Pathogenesis Of Osteonecrosis Of The Femoral Head Research Articles

Cortistatin prevents glucocorticoid-associated osteonecrosis of the femoral head via the GHSR1a/Akt pathway

Long-term use of glucocorticoids (GCs) is known to be a predominant cause of osteonecrosis of the femoral head (ONFH). Moreover, GCs can mediate apoptosis of various cell types by exaggerating oxidative stress. We have previously found that Cortistatin (CST) antagonizes oxidative stress and improves cell apoptosis in several conditions. In this study, we detected that the CST expression levels were diminished in patients with ONFH compared with femoral neck fracture (FNF). In addition, a GC-induced rat ONFH model was established, which impaired bone quality in the femoral head. Then, administration of CST attenuated these ONFH phenotypes. Furthermore, osteoblast and endothelial cells were cultured and stimulated with dexamethasone (Dex) in the presence or absence of recombinant CST. As a result, Dex induced impaired anabolic metabolism of osteoblasts and suppressed tube formation in endothelial cells, while additional treatment with CST reversed this damage to the cells. Moreover, blocking GHSR1a, a well-accepted receptor of CST, or blocking the AKT signaling pathway largely abolished the protective function of CST in Dex-induced disorder of the cells. Taken together, we indicate that CST has the capability to prevent GC-induced apoptosis and metabolic disorder of osteoblasts in the pathogenesis of ONFH via the GHSR1a/AKT signaling pathway.

Insight into Steroid-Induced ONFH: The Molecular Mechanism and Function of Epigenetic Modification in Mesenchymal Stem Cells.

Osteonecrosis of the femoral head (ONFH) is a common refractory orthopedic disease, which is one of the common causes of hip pain and dysfunction. ONFH has a very high disability rate, which is associated with a heavy burden to patients, families, and society. The pathogenesis of ONFH is not completely clear. At present, it is believed that it mainly includes coagulation dysfunction, abnormal lipid metabolism, an imbalance of osteogenic/adipogenic differentiation, and poor vascularization repair. The prevention and treatment of ONFH has always been a great challenge for clinical orthopedic surgeons. However, recent studies have emphasized that the use of mesenchymal stem cells (MSCs) to treat steroid-induced ONFH (SONFH) is a promising therapy. This review focuses on the role and molecular mechanism of epigenetic regulation in the progress of MSCs in the treatment of SONFH, and discusses the significance of the latest research in the treatment of SONFH from the perspective of epigenetics.

Identification of hub genes and therapeutic drugs in osteonecrosis of the femoral head through integrated bioinformatics analysis and literature mining.

Osteonecrosis of the femoral head (ONFH) is a multifactorial disease leading to severely limited function. By far, the etiology and pathogenesis of ONFH are not fully understood, and surgery is the only effective way to treat ONFH. This study aims to identify hub genes and therapeutic drugs in ONFH. Two gene expression profiles were downloaded from the gene expression omnibus database, and the hub genes and candidate drugs for ONFH were identified through integrated bioinformatics analysis and cross-validated by literature mining. A total of 159 DEGs were identified. PTGS2, LRRK2, ANXA5, IGF1R, MCL1, TIMP2, LYN, CD68, CBL, and RUNX2 were validated as 10 hub genes, which has considerable implications for future genetic research and related research fields of ONFH. Our findings indicate that 85 drugs interact with ONFH, with most drugs exhibiting a positive impact on ONFH by promoting osteogenesis and angiogenesis or inhibiting microcirculation embolism, rather than being anti-inflammatory. Our study provides novel insights into the pathogenesis, prevention, and treatment 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.

FTO rs62033406 A>G associated with the risk of osteonecrosis of the femoral head among the Chinese Han population

BackgroundFat mass and obesity-related (FTO) mRNA was downregulated in osteonecrosis patients. The study aimed to evaluate the correlation between FTO polymorphisms and the susceptibility of osteonecrosis of the femoral head (ONFH).MethodsSix polymorphisms in FTO were genotyped via the Agena MassARRAY in 498 ONFH patients and 498 healthy controls. Multiple genetic models were used to assess the correlation between FTO polymorphisms and ONFH risk by SNPStats. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a logistic regression model adjusted by age, gender, smoking and drinking.ResultsThe risk-increasing association of rs62033406 A>G with ONFH was found (OR = 1.25, 95% CI 1.05–1.50, p = 0.014). Specially, FTO rs62033406 A>G was related to the risk of ONFH in the subgroup at age > 51 years (OR = 1.25, p = 4.00 × 10–4), females (OR = 1.74, p = 1.00 × 10–4), smokers (OR = 1.82, p = 0.005) and drinkers (OR = 1.89, p = 0.002), respectively. The best multi–loci model was the five–loci model, a combination of rs9930333 T>G, rs1558902 T>A, rs56094641 A>G, rs3751812 G>T, and rs62033406 A>G (testing accuracy, 0.5351; p = 0.0004; cross–validation consistency, 10/10).ConclusionOur study first revealed that FTO rs62033406 A>G was a risk factor for ONFH among the Chinese Han population, which might provide the new candidate gene for elucidating the pathogenesis of ONFH.

Symptomatic femoral head necrosis in patients with rheumatoid arthritis: A retrospective case‐control study

ObjectiveWe conducted a retrospective case–control study to investigate the risk factors for osteonecrosis of the femoral head (ONFH) in rheumatoid arthritis (RA) patients.MethodsThe clinical data of patients diagnosed with RA at Fujian Provincial Hospital from January 2013 to December 2020 were retrospectively collected and evaluated. Twenty‐two patients with ONFH were identified. Eighty‐eight age‐, sex‐, and disease duration‐matched RA patients without symptomatic ONFH were randomly selected as controls in a ratio of 1:4. Logistic regression analysis was used to analyze the risk factors.ResultsThe anticardiolipin (ACL)‐immunoglobulin G (IgG) concentration, clinical disease activity index, simplified disease activity index, incidence of hyperlipidemia in the case group were higher than those in the control group. Multivariate logistic regression analysis did not find the independent risk factor in ONFH patients with RA.ConclusionThe pathogenesis of ONFH in RA is related to many factors such as ACL IgG, disease activity index, and hyperlipidemia. While, we went to great lengths to explore the relationship between antiphospholipid antibodies and ONFH, but it plays a very small role.

Decreased Ankyrin Expression Is Associated with Repressed eNOS Signaling, Cell Proliferation, and Osteogenic Differentiation in Osteonecrosis of the Femoral Head.

Reduced nitric oxide synthase (NOS) activity and decreased reparative potentials in stem cells may be involved in the pathogenesis of osteonecrosis of the femoral head (ONFH), but the underlying mechanism is not clear. Ankyrin, a cytoskeletal protein, can promote NOS expression and many cellular functions when it interacts with the CD44 receptors on the stem cells. This study investigated whether ankyrin is involved in the pathogenesis of ONFH. Bone marrow stem cells (BMSCs) from ONFH patients were compared with cells from patients with proximal femoral fracture and BMSC cell lines (PT-2501, Lonza, NC, USA). Differences in the expression levels and downstream signal pathway of ankyrin-Akt-eNOS in BMSCs were studied between ONFH and control. The involvement of ankyrin in the signal cascade, cell proliferation, and differentiation were further investigated by silencing ankyrin using small interfering (si)RNA. We found the basal mRNA levels of ankyrin and CD44 in BMSCs from the ONFH group were significantly lower as compared with those from the control group. The signal transduction of CD44-ankyrin-Akt-eNOS was significantly repressed in the ONFH group as compared with the control group after hyaluronic acid treatment. Knockdown of ankyrin by siRNA could attenuate the eNOS signaling as well as the BMSCs proliferation and osteogenic differentiation. The proliferation ability and osteogenic differentiation potential of the BMSCs from the ONFH group were significantly reduced as compared with the control group, but they can be enhanced to the baseline levels of the control group by hyaluronic acid treatment. The aberrant eNOS signaling, reduced cell proliferation, and osteogenic differentiation potential in BMSCs from ONFH patients are associated with the decreased ankyrin expression. Altered signal transduction, proliferation, and osteogenic differentiation ability in BMSCs may be involved in the pathogenesis of ONFH. These need further studies especially in BMSC-based cell therapy.

Evolutionary course of the femoral head osteonecrosis: Histopathological - radiologic characteristics and clinical staging systems.

Osteonecrosis of the femoral head (ONFH) is a recalcitrant ischemic disorder, which could be classified into two major categories: traumatic and nontraumatic. Regardless of different risk factors, it has been testified that ONFH results from primitive vascular problems, leading to temporary or permanent loss of blood supply to bone tissue. Histopathological and microarchitectural alterations ensues, which is a gradual evolutionary process involving bone marrow and osteocyte necrosis, progressive destruction of subchondral bone, unsuccessful reparative process, and eventual articular collapse and degenerative arthritis. Based on the imaging features of ONFH, different classification systems have been developed to evaluate the severity and prognosis of the disease, which is pivotal for implementation of treatment strategy, especially the joint-preserving surgery. However, patients classified with the same severity stage, especially in the peri-collapse stage, sometimes responded differently after similar joint-preserving surgery. The unusual phenomenon may be attributed to the limitation of the current imaging classification systems, which might underestimate the disease severity, especially when referring to the early stages. In this review, we briefly summarize the etiology and pathogenesis of ONFH. The imaging features and staging classification systems of ONFH are also described. More importantly, we focus on histopathological and microstructural alterations of the femoral head, and provide an overview of their essential contribution to ONFH progression. Given the observation of discordance between imaging characteristics and histopathological alterations, a substantial amount of research on the relationship between imaging and histopathological features is required to further modify and revise the current wide-accepted classification systems.

Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head

ObjectiveThis study aims to identify novel candidate genes associated with osteonecrosis of the femoral head (ONFH).MethodsA transcriptome-wide association study (TWAS) was performed by integrating the genome-wide association study dataset of osteonecrosis (ON) in the UK Biobank with pre-computed mRNA expression reference weights of muscle skeleton (MS) and blood. The ON-associated genes identified by TWAS were further subjected to gene ontology (GO) analysis by the DAVID tool. Finally, a trans-omics comparative analysis of TWAS and genome-wide mRNA expression profiling was conducted to identify the common genes and the GO terms shared by both DNA-level TWAS and mRNA-level expression profile for ONFH.ResultsTWAS totally identified 564 genes that were with PTWAS value <0.05 for MS and blood, such as CBX1 (PTWAS = 0.0001 for MS), SRPK2 (PTWAS = 0.0002 for blood), and MYO5A (PTWAS = 0.0005 for blood). After comparing the genes detected by TWAS with the differentially expressed genes identified by mRNA expression profiling, we detected 59 overlapped genes, such as STEAP4 [PTWAS = 0.0270, FC (fold change)mRNA = 7.03], RABEP1 (PTWAS = 0.010, FCmRNA = 2.22), and MORC3 (PTWAS = 0.0053, FCmRNA = 2.92). The GO analysis of TWAS-identified genes discovered 53 GO terms for ON. Further comparing the GO results of TWAS and mRNA expression profiling identified four overlapped GO terms, including cysteine-type endopeptidase activity (PTWAS = 0.0006, PmRNA = 0.0227), extracellular space (PTWAS = 0.0342, PmRNA = 0.0012), protein binding (PTWAS = 0.0112, PmRNA = 0.0106), and ATP binding (PTWAS = 0.0464, PmRNA = 0.0033).ConclusionSeveral ONFH-associated genes and GO terms were identified by integrating TWAS and mRNA expression profiling. It provides novel clues to reveal the pathogenesis of ONFH.

Noncoding RNAs in Steroid-Induced Osteonecrosis of the Femoral Head.

Steroid-induced osteonecrosis of the femoral head (ONFH) is a severe orthopedic disease caused by the long-term administration of glucocorticoids. The main pathological feature of ONFH is the gradually progressive necrosis of bone cells and the bone marrow, ultimately resulting in structural changes or even complete collapse of the femoral head. However, the exact pathogenic mechanism of ONFH remains unknown. Noncoding RNAs (ncRNAs) have emerged as very powerful regulators of gene expression, functioning at both transcriptional and posttranscriptional levels in the pathogenesis of ONFH. Here, we review the current knowledge of the role of ncRNAs, including microRNAs, long noncoding RNAs, and circular RNAs, in the pathogenesis of steroid-induced ONFH. Further focus and validation of these associations can provide new insight into the pathogenic mechanisms at the molecular level to suggest targets for treatment and prevention.

Huo Xue Tong Luo capsule ameliorates osteonecrosis of femoral head through inhibiting lncRNA-Miat

Ethnopharmacological relevanceTraditional Chinese medicine has a long history of treating various bone diseases including osteoporosis and osteonecrosis etc. In clinical treatment, Huo Xue Tong Luo capsule (HXTL capsule) containing Peach kernel, Safflower carthamus, Angelica sinensis, Ligusticum wallichii etc, is one of the mostly used prescriptions for treating osteonecrosis of the femoral head (ONFH) with promising effects. ObjectivesThis study aims to identify the underlying molecular mechanism of how HXTL capsule exerts its function to ameliorate ONFH. Materials and methodsAll femoral bone tissues were collected during surgeries. Rat bone marrow mesenchymal stem cells (rMSCs) were used. Quantitative real time PCR was used to check the relative expression levels of genes. ChIP assay was performed to evaluate the binding of H3K4me3 and H3K27me3 in Miat promoter. ResultsWe showed that HXTL capsule promoted osteogenesis in rat MSCs as demonstrated by quantitative real time PCR and Alizarin Red S staining. Then we found silencing the endogenous lncRNA-Miat could promote osteogenesis of rMSCs. In addition, the ChIP assay showed that HXTL capsule significantly increased occupancy of H3K27me3 and decreased H3K4me3 in promoter regions of Miat, meaning HXTL capsule inhibited Miat expression through histone modifications. At last, by examining the femoral heads samples obtained from patients with ONFH during total hip arthroplasty surgery, we found the RNA level of hMiat in necrotic tissue was much higher than that of normal tissue. ConclusionsTaken together, our study shows that lncRNA-Miat might play an important role in pathogenesis of ONFH, and HXTL capsule can promote osteogenesis to ameliorate ONFH through inhibiting the transcriptional expression of Miat, at least partially.

Involvement of tumor necrosis factor alpha in steroid-associated osteonecrosis of the femoral head: friend or foe?

BackgroundThe etiology and pathology osteonecrosis of the femoral head (ONFH) are not completely clarified. As a cytokine participating in systemic inflammation, tumor necrosis factor alpha (TNFα) has been shown to be involved in the pathogenesis of ONFH. However, the role of TNFα in ONFH is not clearly clarified. In the present study, we investigated the effects of TNFα on proliferation, angiogenesis, and osteogenic differentiation of rat bone mesenchymal stem cells (rMSCs) and the underlying mechanisms.MethodsAll femoral bone tissues were separated in surgeries. After extracting total RNA and protein, we evaluated TNFα content by ELISA and the relative expression levels of genes by quantitative real-time PCR and western blot. Also, immunohistochemistry staining was performed to observe the expression of Runx2 in the bone samples. Chick embryo chorioallantoic membrane (CAM) assay was performed to observe the effect of TNFα on angiogenesis. The genomic DNAs were treated by bisulfite modification, and methylation status of CpG sites in the CpG islands of human and rat Runx2 gene promoter was determined by DNA sequencing. The binding of H3K4me3 and H3K27me3 in Runx2 promoter was checked by ChIP assay. RNA-seq analysis was used to find out the genes and pathways changed by TNFα in rMSCs.ResultsThe results demonstrate TNFα promotes cell proliferation and angiogenesis whereas inhibits osteogenesis. Epigenetic regulations including DNA methylation and histone modifications play important roles in mediating the effect of TNFα on osteogenic differentiation. We find an increased rate of CpG methylation in rat Runx2 promoter in TNFα-treated rMSCs, as well as significantly increased occupancy of H3K27me3 in Runx2 gene promoter. The content of TNFα in necrotic tissue is much lower than that of normal tissue. And relevantly, human Runx2 promoter is demethylated in necrotic tissue using bone samples from patient with ONFH. In addition, we have observed that Wnt signaling pathway is inhibited by TNFα as multiple Wnts are markedly decreased in TNFα-treated rMSCs by RNA-seq analysis.ConclusionTaken together, our study shows that TNFα plays complicated roles in the pathogenesis of ONFH, including proliferation, angiogenesis, and osteogenesis. Targeting TNFα should not be considered as an applicable strategy to inhibit the progression of ONFH.

MicroRNA-mediated interacting circuits predict hypoxia and inhibited osteogenesis of stem cells, and dysregulated angiogenesis are involved in osteonecrosis of the femoral head.

MicroRNAs (miRNAs) are associated with various pathologic conditions and can serve as diagnostic or therapeutic biomarkers. This study tried to identify the differentially expressed miRNAs to predict the possible pathomechanisms involved in osteonecrosis of the femoral head (ONFH). We compared the peripheral blood miRNAs in 46 patients with ONFH and 85 healthy controls by microarray and droplet digital polymerase chain reaction (ddPCR). Putative interacted networks between the differentially responded miRNAs were analyzed by web-based bioinformatics prediction tools. Microarray identified 51 differentially expressed miRNAs with at least twofold change (upregulation in 34 and downregulation in 17), and the results were validated by ddPCR using six selected miRNAs. Bioinformatics genetic network analysis focusing on the six miRNAs found the upregulated miR-18a and miR-19a are associated with angiogenesis after induction of ischemia; the upregulated miR-138-1 can inhibit osteogenic differentiation of mesenchymal stem cells; the most targeted genes, p53 and SERBP1, are associated with hypoxia and hypofibrinolysis. This study combined the miRNA analysis with the bioinformatics and predicts that hypoxia, inhibited osteogenesis of stem cells, and dysregulated angiogenesis might be orchestrated through the miRNA interacting circuits in the pathogenesis of ONFH.

Emerging roles of MicroRNAs in osteonecrosis of the femoral head.

Osteonecrosis of the femoral head (ONFH) is one of the most common orthopaedic diseases. The exact pathogenic mechanism of ONFH is still unknown. MicroRNAs (miRNAs) are a class of non-coding RNAs that negatively modulate gene expression at post-transcriptional level. An increasing number of studies have shown that miRNAs play crucial roles in different physiological processes, including development, cell proliferation, differentiation and metabolism. Recently, multiple studies demonstrated that miRNAs are involved in the pathogenesis of ONFH. In this review, we summarize dysregulated miRNAs and their functions in ONFH. Furthermore, we discuss their potential clinical applications for diagnosis and treatment of ONFH.

Unique plasma metabolomic signature of osteonecrosis of the femoral head

Metabolomic analysis was performed to determine the metabolomic signature of osteonecrosis of the femoral head (ONFH), and to investigate the underlying relationship between the metabolomic signature and the pathogenesis of ONFH. Plasma samples were collected from 30 ONFH patients and 30 normal subjects. The global metabolomic profile was obtained through a combination of high-throughput liquid- and gas-chromatography-based mass spectrometry analyses. All statistical analyses were conducted using the R software. The results showed clear differences in the metabolomic signature between the plasma of ONFH patients compared with normal subjects. Among the 354 identified metabolites, the expression of 123 metabolites were significantly changed in ONFH patients compared with normal subjects (p < 0.05, q < 0.10). Bioinformatics analysis revealed that these abnormal metabolites were mainly involved in lipid-, glutathione-, nucleotide-, and energy-associated pathways, which might be related to enhanced inflammation, oxidative stress, and energy deficiency due to ONFH. This study provides the first metabolomic analysis of ONFH, and identifies a previously unrecognized metabolic signature in ONFH plasma. The results offer new insights into the pathological mechanisms of ONFH through its influence on metabolic pathways, providing the requisite framework for identifying biomarkers or novel targets for therapeutic intervention. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1158-1167, 2016.

Genetic variation in the coagulation factor V gene and risk of femoral head osteonecrosis.

Osteonecrosis of the femoral head (ONFH) is characterized by the death of the cellular portion of the femoral head due a reduction or disruption in the blood supply. Certain studies have implicated coagulation disorders, including thrombophilia and hypofibrinolysis, in the pathogenesis of ONFH. The factor V (F5) Leiden mutation has been suggested to be a genetic risk factor for venous thromboembolism and osteonecrosis in Caucasian individuals, however, this association remains controversial in other populations. The present study aimed to identify polymorphisms of the F5 gene and performed a case‑control study in a Korean population. The F5 gene was sequenced in 24 unrelated Korean individuals, and 16 polymorphisms were detected. A total of six polymorphisms were genotyped in 423 patients with ONFH and 348 control individuals. Analysis of the association between genotyped single nucleotide polymorphisms and haplotypes and with ONFH was performed. Comparison of the ONFH samples and the control individuals using logistic regression models revealed no statistically significant difference in the frequencies of the F5 polymorphisms and haplotypes. These findings suggested that F5 polymorphisms were not significant in the susceptibility to ONFH in the Korean population.

Preliminary screening of differentially expressed circulating microRNAs in patients with steroid-induced osteonecrosis of the femoral head

microRNAs have been shown to be stable and detectable in circulating blood, and circulating microRNAs are specifically expressed in numerous diseases. However, to date, the association between microRNAs and osteonecrosis of the femoral head (ONFH) has remained elusive. It was hypothesized that specific microRNAs in the serum of ONFH patients may participate in the pathogenesis of ONFH. In the present study, therefore, the ONFH‑specific serum microRNAs were screened using deep sequencing technology. Peripheral blood serum was collected from three steroid‑induced ONFH patients with systemic lupus erythematosus (SLE), three SLE controls and three healthy controls, respectively. Total RNA was extracted from the serum and a microRNA cDNA library was built. High‑throughput sequencing was then used to sequence the serum microRNAs of the samples and screen differentially expressed serum microRNAs in patients with steroid‑induced ONFH. 27 differentially expressed microRNAs from ONFH serum were selected; of these, 15 microRNAs were over‑expressed and 12 were under‑expressed compared with SLE controls and healthy controls. The present study showed that abnormally expressed microRNAs existed in the serum of ONFH patients and therefore have the potential to be diagnostic markers.

Microparticles as biomarkers of osteonecrosis of the hip in sickle cell disease.

Osteonecrosis of the femoral head (ONFH) is a common complication of sickle cell disease (SCD). To examine the association between microparticles and ONFH in SCD, we compared plasma microparticle levels in 20 patients with and without ONFH. Microparticles were quantified using nanoparticle tracking analysis and found to be 2·3-fold higher in patients with ONFH compared to patients without ONFH, and 2·5-fold higher than in healthy controls. These results suggest that microparticles may be a clinically useful biomarker of ONFH in SCD. Further investigations are needed to determine the functional relevance of microparticles in the pathogenesis of ONFH in SCD.

Association of a polymorphism in PON-1 gene with steroid-induced osteonecrosis of femoral head in Chinese Han population

BackgroundTreatment with steroids covers a wide spectrum of diseases in clinic. However, some users are suffering from serious side effects of steroid administration, while we enjoy the benefit it brings about. Osteonecrosis of the femoral head (ONFH) is a troublesome one among them. Recent studies have demonstrated that lipid metabolism disorder may play a vital role in pathogenesis of ONFH and mutation of the paraoxonase-1 (PON-1) gene may be involved in the occurrence of this disease. However, the relationship between polymorphisms of PON-1 and ONFH has not been thoroughly studied. The aim of this study was to determine whether PON-1 polymorphisms are associated with steroid-induced ONFH through a cohort study among Chinese Han population.MethodsThis trial applied a case–control scheme to compare the clinical data including PON-1 SNP among 94 patients and 106 control subjects to analyze the association between SNP and risk of steroid-induced ONFH. Time of Flight Mass Spectrometer is utilized for genotyping and the result was analyzed in multivariate analysis models.ResultsAccording to polymorphism test of rs662, its SNP was significantly associated with the risk of ONFH in overdominant analysis model [P value: 0.022; odds ratio (OR): 0.39]. However, genotype frequencies of rs662 of PON-1 gene between case and control group showed no differences (P > 0.05).ConclusionsOur data suggest for the first time that SNP (rs662) of the PON-1 gene was associated with the risk of steroid-induced ONFH. In addition, PAI-1 SNPs may play an important role in pathogenesis of ONFH.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticphatology.diagnomx.eu/vs/1501829501107336.

The suppression of TRIM21 and the accumulation of IFN-α play crucial roles in the pathogenesis of osteonecrosis of the femoral head

Osteonecrosis of the femoral head (ONFH), the pathogenesis of which remains unclear, has been observed in autoimmune disease patients treated with corticosteroids. Recently, it has been shown that anti-tripartite motif-containing 21 (TRIM21) autoantibodies, which are often present in patients with systemic lupus erythematosis and Sjögren's syndrome, inhibit the E3 ligase activity of TRIM21. TRIM21 negatively regulates nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) 3 and 7, three downstream transcription factors, via toll-like receptor 4 signaling. The aim of this study was to clarify the role of TRIM21 in the pathogenesis of ONFH using an animal model. Male Wistar rats were injected with lipopolysaccharide (LPS) twice and with methylprednisolone (MPSL) or saline three times. N-acetyl cysteine (NAC) was administered either concurrently with MPSL or once daily for the 3 days following the last MPSL injection. The incidence of ONFH in the MPSL group was 23.5%. Co-treatment of NAC and MPSL increased the incidence of ONFH to 55.6%. MPSL treatment decreased the activity of NF-κB in the liver and significantly increased the activity of both IRF3 and IRF7. No significant differences were observed in the activity of any of these three transcription factors between the MPSL and the co-treatment groups. In the femoral head, co-treatment with NAC and MPSL significantly decreased the expression of TRIM21 at 3 h and significantly increased the expression of interferon (IFN)-α at 24 h when compared with the MPSL group. IFN-α is known to induce cell death. These findings suggest that the suppression of TRIM21 in the femoral head causes an accumulation of IFN-α, which in turn leads to the development of ONFH. In conclusion, the suppression of TRIM21 resulting from altered NF-κB and IRF homeostasis accelerates the ONFH in rats treated with corticosteroids following LPS administration.