Development Of Osteonecrosis Of The Femoral Head Research Articles

17 variants interaction of Wnt/β-catenin pathway associated with development of osteonecrosis of femoral head in Chinese Han population

The genes of Wnt/β-catenin pathway may have potential roles in fat accumulation of Non-traumatic osteonecrosis of the femoral head (ONFH), but the effects of their variants in the pathway on ONFH development have been remained unclear. To explore the potential roles of the variants in the development of ONFH, we completed the investigation of the paired interactions as well as their related biological functions of 17 variants of GSK3β, LRP5, and FRP4 genes etc. in the pathway. The genotyping of the 17 variants were finished by MASS ARRAY PLATFORM in a 560 ONFH case–control system. The association of variants interactions with ONFH risk and clinical traits was evaluated by logistic regression analysis etc. and bioinformatics technology. The results showed that the genotype, allele frequency, and genetic models of Gsk3β rs334558 (G/A), SFRP4 rs1052981 (A/G), and LRP5 rs312778 (T/C) were significantly associated with the increased and decreased ONFH risk and clinical traits, respectively (P < 0.001–0.0002). Particularly, the paired interactions of six variants as well as eight variants also showed statistically increased and decreased ONFH risk, bilateral hip lesions risk and stage IV risk of ONFH, respectively (P < 0.044–0.004). Our results not only at the first time simultaneously showed exact serum lipid disorder and abnormal platelet function of ONFH in the same study system with the 17 variants polymorphisms of Wnt/β-catenin pathway but also shed light on the variants closely intervening the lipid disorder and abnormal coagulation of ONFH.

Role and mechanism of macrophage-mediated osteoimmune in osteonecrosis of the femoral head

To summarize the research progress on the role of macrophage-mediated osteoimmune in osteonecrosis of the femoral head (ONFH) and its mechanisms. Recent studies on the role and mechanism of macrophage-mediated osteoimmune in ONFH at home and abroad were extensively reviewed. The classification and function of macrophages were summarized, the osteoimmune regulation of macrophages on chronic inflammation in ONFH was summarized, and the pathophysiological mechanism of osteonecrosis was expounded from the perspective of osteoimmune, which provided new ideas for the treatment of ONFH. Macrophages are important immune cells involved in inflammatory response, which can differentiate into classically activated type (M1) and alternatively activated type (M2), and play specific functions to participate in and regulate the physiological and pathological processes of the body. Studies have shown that bone immune imbalance mediated by macrophages can cause local chronic inflammation and lead to the occurrence and development of ONFH. Therefore, regulating macrophage polarization is a potential ONFH treatment strategy. In chronic inflammatory microenvironment, inhibiting macrophage polarization to M1 can promote local inflammatory dissipation and effectively delay the progression of ONFH; regulating macrophage polarization to M2 can build a local osteoimmune microenvironment conducive to bone repair, which is helpful to necrotic tissue regeneration and repair to a certain extent. At present, it has been confirmed that macrophage-mediated chronic inflammatory immune microenvironment is an important mechanism for the occurrence and development of ONFH. It is necessary to study the subtypes of immune cells in ONFH, the interaction between immune cells and macrophages, and the interaction between various immune cells and macrophages, which is beneficial to the development of potential therapeutic methods for ONFH.

SOX9 Inhibits the Progression of Osteonecrosis of the Femoral Head via the Activation of the Wnt/Beta-Catenin Pathway

Background: In this study, we aimed to explore whether the SRY-box transcription factor 9 (SOX9) can play protective roles against the occurrence and development of osteonecrosis of the femoral head (ONFH) by regulating the proliferation, apoptosis, and osteogenic differentiation of human bone marrow stromal cells (hBMSCs) via the Wnt/β-catenin pathway. Methods: We used 1600 mg of glucocorticoid (GC) to induce hBMSCs to establish an ONFH cell model and performed various experiments. Reverse transcription-quantitative polymerase chain reaction and western blotting assays were used to determine the expression levels of SOX9 and osteoblast markers, such as the RUNX family transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osterix, Wnt3a, and β-catenin. An ALP detection kit was used to measure the ALP activity. Flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were performed to determine the cell viability. Results: GC treatment decreased the expression levels of RUNX2, ALP, and osterix, suppressed ALP activity, and inhibited SOX9 expression. SOX9 overexpression promoted GC-induced cell proliferation and decreased cell apoptosis. Additionally, hBMSCs were transfected with SOX9-small interfering RNA in GC treatment, and SOX9 knockdown was found to suppress the osteogenic differentiation of cells and decrease their viability. Conclusion: Our results revealed that SOX9 is related to the Wnt/β-catenin pathway in ONFH. Moreover, SOX9 participated in ONFH development by activating the Wnt/β-catenin pathway.

Decreased serum MMP-9 levels in patients with nontraumatic osteonecrosis of the femoral head

BackgroundMatrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) are involved in the pathological mechanism of osteonecrosis of the femoral head (ONFH). This study aimed to investigate the relationship of serum MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio with disease severity in patients with nontraumatic ONFH.MethodsSerum levels of MMP-9 and TIMP-1 among 102 nontraumatic ONFH patients and 96 healthy individuals were determined by enzyme-linked immunosorbent assay (ELISA). Imaging severity was determined using the FICAT classification system. The Harris hip score (HHS) and visual analogue scale (VAS) were used to evaluate clinical progress. The correlations of serum MMP-9 and TIMP-1 levels with imaging severity and clinical progress was evaluated statistically. The diagnostic value of MMP-9 for NONFH disease severity was evaluated by examining receiver operating characteristic (ROC) curves.ResultsThe serum MMP-9 levels and the MMP-9/TIMP-1 ratio were significantly increased in patients with ONFH compared to normal controls, and TIMP-1 levels did not differ between the two groups. Serum MMP-9 levels and the MMP-9/TIMP-1 ratio were positively correlated with FICAT stage and VAS and were negatively correlated with the HHS score. The ROC curve results indicated that MMP-9 could be used as a potential marker of nontraumatic ONFH imaging progression.ConclusionsWe hypothesize that increased MMP-9 expression and an imbalance in the MMP-9/TIMP-1 ratio play a role in the development of ONFH and are correlate with the severity of ONFH. The determination of MMP-9 can be a useful tool to assess the severity of the disease in patients with nontraumatic ONFH.

Research progress of immune cells regulating the occurrence and development of osteonecrosis of the femoral head

To summarize the characteristics of the occurrence and development of osteonecrosis of the femoral head (ONFH), and to review the important regulatory role of immune cells in the progression of ONFH. The domestic and foreign literature on the immune regulation of ONFH was reviewed, and the relationship between immune cells and the occurrence and development of ONFH was analyzed. The ONFH region has a chronic inflammatory reaction and an imbalance between osteoblast and osteoclast, while innate immune cells such as macrophages, neutrophils, dendritic cells, and immune effector cells such as T cells and B cells are closely related to the maintenance of bone homeostasis. Immunotherapy targeting the immune cells in the ONFH region and the key factors and proteins in their regulatory pathways may be a feasible method to delay the occurrence, development, and even reverse the pathology of ONFH.

Emerging roles of growth factors in osteonecrosis of the femoral head.

Osteonecrosis of the femoral head (ONFH) is a potentially disabling orthopedic condition that requires total hip arthroplasty in most late-stage cases. However, mechanisms underlying the development of ONFH remain unknown, and the therapeutic strategies remain limited. Growth factors play a crucial role in different physiological processes, including cell proliferation, invasion, metabolism, apoptosis, and stem cell differentiation. Recent studies have reported that polymorphisms of growth factor-related genes are involved in the pathogenesis of ONFH. Tissue and genetic engineering are attractive strategies for treating early-stage ONFH. In this review, we summarized dysregulated growth factor-related genes and their role in the occurrence and development of ONFH. In addition, we discussed their potential clinical applications in tissue and genetic engineering for the treatment of ONFH.

Bone marrow mesenchymal stem cells-derived exosomes mediate nuclear receptor coactivator-3 expression in osteoblasts by delivering miR-532-5p to influence osteonecrosis of the femoral head development.

Exosomes (Exo) originated from bone marrow mesenchymal stem cells (BMSCs) have therapeutic impacts on osteonecrosis of the femoral head (ONFH), and microRNA (miR)-532-5p has been confirmed to participate in ONFH progression. In the research, it was figured out whether BMSCs-Exo could relieve ONFH by delivering miR-532-5p. MG-63 cells were treated with DEX to construct an ONFH cell model in vitro. The effects of Exo and miR-532-5p on the cell viability, lactate dehydrogenase (LDH) content, and apoptosis of BMSCs were detected. The ONFH rat model was established, and the effect of BMSCs-Exo delivering miR-532-5p on the pathological damage of ONFH rats was evaluated. Changes in nuclear receptor coactivator-3 (NCOA3) and apoptotic proteins were assessed by western blot. The relationship between miR-532-5p and NCOA3 was verified by dual luciferase reporter experiments. miR-532-5p was elevated in vivo and in vitro ONFH-models, while NCOA3 expression was reduced. Overexpression of miR-532-5p aggravated DEX toxicity in osteoblasts, decreased cell viability, and promoted apoptosis. Knockdown of miR-532-5p made Exo further attenuate the toxic effect of DEX on osteoblasts and inhibited apoptosis. The protective effect of miR-532-5p-delivering Exo on osteoblasts was reversed by NCOA3 silencing. In addition, in vivo experiments also confirmed that knockdown of miR-532-5p enhanced the therapeutic effect of Exo on ONFH rats. This study demonstrates that miR-532-5p-delivering BMSCs-Exo inhibits osteoblast viability and promote apoptosis by targeting NCOA3, thereby aggravating ONFH development.

The Role of Structural Deterioration and Biomechanical Changes of the Necrotic Lesion in Collapse Mechanism of Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is a crippling disease which is due to a lack of effective therapeutic measures. Its natural progression is rapid, the internal bone structure of the femoral head changes dramatically, and the subsequent fractures and collapse cause severe hip pain and loss of hip function. Femoral head collapse is a critical turning point in the development of ONFH and is related to the prognosis of patients. Early prevention and intervention help to preserve the hip joint and delay femoral head collapse. However, the mechanism of collapse still needs to be further studied because it is affected by different complex factors. This review discusses the underlying causes of femoral head collapse from two aspects: structural degradation and regional changes of biomechanical properties in the necrotic femoral head.

Osteogenesis-Related Long Noncoding RNA GAS5 as a Novel Biomarker for Osteonecrosis of Femoral Head.

Background: The lack of effective biomarkers makes it difficult to achieve early diagnosis and intervention for osteonecrosis of the femoral head (ONFH). Hence, we aimed to identify novel long noncoding RNA (lncRNA) biomarkers for ONFH. Methods: High-throughput RNA sequencing was performed to detect lncRNA and mRNA expression levels in subchondral bone samples from three patients with ONFH and three patients with femoral neck fractures. Integrated bioinformatics analyses were conducted to identify lncRNAs associated with ONFH development and their potential functions and signaling pathways. A co-expression network was constructed based on the gene time-series expression data in GSE113253. After selecting lncRNA GAS5 as a novel biomarker for ONFH, bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation assays were performed to verify the association between lncRNA GAS5 and osteogenic differentiation. Alkaline phosphatase (ALP) staining and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to measure the osteogenic phenotype and lncRNA GAS5 expression. Finally, for further validation, ONFH rat models were established, and lncRNA GAS5 expression in subchondral bone was detected by RT-qPCR. Results: We identified 126 and 959 differentially expressed lncRNAs and genes, respectively. lncRNA GAS5 expression level was significantly downregulated in patients with ONFH compared to the control group patients. The BMSC osteogenic differentiation assays showed that ALP activity increased gradually from days 3 to 7, while the lncRNA GAS5 expression level was significantly upregulated in the osteogenic differentiation induction groups. Furthermore, in vivo experiments suggested that the bone volume/tissue volume value and trabecular thickness significantly decreased in the ONFH rat model group compared to the control group, whereas the trabecular space significantly increased in the ONFH group compared to the control group. In addition, the lncRNA GAS5 expression level significantly decreased in the ONFH rat model group. Conclusion: The lncRNA GAS5 expression level was highly associated with BMSC osteogenic differentiation and was significantly downregulated in both the subchondral trabecular bone tissue of ONFH patients and ONFH rat models. Therefore, lncRNA GAS5 can serve as an ONFH osteogenic biomarker to provide an effective target for early diagnosis and molecular therapy of ONFH.

Comparing the Risk of Osteonecrosis of the Femoral Head Following Intra-Articular Corticosteroid and Hyaluronic Acid Injections.

Although intra-articular corticosteroid injections (CSIs) are a cornerstone in the nonoperative management of hip pathology, recent reports have raised concerns that they may cause osteonecrosis of the femoral head (ONFH). However, these studies might have been limited by nonrepresentative patient samples. Therefore, the purpose of this study was to assess the incidence of ONFH after CSI and compare it with the incidence in a similar patient population that received a non-CSI injection. This was a retrospective propensity-matched cohort study of patients in the MarketScan database who underwent an intra-articular hip injection from 2007 to 2017. Patients receiving hip CSIs were matched 4:1 with patients receiving hip hyaluronic acid injections (HAIs) based on age, sex, geographic region, comorbidities, type of hip pathology, injection year, and baseline and follow-up time using propensity scores. The patients' first injections were identified, and the time to development of ONFH was analyzed using Kaplan-Meier curves and Cox proportional-hazards models. Patients with a history of osteonecrosis or those who received both types of injections were excluded. A total of 3,710 patients undergoing intra-articular hip injection were included (2,968 CSIs and 742 HAIs; mean [standard deviation] age, 53.1 [9.2] years; 55.4% men). All baseline factors were successfully matched between the groups (all p > 0.57). The estimated cumulative incidence (95% confidence interval [CI]) of ONFH for CSI and HAI patients was 2.4% (1.8% to 3.1%) versus 2.1% (1.1% to 3.5%) at 1 year and 2.9% (2.2% to 3.7%) versus 3.0% (1.7% to 4.8%) at 2 years (hazard ratio, 1.05; 95% CI, 0.59 to 1.84; p = 0.88). The results held across a range of sensitivity analyses. The incidence of ONFH after intra-articular hip injection was similar between patients who received CSIs and those who received HAIs. Although this study could not determine whether intra-articular injections themselves (regardless of the drug that was used) lead to ONFH, the results suggest that ONFH after CSI often may be due, in part, to the natural course of the underlying disease. Future randomized controlled trials are needed to definitively answer this question; in the interim, clinicians may be reassured that they may continue judicious use of CSIs as clinically indicated. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

An intron SNP rs2069837 in IL-6 is associated with osteonecrosis of the femoral head development

BackgroundGenetic polymorphisms play a crucial role in the development of osteonecrosis of the femoral head (ONFH). This study mainly explored the association of IL-6 variants and ONFH susceptibility among the Chinese Han population.MethodsTwo variants (rs2069837, and rs13306435) in the IL-6 gene were identified and genotyped from 566 patients with ONFH and 566 healthy controls. The associations between IL-6 polymorphisms and ONFH susceptibility were assessed using odds ratio (OR) and 95% confidence interval (95% CI) via logistic regression. The potential function of these two variants was predicted by the HaploReg online database.ResultsThe results of the overall analysis revealed that IL-6 rs2069837 was correlated with decreased risk of ONFH among the Chinese Han population (p < 0.05). In stratified analysis, rs2069837 also reduced the susceptibility to ONFH in older people (> 51 years), males, nonsmokers, and nondrinkers (p < 0.05). However, no associations between rs13306435 and ONFH susceptibility were observed (p > 0.05).ConclusionsTo sum up, we suggested that rs2069837 G>A polymorphism in the IL-6 gene was significantly associated with a decreased risk of ONFH among the Chinese Hans. These findings underscored the crucial role of IL-6 rs2069837 in the occurrence of ONFH.

Clinical significance of different imaging manifestations of osteonecrosis of femoral head in the peri-collapse stage

To explore the different imaging manifestations of osteonecrosis of the femoral head (ONFH) and their correlation with the occurrence of pain during the peri-collapse period. The 372 patients (624 hips) with ONFH in the peri-collapse stage who were admitted between December 2016 and October 2019 and met the selection criteria were selected as the research objects. Among them, there were 270 males and 102 females, with an average age of 35.3 years (mean, 15-65 years). There were 120 cases of unilateral hip and 252 cases of bilateral hips. There were 39 cases (39 hips) of traumatic ONFH, 196 cases (346 hips) of hormonal ONFH, 102 cases (178 hips) of alcoholic ONFH, and 35 cases (61 hips) of idiopathic ONFH. Among them, there were 482 hips with pain symptoms and 142 hips without pain. The pain duration was less than 3 months in 212 hips, 3-6 months in 124 hips, 6-12 months in 117 hips, and more than 12 months in 29 hips. According to the Association Research Circulation Osseous (ARCO) staging, the ONFH was rated as stage Ⅱ in 325 hips and stage Ⅲ in 299 hips. The patients were grouped according to ONFH etiology and ARCO staging, and hip joint pain and X-ray film (crescent sign and cystic changes), CT (subchondral bone fractures and cystic changes), and MRI (bone marrow edema, joint effusion, and subchondral hypointensity zone) were compared. Spearman rank correlation was used to determine the correlation between ONFH pain duration and X-ray film, CT, and MRI imaging manifestations. There were significant differences ( P<0.05) between ONFH patients with different etiologies in crescent sign on X-ray film, subchondral bone fracture on CT, and joint effusion on MRI. And there were significant differences ( P<0.05) between ONFH patients with different ARCO stages in hip pain duration and all imaging manifestations. Correlation analysis showed that the pain duration of ONFH patients was correlated with all imaging manifestations ( P<0.05). The cystic change on CT was correlated with the subchondral hypointensity zone and joint effusion grade on MRI, and subchondral hypointensity zone and joint effusion grade on MRI were also correlated ( P<0.05). The cystic changes, subchondral hypointensity zone, and joint effusion are closely related to the collapse of the femoral head and hip pain in patients with ONFH in the peri-collapse stage. The above-mentioned signals in stage Ⅱ ONFH indicate the instability of the femoral head, which is to predict the development of ONFH and the rational choice of hip-preserving treatment methods provides a basis.

Exosomes from miRNA-378-modified adipose-derived stem cells prevent glucocorticoid-induced osteonecrosis of the femoral head by enhancing angiogenesis and osteogenesis via targeting miR-378 negatively regulated suppressor of fused (Sufu)

BackgroundLocal ischemia and defective osteogenesis are implicated in the progression of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Recent studies have revealed that exosomes released from adipose-derived stem cells (ASCs) play important roles in ONFH therapy. The present study aimed to investigate whether exosomes derived from miR-378-overexpressing ASCs (miR-378-ASCs-Exos) could promote angiogenesis and osteogenesis in GC-induced ONFH.MethodsIn vitro, we investigated the osteogenic potential of miR-378-ASCs-Exos on bone marrow stromal cells (BMSCs) by alkaline phosphatase staining and western blotting. The angiogenic effects of miR-378-ASCs-Exos on human umbilical vein endothelial cells (HUVECs) were examined by evaluating their proliferation, migration, and tube-forming analyses. We identified the underlying mechanisms of miR-378 in osteogenic and angiogenic regulation. In addition, an ONFH rat model was established to explore the effects of miR-378-ASCs-Exos through histological and immunohistochemical staining and micro-CT in vivo.ResultsAdministration of miR-378-ASCs-Exos improved the osteogenic and angiogenic potentials of BMSCs and HUVECs. miR-378 negatively regulated the suppressor of fused (Sufu) and activated Sonic Hedgehog (Shh) signaling pathway, and recombinant Sufu protein reduced the effects triggered by miR-378-ASCs-Exos. In vivo experiments indicated that miR-378-ASCs-Exos markedly accelerated bone regeneration and angiogenesis, which inhibited the progression of ONFH.ConclusionOur study indicated that miR-378-ASCs-Exos enhances osteogenesis and angiogenesis by targeting Sufu to upregulate the Shh signaling pathway, thereby attenuating GC-induced ONFH development.

Non-coding RNA Identification in Osteonecrosis of the Femoral Head Using Competitive Endogenous RNA Network Analysis.

ObjectiveTo investigate the regulatory network of long non‐coding RNA (lncRNA) as competing endogenous RNAs (ceRNAs) in osteonecrosis of the femoral head (ONFH).MethodsThe gene expression profile GSE74089 of ONFH and microRNA (miRNA) expression profile of GSE89587 were obtained from the Gene Expression Omnibus (GEO) database. The GSE74089 contained four ONFH samples and four controls. The GSE89587 included 10 ONFH samples and 10 control samples. The differentially expressed lncRNAs (DE‐lncRNAs) and DE‐mRNAs between ONFH group and control group were identified from GSE74089 using the limma package based on criteria of adjusted P value <0.05 and |log fold change (FC)| ≥2. The DEmiRNAs between ONFH group and control group were screened from GSE89587 on the basis of adjusted P value <0.05. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for DE‐mRNAs were analyzed using DAVID 6.7 and GSEA 3.0, respectively. Coexpressed lncRNA‐mRNA pairs were identified by corr.test method in R based on the criteria of adjusted P value <0.01 and |r| ≥ 0.9. A ceRNA network was constructed and visualized using cytoscape 3.7.0 by integrating the DE‐lncRNA, DE‐miRNA, and DEmRNA data. The key mRNAs and lncRNAs in the ceRNA network were further validated in an independent dataset of GSE123568.ResultsBased on our analysis, a total of 28 DE‐lncRNAs, 1403 DE‐mRNAs, and 134 DE‐miRNAs were identified, respectively. The DE‐mRNAs were significantly enriched in the function of “skeletal system development,” “collagen fibril organization,” “blood vessel development,” and “regulation of nervous system development.” Besides, 72 KEGG pathways, including eight active pathways and 64 suppressed pathways were identified, including which immune pathway was the most significantly activated one and which ribosome‐related function was the most suppressed. A co‐expression network including 161 DE‐mRNAs and 16 DE‐lncRNAs was built. Highly connected nodes were identified among lncRNAs such as H19, C20orf203, LINC00355, SFTA3, CRNDE, CASC2, LINC00494, C9orf163, C10orf91, and LINC00301. The ceRNA network indicated that lncRNA H19 functioned as a ceRNA of hsa‐miR‐519b‐3p and hsa‐miR‐296‐5p in ANKH and ECHDC1 regulation; lncRNA C9orf163 functioned as a ceRNA of hsa‐miR‐424‐5p in CCNT1 regulation. The expression trends of ANKH, CCNT1, and C9orf163 were successfully validated in independent dataset of GSE123568.ConclusionThe ceRNAs of lncRNA H19‐ hsa‐miR‐519b‐3p/hsa‐miR‐296‐5p‐ANKH and lncRNA c9orf163‐ hsa‐miR‐424‐5p‐CCNT1 might play important roles in ONFH development. Our research provided an understanding of the important role of lncRNA–related ceRNAs in ONFH.

Risk factors for osteonecrosis of the femoral head in brain tumor patients receiving corticosteroid after surgery.

PurposeNon-traumatic osteonecrosis of the femoral head (ONFH) is a plausible complication in brain tumor patients. Frequent use of corticosteroid therapy, chemotherapy, and oxidative stress for managing brain tumors may be associated with the development of ONFH. However, there is little knowledge on the prevalence and risk factors of ONFH from brain tumor. This study aimed to investigate the prevalence and risk factors of ONFH in patients with primary brain tumors.MethodsThis retrospective cohort study included data from consecutive patients between December 2005 and August 2016 from a tertiary university hospital in South Korea. A total of 73 cases of ONFH were identified among 10,674 primary brain tumor patients. After excluding subjects (25 out of 73) with missing data, history of alcohol consumption or smoking, history of femoral bone trauma or surgery, comorbidities such as systemic lupus erythematosus (SLE), sickle cell disease, cancer patients other than brain tumor, and previous diagnosis of contralateral ONFH, we performed a 1:2 propensity score-matched, case–control study (ONFH group, 48; control group, 96). Risk factors of ONFH in primary brain tumor were evaluated by univariate and multivariate logistic regression analyses.ResultsThe prevalence of ONFH in patients with surgical resection of primary brain tumor was 683.9 per 100,000 persons (73 of 10,674). In this cohort, 55 of 74 patients (74.3%) underwent THA for ONFH treatment. We found that diabetes was an independent factor associated with an increased risk of ONFH in primary brain tumor patients (OR = 7.201, 95% CI, 1.349–38.453, p = 0.021). There was a significant difference in univariate analysis, including panhypopituitarism (OR = 4.394, 95% CI, 1.794–11.008, p = 0.002), supratentorial location of brain tumor (OR = 2.616, 95% CI, 1.245–5.499, p = 0.011), and chemotherapy (OR = 2.867, 95% CI, 1.018–8.069, p = 0.046).ConclusionsThis study demonstrated that the prevalence of ONFH after surgical resection of primary brain tumor was 0.68%. Diabetes was an independent risk factor for developing ONFH, whereas corticosteroid dose was not. Routine screening for brain tumor-associated ONFH is not recommended; however, a high index of clinical suspicion in these patients at risk may allow for early intervention and preservation of the joints.

Digital Subtraction Angiography and Magnetic Resonance Imaging-Based Staging of Circulatory Obstruction in the Femoral Head During Osteonecrosis of the Femoral Head Development.

Nontraumatic osteonecrosis of the femoral head (NONFH) is a common and difficult disease in orthopedics. Magnetic resonance imaging (MRI) assessment of NONFH and bone marrow edema was combined with digital subtraction angiography (DSA) to evaluate the circulatory status of NONFH in different Association Research Circulation Osseous stages. Based on the circulatory obstruction status (venous stasis, arterial ischemia, and arterial occlusion), appropriate perioperative management was adopted to achieve hip joint preservation and effectively delay the time for total hip arthroplasty in young patients. From January 2013 to March 2019, 41 orthopedic patients were evaluated for medical imaging. Sixty-one ONFH cases were enrolled. The inclusion criteria include: (1) Clear diagnosis of osteonecrosis of the femoral head. (2) No history of infection in the affected hip, no history of hip surgery, and no congenital hip diseases. The patients enrolled in this study were 8 women and 33 men between the ages of 19 and 64 years (mean, 39.25 ± 8.90 years). Preoperative X-ray, computed tomography, MRI, DSA, and histological data were taken. The combination of DSA and MRI can efficiently show blood supply changes in the femoral head of NONFH patients at different Association Research Circulation Osseous stages; and also can possibly reveal the causes and development of NONFH. Different stages of circulatory obstruction of the femoral head can be clearly distinguished and used to determine the required perioperative management, thus yielding successful surgical outcomes. The existing classification systems do not fully reflect the progression of circulatory obstruction in ONFH. Each stage of NONFH development has its own characteristics circulatory obstruction. Early-stage NONFH displays characteristic venous stasis of the femoral head, whereas advanced stage NONFH is characterized by insufficient arterial blood supply to the femoral head. Corresponding NONFH treatment strategies should be considered based on their specific circulatory status. This work also provides guidance and recommendations for adopting corresponding femoral head preserving strategies for young patients in different NONFH circulatory status.

The proton pump inhibitor, lansoprazole, prevents the development of non-traumatic osteonecrosis of the femoral head: an experimental and prospective clinical trial

BackgroundAn effective prevention strategy for osteonecrosis of the femoral head (ONFH) has yet to be established. We previously reported that the innate immune system via the toll-like receptor (TLR) response induced by corticosteroids leads to the development of ONFH and that repression of IRF7 activity by an inhibitor could interfere with the development of ONFH while maintaining the therapeutic effect of the corticosteroids.ObjectiveIn the present study, we hypothesize that lansoprazole has the potential to suppress IRF7 activity and prevent corticosteroid-induced ONFH in rats. Furthermore, we conducted a preliminary clinical trial to prevent corticosteroid-induced ONFH in autoimmune disease patients.MethodsMale Wistar rats were randomly divided into four groups. On Day 1, each rat was injected with TLR4 ligand (LPS) or TLR7 ligand (imiquimod), followed by methylprednisolone with or without lansoprazole on Day 2. They were killed at 1 or 14 days after the last injection.We prospectively recruited 30 patients requiring primary high-dose corticosteroid treatment for immune diseases. All patients were administered lansoprazole, starting the night before corticosteroid treatment began. MRI was performed before corticosteroid treatment, and at 4, 12 and 24 weeks afterward.ResultsIn rats, co-treatment of lansoprazole with corticosteroids significantly repressed both IRF7 activity and the development of ONFH. Moreover, in the human patients, the incidence of ONFH was significantly decreased from 53.4 to 13.3%.ConclusionsAlthough the present study is preliminary, the results show that co-treatment of lansoprazole with corticosteroids prevents ONFH development. Lansoprazole may be both safe and effective in preventing osteonecrosis of the femoral head in patients needing corticosteroid treatment.

Changed cellular functions and aberrantly expressed miRNAs and circRNAs in bone marrow stemcells in osteonecrosis of the femoral head.

The present study aimed to detect the correlations between altered cellular functions in bone marrow stem cells (BMSCs) and osteonecrosis of the femoral head (ONFH). By profiling the aberrant expression of miRNAs and circRNAs in BMSCs isolated from ONFH patients, the present study aimed to further explore the potential regulatory mechanisms of action of circRNAs in ONFH using integrated bioinfor-matics analysis. BMSCs were isolated from seven ONFH patients and seven controls. Cellular functions, including proliferation, apoptosis and differentiation, were compared. miRNA and circRNA sequencing were conducted using RNA samples of three ONFH patients and three controls to identify differentially expressed circRNAs and miRNAs. The expression of hsa_circ_0000219, hsa_circ_0004588 and hsa_circ_0005936 were validated by qPCR. Target miRNAs were also predicted and validated by qPCR and circRNA-miRNA co-expression networks were constructed. BMSCs of ONFH patients displayed decreased proliferation and increased apoptosis during in vitro culturing. In addition, reduced osteogenesis and enhanced adipogenesis were found in the ONFH group. A total of 129 miRNAs and 231 circRNAs were detected to be differentially expressed. The expression levels of hsa_circ_0000219, hsa_circ_0004588 and hsa_circ_0005936 were significantly decreased in BMSCs of ONFH patients. A number of target miRNAs related to cell proliferation, apoptosis and differentiation were predicted for hsa_circ_0000219 and hsa_circ_0005936. The expression levels of miR-144-3p and miR-1270 were found to be elevated in ONFH patients, which was consistent with miRNA sequencing data and competitive endogenous RNA hypothesis. Time-dependent expression patterns of hsa_circ_0000219, hsa_circ_0004588, hsa_circ_0005936, miR-144-3p and miR-1270 were also validated during osteogenic and adipogenic differentiation in BMSCs. The results of the present study substantiated the involvement of BMSCs in ONFH development. hsa_circ_0000219 and hsa_circ_0005936 may regulate the progression of ONFH by mediating the proliferation and differentiation of BMSCs by sponging miRNAs.

S100 Calcium Binding Protein A9 Represses Angiogenic Activity and Aggravates Osteonecrosis of the Femoral Head.

Ischemic damage aggravation of femoral head collapse is a prominent pathologic feature of osteonecrosis of the femoral head (ONFH). In this regard, S100 calcium binding protein A9 (S100A9) is known to deteriorate joint integrity, however, little is understood about which role S100A9 may play in ONFH. In this study, a proteomics analysis has revealed a decrease in the serum S100A9 level in patients with ONFH upon hyperbaric oxygen therapy. Serum S100A9 levels, along with serum vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), and tartrate-resistant acid phosphatase 5b levels were increased in patients with ONFH, whereas serum osteocalcin levels were decreased as compared to healthy controls. Serum S100A9 levels were increased with the Ficat and Arlet stages of ONFH and correlated with the patients with a history of being on glucocorticoid medication and alcohol consumption. Osteonecrotic tissue showed hypovasculature histopathology together with weak immunostaining for vessel marker CD31 and von Willrbrand factor (vWF) as compared to femoral head fracture specimens. Thrombosed vessels, fibrotic tissue, osteocytes, and inflammatory cells displayed strong S100A9 immunoreactivity in osteonecrotic lesion. In vitro, ONFH serum and S100A9 inhibited the tube formation of vessel endothelial cells and vessel outgrowth of rat aortic rings, whereas the antibody blockade of S100A9 improved angiogenic activities. Taken together, increased S100A9 levels are relevant to the development of ONFH. S100A9 appears to provoke avascular damage, ultimately accelerating femoral head deterioration through reducing angiogenesis. This study provides insight into the molecular mechanism underlying the development of ONFH. Here, analysis also highlights that serum S100A9 is a sensitive biochemical indicator of ONFH.

BMSC-derived exosomes carrying microRNA-122-5p promote proliferation of osteoblasts in osteonecrosis of the femoral head.

Mesenchymal stem cells (MSCs) with multipotential differentiation capacity can differentiate into bone cells under specific conditions and can be used to treat osteonecrosis (ON) of the femoral head (ONFH) through cell transplantation. The current study aims to explore the role of bone marrow (BM) MSCs (BMSCs)-derived exosomes carrying microRNA-122-5p (miR-122-5p) in ONFH rabbit models.First, rabbit models with ONFH were established. ONFH-related miRNAs were screened using the Gene Expression Omnibus (GEO) database. A gain-of-function study was performed to investigate the effect of miR-122-5p on osteoblasts and BMSCs and effects of exosomes carrying miR-122-5p on ONFH. Co-culture experiments for osteoblasts and BMSCs were performed to examine the role of exosomal miR-122-5p in osteoblast proliferation and osteogenesis. The target relationship between miR-122-5p and Sprouty2 (SPRY2) was tested.MiR-122, significantly decreased in ONFH in the GSE89587 expression profile, was screened. MiR-122-5p negatively regulated SPRY2 and elevated the activity of receptor tyrosine kinase (RTK), thereby promoting the proliferation and differentiation of osteoblasts. In vivo experiments indicated that bone mineral density (BMD), trabecular bone volume (TBV), and mean trabecular plate thickness (MTPT) of femoral head were increased after over-expressing miR-122-5p in exosomes. Significant healing of necrotic femoral head was also observed.Exosomes carrying over-expressed miR-122-5p attenuated ONFH development by down-regulating SPRY2 via the RTK/Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Findings in the present study may provide miR-122-5p as a novel biomarker for ONFH treatment.