end point outcome measurement was the need for any operative intervention. RESULTS: Operative intervention was necessary in eight out of 34 hips (23.5%), within an average of 2.5 years (range 1 to 5 years). A hip salvage was achieved in 76.5%. Function was improved with the Harris Hip Score from a mean of 54.6 to 80.4 (P value using paired t test ≤ 0.05). Pain assessed with Visual Analog Scale improved from 5.73 to 2.75 (P value using paired t test ≤ 0.05). CONCLUSION: We do recommend the use of ESWT in treating AVN of bone whether of femoral head or other sites prior to the collapse of the articular surface. Further studies are needed to compare using two or more sessions as well as using four or six points for ESWT.

Analysis of MR Signs to Distinguish Between ARCO Stages 2 and 3A in Osteonecrosis of the Femoral Head.

BACKGROUND: MRI is the most effective diagnostic tool of osteonecrosis of the femoral head (ONFH), especially for early diagnosis, but its detection of subchondral or cortical fractures is less accurate than CT. Therefore, it is difficult to accurately stage ONFH in the peri-collapse period by MRI. PURPOSE: To improve the accuracy of MR for distinguishing between Association Research Circulation Osseous (ARCO) stages 2 and 3A in ONFH. STUDY TYPE: Retrospective. SUBJECTS: One hundred and fifty five cases of ARCO stage 2/3A of ONFH underwent MR examinations, M/F = 72/83. CT was used as reference standard for collapse, which was decided by an orthopedist and a radiologist in consultation. FIELD STRENGTH/SEQUENCE: 3 T/axial and coronal T1 -weighted Turbo Spin Echo (T1 W TSE) sequence, axial T2 -weighted fat-saturated (T2 W FS) TSE sequence, and coronal proton density-weighted imaging (PDWI)-FS-Dixon fat/water image. ASSESSMENT: Five potential MR signs (the maximum width of the necrotic-viable interface, bone marrow edema (BME), irregular articular surface of the femoral head, T2 heterogeneous high signal, and the absence of a necrotic-viable interface with the morphology of closed loop) were evaluated blindly by five radiologists independently and the total scores of different combinations of MR signs were calculated. STATISTICAL TESTS: Mann-Whitney U test and Chi-square test were used to evaluate age, gender, and MR signs differences between the two groups. ROC curve was used to access the distinguishing value of MR signs. The consistency of the five radiologists was analyzed by intraclass correlation coefficient. RESULTS: The area under the curve of the combined MR signs 2 for distinguishing between ARCO stages 2 and 3A was the greatest (0.967), sensitivity and specificity were 100.00% and 88.71% respectively, and greater than 1 was the threshold. DATA CONCLUSION: Combined MR signs 2 has great values in distinguishing between ARCO stages 2 and 3A in ONFH, thus helping clinical therapy. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Serum ß-catenin changes vary among different stages of osteonecrosis of the femoral head: an exploratory biomarker study.

BACKGROUND: Wnt/ß-catenin signaling pathway is closely related to the pathogenesis Osteonecrosis of the femoral head (ONFH). ß-catenin, as a major component of Wnt signaling pathway, plays a vital role in the proliferation of osteoblasts. But the effect of altering ß-catenin level on the early diagnosis and staging of ONFH has not been studied. Our purpose is to investigate the role of ß-catenin level in the progress of ONFH. METHOD: One hundred and one patients with three stages of ONFH and fifty healthy controls were recruited between May 2016 and November 2016. We divided the patients into 32 cases of stage II, 41 cases of stage III and 28 cases of stage IV according to the Association Research Circulation Osseous (ARCO) classification. We evaluated the clinical bone histomorphology, expression position and level of ß-catenin as well as the plasma ß-catenin level. We investigated the level of ß-catenin from the serum and tissue samples using ELISA and Western Blot assay. We also evaluated the expression of ß-catenin in bone tissue by immunohistochemistry. Data were analyzed by independent t-test and ANOVA. RESULTS: We found that the mean (± SD) serum level of ß-catenin was 66.99 ± 3.032 ng/ml in the ONFH patients, which was higher than 20.14 ± 1.715 ng/ml observed in the control group (P < 0.001). Moreover, the ß-catenin levels were 49.30 ± 4.649 ng/ml, 72.54 ± 4.864 ng/ml and 79.10 ± 4.773 ng/ml in the ONFH patients with ARCO stage II, stage III and stage IV respectively, showing significant difference among them (P < 0.001). We also found that the area under the curve (AUC) calculated by ROC curve analysis to determine the values for ß-catenin levels in ONFH compared with those in the control group was 0.9358 (P < 0.001), where the sensitivity was 77.23% and specificity was 98.00%. CONCLUSION: Our results indicate that the increased ß-catenin may play a vital role in the progress of ONFH and the level of ß-catenin is correlated with ARCO stages. The cut-off concentration may be used as one of the sensitive marks to assess the disease process of ONFH.

A modified surgical method for the treatment of ONFH: quadratus femoris muscle pedicle bone grafting with preservation of the posterior superior retinacular artery.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) can lead to pain and loss of function of the hip joint, which places a great burden on patients and society. Surgery is the main treatment for osteonecrosis of the femoral head, and quadratus femoris muscle pedicle bone grafting has a definite therapeutic effect as one method of surgery for the treatment of ONFH. However, the posterior superior retinacular artery is often injured during quadratus femoris muscle pedicle bone graft surgery. There is evidence that this artery is extremely important to the femoral head, as injury to this artery will seriously affect the blood supply of the femoral head. Therefore, this situation restricts the clinical application of quadratus femoris muscle pedicle bone grafts. We aimed to explore a new surgical method of quadratus femoris muscle pedicle bone grafting that can preserve the integrity of the posterior superior retinacular artery. METHODS: We modified the traditional quadratus femoris muscle pedicle bone graft and preserved the integrity of the posterior superior retinacular artery. To explore the safety and feasibility of the operation, we simulated the operation on 6 fresh frozen cadavers (12 hips) and measured the related data. We also tried this modified surgical method in the clinic and collected detailed data from the patients. RESULTS: By simulating the modified quadratus femoris muscle pedicle bone graft on the hip joints of fresh frozen cadavers, we found that the posterior superior retinacular artery existed in all cadaver specimens and that the sources may be different (MFCA or IGA). In the modified operation, the joint capsule did not need to be cut during the operation; therefore, the integrity of the posterior superior retinacular artery was preserved. The quadratus femoris muscle was exposed via the posterior approach of the hip joint, and then the quadratus femoris muscle pedicle bone flap was chiseled. After the pedicle of the quadratus femoris muscle was loosened properly, the migration distance of the quadratus femoris muscle pedicle bone flap reached 5.89 ± 0.45 (χ ± s) cm. The bone flap was trimmed properly and placed on one side. Next, we drilled a bone tunnel from the external intertrochanteric aspect of the capsule of the hip joint, and the bone tunnel broke through the sclerosing zone and proceeded straight to the necrotic area of the femoral head. Next, the necrotic bone was removed with a ring saw and arc bone knife, autogenous bone or allogeneic bone was filled into the bone groove according to the situation, and the cancellous bone in the bone groove was tamped by percussion. Then, the bone flap was inserted into the bone groove, and appropriate pressurization was performed. The depth of the bone groove was determined by the location of ONFH. We found that the furthest distance between the bone groove and the femoral head was 4.76 ± 0.07 (χ ± s) cm and that the length of the bone flap was (4.91 ± 0.23) (χ ± s) cm. This means that when the depth of the bone groove reached the area of ONFH, the quadratus femoris muscle pedicle bone flap had a sufficient length and migration distance to be embedded in the area of ONFH and firmly fixed, and the quadratus femoris did not have much tension. The closest distance between the posterior superior retinacular artery and the bone groove was (1.11 ± 0.96) (χ ± s) cm. When the bone groove was created in this area, the edge of the bone groove had a safe distance of at least 1 cm from the posterior superior retinacular artery of the femoral head. We attempted to implement this modified operation clinically. During the procedure, the quadratus femoris muscle pedicle bone flap was embedded into the drilled bone groove and fixed with a magnesium nail. There was no sliding of the bone flap after the operation, and the posterior superior retinacular artery was intact. We followed the patient for 3 months and found that the patient recovered well with no weight-bearing by the affected limb. The duration of the modified operation was shorter than that of the traditional quadratus femoris muscle pedicle bone graft, the amount of bleeding was significantly reduced, the postoperative pain was lessened, and no special discomfort was reported. Postoperative imaging examination showed that the collapse of the femoral head had been partially corrected and that the bone flap had gradually fused with the surrounding bone. CONCLUSIONS: Through this experimental study, we confirmed the feasibility of the modified method for quadratus femoris muscle pedicle bone grafting with preservation of the posterior superior retinacular artery. This modified operation not only retains the integrity of the posterior superior retinacular artery of the femoral head but also reduces the difficulty of the operation and shortens the surgical time, which is of great clinical significance.

Plasminogen activator inhibitor-1 promoter sequence variations in idiopathic osteonecrosis of head of femur.

Background & objectives: Primary or idiopathic osteonecrosis of femur head (ONFH) is the second most commonly observed cause among Indian patients suffering from ischemic ONFH. Although a number of genetic polymorphisms have been associated with idiopathic ONFH pathogenesis in Korean and Chinese populations, there are no studies in the Indian population. This is an exploratory study designed to implicate in promoter sequence polymorphisms of a critical fibrinolytic system regulator, plasminogen activator inhibitor-1 (PAI-1) gene, in cases of idiopathic osteonecrosis. Promoter sequence variations can affect expression levels of PAI-1 gene and may disrupt the coagulation/fibrinolytic equilibrium, which may finally culminate into osteonecrosis. Hence, the aim of the study was to investigate the role of single-nucleotide polymorphisms (SNPs) in the promoter region of PAI-1 gene and osteonecrosis development. Methods: Two SNPs of the PAI-1 gene (rs2227631, -844 G/A; rs1799889, -675 4G/5G) were genotyped in 25 patients diagnosed with idiopathic ONFH and 25 control subjects, using direct sequencing. Subsequently, association analyses were performed for the genotyped SNPs. Results: Both the rs2227631 and rs1799889 genotype and allele frequencies of PAI-1 gene showed an insignificant association with osteonecrosis risk (P=0.717, 0.149). Haplotype frequencies of rs2227631 and rs1799889 were also calculated in patients having idiopathic ONFH and controls. Although the distribution of haplotype GA-4G 4G was found to be the highest among the cases, it was not significantly different when compared with the controls. Interpretation & conclusions: Our findings demonstrate that the minor alleles of promoter region sequences of the PAI-1 gene do not contribute to an increase in ONFH predisposition. However, this is a preliminary study and its findings should be considered as suggestive for studies to be done in a larger sample size.

DNA methylation in the OPG/RANK/RANKL pathway is associated with steroid-induced osteonecrosis of the femoral head.

BACKGROUND: Dysregulation of the OPG/RANK/RANKL signalling pathway is a key step in the occurrence of steroid-induced osteonecrosis of the femoral head (ONFH). This study aims to understand the degree of methylation of the OPG, RANK, and RANKL genes in steroid-related ONFH. METHODS: A case-control study was designed, including 50 patients (25 males and 25 females) and 50 matched controls. The European Molecular Biology Open Software Suite (EMBOSS) was used to predict the existence and location of CpG islands in the OPG, RANK, and RANKL genes. The Agena MassARRAY platform was used to detect the methylation status of the above genes in the blood of subjects. The relationship between the methylation level of CpG sites in each gene and steroid-related ONFH was analysed by the chi-square test, logistic regression analysis, and other statistical methods. RESULTS: In the CpG islands of the OPG, RANK, and RANKL genes in patients with steroid-related ONFH, several CpG sites with high methylation rates and high methylation levels were found. Some hypermethylated CpG sites increase the risk of steroid-related ONFH. In addition, a few hypermethylated CpG sites have predictive value for the early diagnosis of steroid-related ONFH. CONCLUSION: Methylation of certain sites in the OPG/RANK/RANKL signalling pathway increases the risk of steroid-related ONFH. Some hypermethylated CpG sites may be used as early prediction and diagnostic targets for steroid-related ONFH.

No association between telomere length and osteonecrosis of the femoral head.

BACKGROUND: Telemore length (TL) shortening has been found in many diseases. However, clinical characteristics of TL shortening in osteonecrosis of the femoral head (ONFH) has not been investigated. Therefore, we studied whether TL changes have clinicopathological values in ONFH. METHODS: The TL in the synovial tissues of 36 ONFH and 127 control patients (femoral neck fracture) was examined by quantitative real-time PCR as relative length, Δ Ct value. In addition, the correlation between TL and clinical features of ONFH and controls was analyzed. RESULTS: The average TL in the femoral tissues was 1.46 ± 3.12 (standard deviation). The average TL in the ONFH and control tissues was 1.92 ± 4.11 and 1.34 ± 2.78, respectively, however, the difference was absent (p = 0.324). Furthermore, a shorter TL was tended to be associated with erythrocyte sedimentation rate (100% vs. 61.5%, p = 0.073); however, the association was not statistically significant. CONCLUSIONS: In this study, we demonstrated that there is no association between the TL and clinicopathologic characteristics of ONFH patients. However, further studies considering the genetic factors are needed to be performed.

Efficacy of various core decompression techniques versus non-operative treatment for osteonecrosis of the femoral head: a systemic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Various Joint-preserving therapy (JPT) methods have been performed and tried in recent decades, but their results and efficacy were inconsistent and controversial. The purpose of this study is to evaluate its effectiveness and whether there are statistical differences in treatment between different interventions based on published RCT studies. METHODS: Following the PRISMA-NMA checklist, Medline, EMBASE, Web of Science, and Cochrane Library databases were searched and collected related RCT studies. The sources were searched from inception up to October 30, 2020. The primary outcomes including the rate of radiographic progression and conversion to THA and the secondary outcome -Harris Hip Scores (HHS) were extracted and compared in a Network meta-analysis. RESULTS: Seventeen RCT studies involving 784 patients (918 hips) with seven interventions including CD (core decompression), CD + BG (bone graft), CD + TI (tantalum rod implantation), CD + CT (Cell therapy), CD + BG + CT, VBG (vascularized bone graft), and nonsurgical or conservative treatment for ONFH were evaluated. In the radiographic progression results, CD + CT showed a relatively better result than CD, CD + BG and non-surgical treatment, the surface under the cumulative ranking curve (SUCRA) plot displayed that CD + CT (96.4%) was the best, followed by CD (64.1%).In conversion to THA results, there were no significant differences between the JPT methods and non-surgical treatment. In HHS, there was also no significant difference, other than CD + BG showed a statistical difference than non-surgical treatment only in terms of Cis, but the SUCRA was highest in non-surgical treatment (80.5%) followed by CD + CT (72.8%). CONCLUSIONS: This Net-work meta-analysis demonstrated that there was no statistical difference in the outcome of radiographic progression and conversion to THA, also in HHS, other than CD + CT showed a relatively superior result in radiographic progression than nonsurgical treatment, namely, it's maybe an effective method for delaying disease progression or reducing disease development based on current evidence.

Icariin regulates miR-23a-3p-mediated osteogenic differentiation of BMSCs via BMP-2/Smad5/Runx2 and WNT/ß-catenin pathways in osteonecrosis of the femoral head.

Icariin is commonly used for the clinical treatment of osteonecrosis of the femoral head (ONFH). miR-23a-3p plays a vital role in regulating the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). The present study aimed to investigate the roles of icariin and miR-23a-3p in the osteogenic differentiation of BMSCs and an ONFH model. BMSCs were isolated and cultured in vitro using icariin-containing serum at various concentrations, and BMSCs were also transfected with a miR-23a inhibitor. The alkaline phosphatase (ALP) activity and cell viability as well as BMP-2/Smad5/Runx2 and WNT/ß-catenin pathway-related mRNA and protein expression were measured in BMSCs. Additionally, a dual-luciferase reporter assay and pathway inhibitors were used to verify the relationship of icariin treatment/miR-23a and the above pathways. An ONFH rat model was established in vivo, and a 28-day gavage treatment and lentivirus transfection of miR-23a-3p inhibitor were performed. Then, bone biochemical markers (ELISA kits) in serum, femoral head (HE staining and Digital Radiography, DR) and the above pathway-related proteins were detected. Our results revealed that icariin treatment/miR-23a knockdown promoted BMSC viability and osteogenic differentiation as well as increased the mRNA and protein expression of BMP-2, BMP-4, Runx2, p-Smad5, Wnt1 and ß-catenin in BMSCs and ONFH model rats. In addition, icariin treatment/miR-23a knockdown increased bone biochemical markers (ACP-5, BAP, NTXI, CTXI and OC) and improved ONFH in ONFH model rats. In addition, a dual-luciferase reporter assay verified that Runx2 was a direct target of miR-23a-3p. These data indicated that icariin promotes BMSC viability and osteogenic differentiation as well as improves ONFH by decreasing miR-23a-3p levels and regulating the BMP-2/Smad5/Runx2 and WNT/ß-catenin pathways.

Mesenchymal stem cells-derived and siRNAs-encapsulated exosomes inhibit osteonecrosis of the femoral head.

Osteonecrosis of the femoral head (ONFH) is a progressive, obstinate and disabling disease. At present, the treatment of ONFH is still a global medical problem. We aim to explore the role of bone mesenchymal stem cells (BMSCs)-derived and siRNAs-encapsulated exosomes (siRNAs-encapsulated BMSCexos) in ONFH. We first isolated BMSCexos and screened siRNAs of 6 ONFH-related genes for siRNAs-encapsulated BMSCexo. The expression of these 6 ONFH-related genes in dexamethasone (DXM)-treated MC3T3-E1 cell, cell model of ONFH, was detected by RT-qPCR and Western blot analysis. And then, we performed CCK-8 assay, angiogenesis assay and HE staining analysis to test the promotion role of the siRNAs-encapsulated BMSCexo for angiogenesis during ONFH repair. The results suggest that the obtained particles were BMSCexos. The screened effective siRNAs could effectively knock down their expression in VECs. Moreover, siRNAs-encapsulated BMSCexo could effectively knock down the expression of these genes in VECs. In addition, siRNAs-encapsulated BMSCexo promote angiogenesis during ONFH repair. In conclusion, we found siRNAs-encapsulated BMSCexos could promote ONFH repair by angiogenesis, and indicated exosome as the new siRNA carrier is of great significance to improve the efficiency of RNAi.

Administration of mircoRNA-135b-reinforced exosomes derived from MSCs ameliorates glucocorticoid-induced osteonecrosis of femoral head (ONFH) in rats.

Exosomes were found to exert a therapeutic effect in the treatment of osteonecrosis of the femoral head (ONFH), while miR-135b was shown to play an important role in the development of ONFH. In this study, we investigated the effects of concomitant administration of exosomes and miR-135b on the treatment of ONFH. A rat mode of ONFH was established. TEM, Western blotting and nanoparticle analysis were used to characterize the exosomes collected from human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPS-MSC-Exos). Micro-CT was used to observe the trabecular bone structure of the femoral head. Real-time PCR, Western blot analysis, IHC assay, TUNEL assay, MTT assay and flow cytometry were performed to detect the effect of hiPS-MSC-Exos and miR-135b on cell apoptosis and the expression of PDCD4/caspase-3/OCN. Moreover, computational analysis and luciferase assay were conducted to identify the regulatory relationship between PDCD4 mRNA and miR-135b. The hiPS-MSC-Exos collected in this study displayed a spheroidal morphology with sizes ranging from 20 to 100 nm and a mean concentration of 1 × 1012 particles/mL. During the treatment of ONFH, the administration of hiPS-MSC-Exos and miR-135b alleviated the magnitude of bone loss. Furthermore, the treatment of MG-63 and U-2 cells with hiPS-MSC-Exos and miR-135b could promote cell proliferation and inhibit cell apoptosis. Moreover, PDCD4 mRNA was identified as a virtual target gene of miR-135b. HiPS-MSC-Exos exerted positive effects during the treatment of ONFH, and the administration of miR-135b could reinforce the effect of hiPS-MSC-Exos by inhibiting the expression of PDCD4.

Effects of hypoxia environment on osteonecrosis of the femoral head in Sprague-Dawley rats.

INTRODUCTION: Osteonecrosis of the femoral head (ONFH) is a disease in which the blood supply of the femoral head is interrupted or damaged, resulting in joint dysfunction. Hypoxic environments increase the expression of EPO, VEGF, and HIF causes vascular proliferation and increases the blood supply. It also causes the organism to be in a state of hypercoagulability and increases thrombosis. Therefore, the purpose of this study was to explore the occurrence of ONFH after the use of glucocorticoids (GCs) under conditions of hypoxia tolerance for a long time. MATERIALS AND METHODS: Sprague-Dawley rats were fed in a hypobaric hypoxic chamber at an altitude of 4000 m, the whole blood viscosity, and plasma viscosity were determined to analyze the blood flow and hemagglutination. Western blotting, polymerase chain reaction, and immunohistochemistry were used to detect EPO, VEGF, CD31, and osteogenesis related proteins. Femoral head angiography was used to examine the local blood supply and micro-CT scanning was used to detect the structure of the bone trabecula. RESULTS: Under hypoxic environments, the expression of EPO and VEGF increased, which increased the local blood supply of the femoral head, but due to more severe thrombosis, the local blood supply of the femoral head decreased. CONCLUSIONS: Hypoxic environments can aggravate ONFH in SD rats; this aggravation may be related to the hypercoagulable state of the blood. We suggest that long-term hypoxia should be regarded as one of the risk factors of ONFH and we need to conduct a more extensive epidemiological investigation on the occurrence of ONFH in hypoxic populations.

Osteonecrosis of the femoral head due to brucellosis: a case report.

BACKGROUND: Brucellosis is a zoonotic infection transmitted from infected animals to humans, osteonecrosis of the femoral head (ONFH) is a devastating disease that affects patients' life with pain, dysfunction of walking and always lead to total hip arthroplasty (THA). We presented a case of ONFH which was very likely due to the infection of Brucella spp. CASE PRESENTATION: The patient was a 49 years-old male who was a herder living in Inner Mongolia, the northern part of China. He first showed recurrent fever then presented bilateral hip pain, which was confirmed to be brucellosis and ONFH on the right side of the hip. He was admitted to our center showed bilateral ONFH with the restrictive movement of both hips. We performed THA after it was confirmed that the infection has been cured. The patient can walk with the help of the walker the second day after surgery. CONCLUSION: Brucellosis is still a common epidemic disease worldwide, which can lead to many complications, brucellosis arthritis is the most common complication of Brucellosis. Osteonecrosis of the femoral head can also present in the patients with brucellosis. All the patients presented with recurrent fever and hip pain, who is from the epidemic region, should be taken both septic arthritis and ONFH into consideration.

Clinical Characteristics of Mitochondrial DNA Copy Number in Osteonecrosis of the Femoral Head.

Background and objectives: Alterations in mitochondrial DNA (mtDNA) have been observed and studied in various diseases. However, the clinical value of the mtDNA copy number (mtDNA-CN) alterations in osteonecrosis of the femoral head (ONFH) is poorly understood. In the present study, we investigated whether alterations in mtDNA-CNs are associated with clinicopathological parameters in ONFH. Materials and methods: MtDNA-CNs in the synovial tissue of 34 patients with ONFH and 123 control tissues (femoral neck fracture) were measured using quantitative real-time PCR. The present study then analyzed the correlation between the mtDNA-CN and the clinicopathological characteristics of ONFH and fracture patients. Results: The average mtDNA-CN (mean ± standard deviation) was 23.82 ± 22.37 and 25.04 ± 24.27 in ONFH and control tissues, respectively, and was not significantly different between the groups (p = 0.792). The mtDNA-CN was positively associated with age (27.7% vs. 45.9%, p = 0.018) and negatively associated with the erythrocyte sedimentation rate (ESR) (11.8% vs. 39.7%, p = 0.024) in all of the samples. The study also found further associations with age (22.2% vs. 68.8%, p = 0.014), gender (30.0% vs. 64.3%, p = 0.048), and ESR (0% vs. 57.7%, p = 0.043) in ONFH. Conclusions: in this study, we demonstrated that mtDNA-CN might be a significant marker for predicting clinical characteristics in ONFH.

Genetic polymorphisms in IL1B predict susceptibility to steroid-induced osteonecrosis of the femoral head in Chinese Han population.

The purpose of this research was to examine if the IL1B gene polymorphism has impact on the risk of steroid-induced ONFH in Chinese population. We found that IL1B rs1143630 decreased the SANFH's risk and IL1B rs2853550 increased the risk of steroid-induced ONFH. So, we guess that IL1B gene influences the genetic susceptibility of steroid-induced ONFH. INTRODUCTION: Genetic polymorphisms in IL1B gene could be related in the pathogenesis of osteonecrosis. Discusses on the relationship between the IL1B gene and steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) is still less in Chinese Han population. So, in this research, we want to examine whether the IL1B gene polymorphism has impact on the risk of steroid-induced ONFH in Chinese population. METHODS: A total of 286 steroid-induced ONFH patients and 441 controls were recruited, and seven SNPs (rs2853550, rs1143643, rs3136558, rs1143630, rs1143627, rs16944, and rs1143623) in IL1B gene were selected; unconditional logistic regression analysis was used to research the influence on the risk of steroid-induced ONFH. Functional annotations of IL1B variants were performed by RegulomeDB and HaploReg. RESULTS: rs1143630 (A>C) in the IL1B gene decreased the risk of steroid-induced ONFH in the allele model (OR = 0.69, 95%CI 0.51-0.93, p = 0.014). Further genetic model analyses found that IL1B rs2853550 AG genotype increased the risk of steroid-induced ONFH compared with the people who are carriers of the IL1B rs2853550 GG genotype (OR = 1.69, 95%CI 1.16-2.46, p = 0.012). In the dominant model, IL1B rs1143630 GG-GT genotype decreased the risk of steroid-induced ONFH (OR = 0.62, 95%CI 0.44-0.87, p = 0.0051). And further haplotype analysis was performed, while the result was not significant. Using RegulomeDB and HaploReg, rs2853550 is likely to affect TF binding, any motif and DNase peak. CONCLUSIONS: We guess that IL1B gene influences the genetic susceptibility of steroid-induced ONFH.

Supercapsular percutaneously-assisted total hip (SuperPath) versus posterolateral total hip arthroplasty in bilateral osteonecrosis of the femoral head: a pilot clinical trial.

BACKGROUND: The supercapsular percutaneously-assisted total hip arthroplasty (SuperPath) was proposed to be minimally invasive and tissue sparing with possible superior postoperative outcomes to traditional approaches of total hip arthroplasty (THA). Here, we compared the short-term outcomes of staged THA with the SuperPath or through posterolateral approach (PLA) for bilateral osteonecrosis of the femoral head (ONFH). METHODS: Patients with bilateral late-stage ONFH were prospectively recruited from our department from March 2017 to March 2018. Staged bilateral THAs with one side SuperPath and the other side PLA were performed consecutively in the same patients with right and left hips alternating within approaches. The average time interval between the staged THAs was 3 months. Perioperative status (operation time, incision length, intraoperative blood loss, soft tissue damage, and length of hospital stay) and postoperative function (range of motion, pain, and hip function) were recorded and compared between the SuperPath and PLA approaches within 12-month postoperatively. RESULTS: Four male patients (age, 51.00 ± 4.54; BMI, 21.49 ± 1.73) with bilateral alcohol-induced ONFH (Ficat III/IV) were followed up over 12 months postoperatively. Compared with the PLA, the SuperPath yielded shorter incision length (7.62 vs. 11.12 cm), longer operation time (103.25 vs. 66.50 min), more blood loss (1108.50 vs. 843.50 ml), deficient abduction angle of the acetabular cup (38.75° vs. 44.50°), and inferior early-term hip function (Harris hip score, 72.50 vs. 83.25) at 12-month postoperatively. Soft tissue damage, length of hospital stay, postoperative pain, postoperative range of motion, and 12-month patient satisfaction were comparable between both approaches. CONCLUSION: The SuperPath may be a minimally invasive technique but the present study shows less favorable short-term outcomes than PLA for total hip arthroplasty in osteonecrosis of the femoral head. More investigations are required to provide convincing favorable evidences of the SuperPath over other traditional THA approaches. TRIAL REGISTRATION INFORMATION: The trial was retrospectively registered in https://www.researchregistry.com (No. Researchregistry4993) on July 04, 2019. The first participant was enrolled on March 13, 2017.

Mid-term outcomes of arthroscopic-assisted Core decompression of Precollapse osteonecrosis of femoral head-minimum of 5 year follow-up.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a progressive disease that leads to collapse and the development of secondary arthritis. The preferred management of ONFH remains controversial. Arthroscopic-assisted management of ONFH is a new and evolving approach for hip preservation. We hypothesis that arthroscopy is able to improve ONFH outcomes by achieving accurate and minimally invasive decompression while successfully addressing concomitant intraarticular pathologies resulting in reliable mid-term outcomes. METHODS: This was a retrospective cohort analysis. All patients had atraumatic ONFH with a precollapse lesion and a minimum follow-up of 5 years. RESULTS: A total cohort of 11 hips (8 patients) was identified. The mean patient follow-up was 7 years ±1.48 years (range, 64-118 months). The Ficat-Alret classification found on preoperative imaging was Stage I-3 (27.2%), IIa-4 (36.4%), and IIb-4 (36.4%) hips. Four (36.4%) hips experienced mechanical issues, including locking, catching, and buckling. The most common concomitant pathology addressed at the time of arthroscopy, was labral repair/debridement-8 (73%), followed by microfracture-7 (64%). At final follow-up, 6 hips (54.5%) had not converted to THA. Upon further stratification, Stage I-100%, Stage IIa-75%, for a combined 87%, had not converted to THA, in contrast, 100% of hips categorized as Stage IIb had converted to THA. Ficat-Alret staging, especially Stage IIb, was significantly associated with conversion to THA. (p-value = 0.015) There were 0% major or minor complications. CONCLUSIONS: To our knowledge, this is the longest reported follow-up of arthroscopic-assisted management of ONFH. Arthroscopic-assisted management is a promising surgical approach that provides safe, accurate, and minimally invasive decompression, resulting in reliable results with an acceptable conversion rate to THA. LEVEL OF EVIDENCE: Level IV, Case Series.