Osteonecrosis Of The Femoral Head Group Research Articles

Evaluation of articular cartilage degeneration in patients with osteonecrosis of the femoral head using T2 mapping magnetic resonance imaging.

To evaluate and characterise articular cartilage degeneration in patients with osteonecrosis of the femoral head (ONFH) using T2 mapping magnetic resonance imaging (MRI). We reviewed 35 patients with ONFH (20 males and 15 females, mean age 45.7±12.9 years) without obvious cartilage abnormalities on plain MRI (ONFH group) and 25 healthy volunteers (9 males and 16 females, mean age 42.9±5.8 years) (control group). All patients underwent T2 mapping MRI after ONFH onset. The region of interest was defined as the weight-bearing portion of the articular cartilage in the femoral head and acetabulum in the coronal view. The T2 values of the articular cartilage of the acetabulum and femoral head, including necrotic and normal regions, were significantly higher in the ONFH group than those in the control group. These T2 values of the acetabulum and femoral head in stages 3A and 2 were significantly higher in the ONFH group than those in the control group. The articular cartilage of the acetabulum and femoral head can deteriorate after the onset of ONFH, which may affect the natural history of ONFH and ONFH treatment. Our findings suggest the need for early intervention in joint preservation surgery.

Correlation analysis between combined deflection angle and osteonecrosis of femoral head after femoral neck fracture

To evaluate the correlation between pelvic incidence (PI) angle, hip deflection angle (HDA), combined deflection angle (CDA) and osteonecrosis of the femoral head (ONFH) after femoral neck fracture, in order to explore early predictive indicators for ONFH occurrence after femoral neck fracture. A study was conducted on patients with femoral neck fractures who underwent cannulated screw internal fixation between December 2018 and December 2020. Among them, 208 patients met the selection criteria and were included in the study. According to the occurrence of ONFH, the patients were allocated into ONFH group and non-NOFH group. PI, HDA, and CDA were measured based on the anteroposterior X-ray films of pelvis and axial X-ray films of the affected hip joint before operation, and the differences between the two groups were compared. The receiver operating characteristic curve (ROC) was used to evaluate the value of the above imaging indicators in predicting the occurrence of ONFH. Among the 208 patients included in the study, 84 patients experienced ONFH during follow-up (ONFH group) and 124 patients did not experience ONFH (non-ONFH group). In the non-ONFH group, there were 59 males and 65 females, the age was 18-86 years (mean, 53.9 years), and the follow-up time was 18-50 months (mean, 33.2 months). In the ONFH group, there were 37 males and 47 females, the age was 18-76 years (mean, 51.6 years), and the follow-up time was 8-45 months (mean, 22.1 months). The PI, HDA, and CDA were significantly larger in the ONFH group than in the non-ONFH group ( P<0.05). ROC curve analysis showed that the critical value of PI was 19.82° (sensitivity of 40.5%, specificity of 86.3%, P<0.05); the critical value of HDA was 20.94° (sensitivity of 77.4%, specificity of 75.8%, P<0.05); and the critical value of CDA was 39.16° (sensitivity of 89.3%, specificity of 83.1%, P<0.05). There is a correlation between PI, HDA, CDA and the occurrence of ONFH after femoral neck fracture, in which CDA can be used as an important reference indicator. Patients with CDA≥39.16° have a higher risk of ONFH after femoral neck fracture.

What are the differences in the recovery of physical function and clinical score between patients with steroid-related osteonecrosis of the femoral head and hip osteoarthritis undergoing total hip arthroplasty? A propensity score-matched study.

Steroid-related osteonecrosis of the femoral head (ONFH), arising from steroid administration for underlying diseases, represents a unique pathology for total hip arthroplasty (THA) and typically affects a younger demographic compared to osteoarthritis (OA). Given the significant age-related differences, this study aims to employ propensity score matching to align patient backgrounds between these two diseases and compare physical function. Additionally, our objective is to scrutinize the patterns of clinical score recovery over the course of one year following THA. Using propensity score matching, 29 patients each with steroid-related ONFH and OA were selected. Muscle strength (hip abductor and knee extensor) were assessed before and after THA. Additionally, recovery of the Harris Hip Score (HHS) and Oxford Hip Score (OHS) up to one year postoperatively was analyzed. The steroid-related ONFH group exhibited gender bias and significantly younger age compared to the OA group. Propensity score matching achieved balanced patient backgrounds. Physical function showed trends of lower hip abduction and knee extensor strength on the operative side in the steroid-related ONFH group. Notably, nonoperative knee extensor strength decreased significantly after matching. HHS and OHS were poor in steroid-related ONFH up to three months postoperatively but recovered after six months. Patients with steroid-related ONFH experience positive outcomes in clinical score following THA. Propensity score matching effectively identified muscle weakness on both operative and nonoperative sides, highlighting its utility in comparative analyses.

Microarchitecture Alternations of Osteochondral Junction in Patients with Osteonecrosis of the Femoral Head.

The study was aimed to investigate microarchitecture of osteochondral junction in patients with osteonecrosis of the femoral head (ONFH). We hypothesis that there were microarchitecture alternations in osteochondral junction and regional differences between the necrotic region (NR) and adjacent non-necrotic region(ANR) in patients with ONFH. Femoral heads with ONFH or femoral neck fracture were included in ONFH group (n = 11) and control group (n = 11). Cylindrical specimens were drilled on the NR/ANR of femoral heads in ONFH group and matched positions in control group (CO.NR/ CO.ANR). Histology, micro-CT, and scanning electron microscope were used to investigate microarchitecture of osteochondral junction. Layered analysis of subchondral bone plate was underwent. Mankin scores on NR were higher than that on ANR or CO.NR, respectively (P < 0.001, P < 0.001). Calcified cartilage zone on the NR and ANR was thinner than that on the CO.NR and CO.ANR, respectively (P = 0.002, P = 0.002). Tidemark roughness on the NR was larger than that on the ANR (P = 0.002). Subchondral bone plate of NR and ANR was thicker than that on the CON.NR and CON.ANR, respectively (P = 0.002, P = 0.009). Bone volume fraction of subchondral bone plate on the NR was significantly decreasing compared to ANR and CON.NR, respectively (P = 0.015, P = 0.002). Subchondral bone plate on the NR had larger area percentages and more numbers of micropores than ANR and CON.NR (P = 0.002/0.002, P = 0.002/0.002). Layered analysis showed that bone mass loss and hypomineralization were mainly on the cartilage side of subchondral bone plate in ONFH. There were microarchitecture alternations of osteochondral junction in ONFH, including thinned calcified cartilage zone, thickened subchondral bone plate, decreased bone mass, altered micropores, and hypomineralization of subchondral bone plate. Regional differences in microarchitecture of osteochondral junction were found between necrotic regions and adjacent non-necrotic regions. Subchondral bone plate in ONFH had uneven distribution of bone volume fraction and bone mineral density, which might aggravate cartilage degeneration by affecting the transmission of mechanical stresses.

A prediction model for osteonecrosis of femoral head after internal fixation with multiple cannulated compression screws for adult femoral neck fractures.

This study aims to investigate the high-risk factors for osteonecrosis of the femoral head (ONFH) after internal fixation with multiple cannulated compression screws for adult femoral neck fractures and to construct a prediction model. Between from January 2012 and December 2020, a total of 268 patients (138 males, 130 females; mean age: 53±10 years; range, 23 to 70 years) with ONFH who had complete follow-up data were included. Closed reduction in combination with open reduction were performed. All patients received internal fixation with multiple cannulated compression screws and were assigned to ONFH and non-ONFH groups. Logistic regression model was utilized to identify independent risk factors for postoperative ONFH, followed by constructing a nomogram prediction model. The predictive ability of the model was evaluated by receiver operating characteristic curve, Hosmer-Lemeshow test, and calibration curve. Multivariate analysis revealed that older age (odds ratio [OR]: 2.307, 95% confidence interval [CI]: 1.295-4.108], Charlson Comorbidity Index (CCI) ≥2 (OR: 2.214, 95% CI: 1.035-4.739), fracture displacement (OR: 2.426, 95% CI: 1.122-5.247), unsatisfactory reduction (OR: 2.629, 95% CI: 1.275-5.423), postoperative removal of internal fixation implant (OR: 2.200, 95% CI: 1.051-4.604) were independent risk factors for postoperative ONFH (p<0.05). The nomogram prediction model constructed based on these clinical characteristics showed high predictive value (AUC=0.807) and consistency (p>0.05). Age, comorbidity index, fracture type, reduction quality and postoperative removal of internal fixation implant are of utmost importance for postoperative ONFH in patients with femoral neck fractures. The established nomogram prediction model can accurately predict the occurrence of postoperative ONFH.

Incidence and risk factors for osteonecrosis of the femoral head in five hundred and ten sickle cell disease paediatric patients.

Osteonecrosis of the femoral head (ONFH) is a degenerative and progressive disorder that mainly affects people with sickle cell disease (SCD). Herein, we aimed to search for a better understanding of markers that can act as risk factors for ONFH in patients with SCD. We conducted a retrospective study including 510 SCD patients followed over 23years. Patients were divided into the ONFH group and the no-ONHF control group. Univariate and multivariate logistic regression analyses were performed to identify risk factors. Among 510 SCD patients, 41(8%) were diagnosed with ONFH at a mean age of 167months ± 64 (72-288). The cumulative incidence of ONHF increased from 2.3% at tenyears to 18.3% at 20years of age. The radiological grade 3 ONHF was predominant. No significant differences in sex, age at diagnosis of SCD, and Hb genotype were found between groups. The patient age and the time since diagnosis of SCD were statistically higher in patients with ONHF in univariate and multivariate analysis. ONHF was also associated with higher creatinine level (p = 0.001) lower LDH level (p = 0.006), and higher number of vaso-occlusive crisis (VOC)/patient/year (p < 0.001). The cumulative incidence of ONHF in patients having more than 3 VOC/year was significantly higher (43% versus 18.9% at 20years, p < 0.001). In addition, infections, gallstones, growth delay, delayed initiation of hydroxyurea, and a higher transfusion rate were significantly associated with ONFH. These findings confirm that ONFH is closely related to the age, severity, and duration of SCD. Better management of this disease prevents acute and chronic complications, and early screening of the ONFH as soon as the first signs of the severity of the disease are detected provides a better functional prognosis.

Analysis of incidence and clinical characteristics of osteonecrosis of femoral head in patients with systemic lupus erythematosus treated with glucocorticoid: A descriptive study based on a prospective cohort

To describe the disease characteristics of osteonecrosis of the femoral head (ONFH) in patients with systemic lupus erythematosus (SLE) who experiencing prolonged glucocorticoid (GC) exposure. Between January 2016 and June 2019, 449 SLE patients meeting the criteria were recruited from multiple centers. Hip MRI examinations were performed during screening and regular follow-up to determine the occurrence of ONFH. The cohort was divided into ONFH and non-ONFH groups, and the differences in demographic baseline characteristics, general clinical characteristics, GC medication information, combined medication, and hip clinical features were compared and comprehensively described. The age at SLE diagnosis was 29.8 (23.2, 40.9) years, with 93.1% (418 cases) being female. The duration of GC exposure was 5.3 (2.0, 10.5) years, and the cumulative incidence of SLE-ONFH was 9.1%. Significant differences ( P<0.05) between ONFH and non-ONFH groups were observed in the following clinical characteristics: ① Demographic baseline characteristics: ONFH group had a higher proportion of patients with body mass index (BMI)<20 kg/m 2 compared to non-ONFH group. ② General clinical characteristics: ONFH group showed a higher proportion of patients with cutaneous and renal manifestations, positive antiphospholipid antibodies (aPLs) and anticardiolipin antibodies, severe SLE patients [baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥15], and secondary hypertension. Fasting blood glucose in ONFH group was also higher. ③ GC medication information: ONFH group had higher initial intravenous GC exposure rates, duration, cumulative doses, higher cumulative GC doses in the first month and the first 3 months, higher average daily doses in the first 3 months, and higher proportions of average daily doses ≥15.0 mg/d and ≥30.0 mg/d, as well as higher full-course average daily doses and proportion of full-course daily doses ≥30.0 mg/d compared to non-ONFH group. ④ Combined medications: ONFH group had a significantly higher rate of antiplatelet drug use than non-ONFH group. ⑤ Hip clinical features: ONFH group had a higher proportion of hip discomfort or pain and a higher incidence of hip joint effusion before MRI screening than non-ONFH group. The incidence of ONFH after GC exposure in China's SLE population remains high (9.1%), with short-term (first 3 months), medium-to-high dose (average daily dose ≥15 mg/d) GC being closely associated with ONFH. Severe SLE, low BMI, certain clinical phenotypes, positive aPLs, and secondary hypertension may also be related to ONFH.

Risk factors for osteonecrosis of femoral head after femoral neck fracture fixation with femoral neck system

To explore the risk factors for osteonecrosis of the femoral head (ONFH) after treatment of femoral neck fractures with femoral neck system (FNS). Between January 2020 and February 2021, 179 patients (182 hips) with femoral neck fractures treated by FNS fixation were selected for retrospective analysis. There were 96 males and 83 females with an average age of 53.7 years (range, 20-59 years). There were 106 cases of low-energy-induced injury and 73 cases of high-energy-induced injury. The fractures were classified as type Ⅱ in 40 hips, type Ⅲ in 78 hips, and type Ⅳ in 64 hips according to Garden classification standard, and as typeⅠin 23 hips, type Ⅱ in 66 hips, and type Ⅲ in 93 hips according to Pauwels classification standard. There were 21 patients with diabetes. Patients were divided into ONFH group and non-ONFH group according to whether ONFH occurred at last follow-up. The data of the patients were collected, including age, gender, body mass index (BMI), trauma mechanism, bone mineral density, having diabetes or not, Garden classification and Pauwels classification of fractures, fracture reduction quality, femoral head retroversion angle, and removal of internal fixator or not. The above factors were analyzed by univariate analysis, and then multivariate logistic regression analysis was used to identify risk factors. Total 179 patients (182 hips) were followed up 20-34 months (mean, 26.5 months). Of these, 30 cases (30 hips) developed ONFH at 9-30 months after operation (ONFH group), and the incidence of ONFH was 16.48%. And 149 cases (152 hips) had no ONFH at last follow-up (non-ONFH group). The univariate analysis showed that there were significant differences between groups in bone mineral density, having diabetes or not, Garden classification, femoral head retroversion angle, and fracture reduction quality ( P<0.05). The multivariate logistic regression analysis showed that the Garden type Ⅳ fracture, reduction quality of grading Ⅲ, femoral head retroversion angle >15°, complicated with diabetes were the risk factors for ONFH after FNS fixation ( P<0.05). For the patients with Garden type Ⅳ fracture, poor quality of fracture reduction, femoral head retroversion angle >15°, and diabetes, the risk of ONFH after FNS fixation increases.

Comparison of Walking Quality Variables between End-Stage Osteonecrosis of Femoral Head Patients and Healthy Subjects by a Footscan Plantar Pressure System.

Background and Objectives: Osteonecrosis of the femoral head (ONFH) is a progressive disease with a complex etiology and unknown pathogenesis. Gait analysis can objectively assess the functional behavior of the foot, thus revealing essential aspects and influencing factors of gait abnormalities. The aim of this study was to evaluate the differences in spatiotemporal parameters, static and dynamic plantar pressure parameters, and symmetry indices between patients with ONFH and healthy subjects. Materials and Methods: The study population consisted of 31 ONFH patients and 31 healthy volunteers. Gait parameters were obtained from the plantar pressure analysis system for both the ONFH and healthy groups. The symmetry index was calculated according to a formula, including spatiotemporal parameters, static and dynamic plantar pressure distribution, percentage of regional impulse, and percentage of the restricted contact area. Results: Compared with healthy controls, patients with ONFH had slower walking speed, shorter step length and stride length, and increased stride time, stance time, and percentage of stance. patients with ONFH had lower plantar static pressure on the affected side and higher contralateral plantar static pressure during stance than controls. During walking, the peak pressures in all regions on the affected side and the peak pressure in the toe 1 and metatarsal 3 regions on the healthy side were lower in ONFH patients than in controls. The percentage of contact area and regional impulse in the heel of both limbs were higher in ONFH patients than in the control group. The symmetry indexes of stride time, stance time, step length, maximum force, impulse and contacted area were significantly increased in ONFH patients compared to controls, with decreased symmetry. Conclusions: Osteonecrosis of the femoral head leads to characteristic changes in plantar pressure distribution. These changes may be interpreted as an attempt by patients with ONFH to reduce the load on the affected limb. Plantar pressure analysis may assist in the diagnosis of ONFH and can provide an objective quantitative indicator for the assessment of subsequent treatment outcomes.

The incidence of focal osteonecrosis of the femoral head and its impact on conversion hip arthroplasty after screw fixation of femoral neck fractures: a multicenter retrospective study based on postoperative magnetic resonance imaging.

Osteonecrosis of the femoral head (ONFH) and subsequent head collapse is a major concern after internal fixation of femoral neck fracture (FNF). Previous studies focused on ONFH incidence using plain radiography; postoperative magnetic resonance imaging (MRI) was rarely performed. We performed a multicenter retrospective study to investigate the incidence of ONFH and the need for conversion hip arthroplasty after FNF screw fixation. We reviewed 195 patients who underwent screw fixation during closed FNF reduction between 2012 and 2017 at three institutions. Except for patients who did not consent to MRI, all patients underwent postoperative MRI either 1-3years after screw fixation. The occurrence of ONFH was investigated through plain radiography and MRI. Thirty patients were diagnosed with ONFH through plain radiography, and an additional 33 patients were diagnosed with MRI, resulting in a total of 63 patients (32.3%) diagnosed with ONFH. The mean time to ONFH diagnosis was 18.9months and the conversion rate to hip arthroplasty was 10.2%. Of the 33 patients who were normal on hip radiography but exhibited ONFH on MRI, all had small focal lesions not associated with head collapse at the last follow-up. The ONFH group diagnosed through plain radiography had more unstable FNFs than the group diagnosed through MRI. Although postoperative MRI revealed a higher incidence of ONFH after FNF screw fixation than reported previously, the small focal MRI lesions were not associated with increased risks of femoral head collapse or conversion to arthroplasty.

Effect of three clinical therapies on cytokines modulation in the hip articular cartilage and bone improvement in rat early osteonecrosis of the femoral head

BackgroundExtracorporeal shockwave therapy (ESWT) and adipose-derived mesenchymal stem cells (ADSCs) have been used clinically for the treatment of osteonecrosis of the femoral head (ONFH). The study elucidated that ESWT, ADSCs, and combination therapy modulated pro-inflammatory cytokines in the articular cartilage and subchondral bone of early rat ONFH. MethodsESWT and ADSCs were prepared and isolated for treatment. Micro-CT, pathological analysis, and immunohistochemistry were performed and analysed. ResultsAfter treatments, subchondral bone of ONFH was improved in trabecular bone volume (BV/TV) (p < 0.001), thickness (Tb.Th) (p < 0.01 and 0.001), and separation (Tb.Sp) (p < 0.001) and bone mineral density (BMD) (p < 0.001) using micro-CT analysis. The articular cartilage was protected and decreased apoptosis markers after all the treatments. The expression of IL33 (p < 0.001), IL5 (p < 0.001), IL6 (p < 0.001), and IL17A (p < 0.01) was significantly decreased in the ESWT, ADSCs, and Combination groups as compared with ONFH group. The IL33 receptor ST2 was significantly increased after treatment (p < 0.001) as compared with ONFH group. The Combination group (p < 0.01) decreased the expression of IL6 better than the ESWT and ADSCs groups. ConclusionESWT, ADSCs and combination therapy significantly protected articular cartilage and subchondral bone of early rat ONFH by modulating the expression of pro-inflammatory cytokines including, IL33 and its receptor ST2, IL5, IL6, and IL17A.

Borderline Developmental Dysplasia of the Hip: A Risk Factor Predicting the Development and Poor Prognosis after Core Decompression for Idiopathic Osteonecrosis of the Femoral Head.

ObjectiveIt is unclear whether idiopathic osteonecrosis of the femoral head (ONFH) is associated with borderline developmental dysplasia of the hip (BDDH). This study aimed to compare the incidence of BDDH between patients with idiopathic ONFH and matched control subjects and determine the influence of BDDH on poor prognosis after core decompression (CD).MethodsWe retrospectively examined 78 consecutive patients (111 hips) with idiopathic ONFH undergoing CD and 1:2 matched with 156 control subjects (222 hips). The anteroposterior pelvic radiographs were used to measure the acetabular anatomical parameters and divide included subjects into BDDH or non‐BDDH group. The incidence of BDDH and acetabular anatomical parameters were compared between patients with idiopathic ONFH and matched controls. Clinical outcomes, such as Harris Hip Score (HHS), progression of collapse, and conversion to total hip arthroplasty (THA), were compared between patients with BDDH and without BDDH in the idiopathic ONFH group, with a mean follow‐up of 72.1 ± 36.6 months.ResultsPatients with idiopathic ONFH had a significantly higher incidence of BDDH than matched controls (29.7% vs 12.2%, p < 0.001). Less acetabular coverage was also found in patients with idiopathic ONFH than in matched controls as demonstrated by lower CEA (28.5° ± 4.7° vs 33.1° ± 5.7°, p < 0.001), AHI (82.4 ± 5.0 vs 86.3 ± 5.4, p < 0.001), ADR (299.6 ± 28.4 vs 318.8 ± 31.3, p < 0.001), and a higher sharp angle (40.0° ± 3.4° vs 37.4° ± 3.7°, p < 0.001). In patients with idiopathic ONFH, the BDDH group had a significantly lower mean HHS at the last follow‐up (83.5 ± 17.4 vs 91.6 ± 9.7, p = 0.015) with a different score distribution (p = 0.004), and a lower 5‐year survival rate with both clinical failure (66.7%, 95% CI 52.4%–84.9% vs 83.7%, 95% CI 75.2%–93.1%; p = 0.028) and conversion to THA (74.6%, 95% CI 60.7%–91.6% vs 92.1%, 95% CI 85.6%–99.0%; p = 0.008) as the endpoints than the non‐BDDH group.ConclusionThe incidence of BDDH was significantly higher in patients with idiopathic ONFH than matched controls, and idiopathic ONFH patients who underwent CD with BDDH had lower mean HHS as well as 5‐year survival rate than those without BDDH. Therefore, BDDH should be considered a risk factor predicting the development of idiopathic ONFH as well as poor prognosis after CD.

Subchondral involvement in osteonecrosis of the femoral head: insight on local composition, microstructure and vascularization

To determine changes of subchondral bone composition, micro-structure, bone marrow adiposity and micro-vascular perfusion in end-stage osteonecrosis of the femoral head (ONFH) compared to osteoarthritis (OA) using a combined in vivo and ex vivo approach. Male patients up to 70 years old referred for total hip replacement surgery for end-stage ONFH were included (n=14). Fifteen patients with OA were controls. Pre-operative MRI was used to assess bone perfusion (dynamic contrast-enhanced (DCE) sequences) and marrow fat content (chemical shift imaging). Three distinct zones of femoral head subchondral bone - necrotic, sclerotic, distant - were compared between groups. After surgery, plugs were sampled in these zones and Raman spectroscopy was applied to characterize bone mineral and organic components (old and newly-formed), and contrast-enhanced micro-computed tomography (CE-μCT) to determine bone micro-structural parameters and volume of bone marrow adipocytes, using conventional 2D histology as a reference. In the necrotic zone of ONFH patients compared to OA patients: 1) the subchondral plate did not exhibit significant changes in composition nor structure; 2) the volume fraction of subchondral trabecular bone was significantly lower; 3) type-B carbonate substitution was less pronounced, 4) collagen maturity was more pronounced; and 5) bone marrow adipocytes were significantly depleted. The sclerotic zone from the ONFH group showed greater trabecular thickness, and higher DCE-MRI AUC and Ktrans. Volume fraction of subchondral bone, trabecular number, and Kep were significantly lower in the distant zone of the ONFH group. This study demonstrated alterations of subchondral bone microstructure, composition, perfusion and/or adipose content in all zones of the femoral head.

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.

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.

Association of MIR17HG and MIR155HG gene variants with steroid-induced osteonecrosis of the femoral head in the population of northern China

IntroductionSteroid-induced osteonecrosis of the femoral head (ONFH) is a disease of the bone. Metabolism and genetic factors are generally considered to play an important role. The purpose of this study was to investigate the relationship between single-nucleotide polymorphisms (SNPs) in MIR17HG and MIR155HG and the risk of steroid-induced ONFH in the population of northern China.MethodsA total of 199 steroid-induced ONFH patients and 506 healthy controls were recruited for the study. Four SNPs of MIR17HG and seven SNPs of MIR155HG were genotyped by Sequenom MassARRAY. ORs and 95% CIs were used to evaluate the relationship between these SNPs and steroid-induced ONFH.ResultsIn the codominant model, patients with the MIR17HG SNPs (rs7318578) AA genotype had an increased risk of steroid-induced ONFH (OR = 1.79, p = 0.039); in the recessive model, patients with the MIR17HG SNP (rs7318578) AA genotype had an increased risk of steroid-induced ONFH (OR = 1.78, p = 0.032). Stratified analysis showed that a MIR17HG SNP (rs7318578) and the MIR155HG SNPs (rs77218221, rs11911469, rs34904192 and rs4143370) were closely related to different unornamented phenotypes of steroid-induced ONFH. Analysis of the clinical indicators revealed significant differences in high-density lipoprotein (HDL-C) levels between the ONFH group and the control group (p = 0.005). In the MIR17HG SNP (rs75267932), patients with different genotypes had different levels of triglyceride (TG). The MIR155HG SNPs (rs77699734, rs1893650, and rs34904192) showed differences in triglyceride (TG), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) levels in patients with different genotypes.ConclusionOur results confirm that MIR17HG and MIR155HG gene mutations are associated with steroid-induced ONFH susceptibility in the population of northern China, providing new evidence for the early detection and prevention of ONFH.

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.

Hidden osteonecrosis of the femoral head after healed femoral neck fractures: magnetic resonance imaging study of 58 consecutive patients.

Several studies investigated the posttraumatic osteonecrosis of the femoral head (ONFH) after femoral neck fracture (FNF). However, no study has investigated the hidden ONFH after FNF, which is missed by simple radiographs, using magnetic resonance imaging (MRI). This retrospective study involved 58 consecutive patients who underwent implant removal surgery after internal fixation due to FNF. MRI was used to investigate the incidence of hidden ONFHs, which were not initially revealed on plain radiographs. The comparisons between hidden ONFH and other groups were performed for patent demographics and clinical variables including ONFH location, lesion size, the progression rate of ONFH collapse, and end-stage arthroplasty conversion rate. Of the 58 patients, 38 exhibited no evidence of ONFH on plain radiograph screening. However, 13 of the 38 patients were confirmed of hidden ONFH via MRI. The collapse progressed in four of the 13 patients, and one of them underwent total hip arthroplasty surgery. No significant differences were found between the hidden and definite ONFH groups in demographics and clinical variables. However, a significant difference exists between the hidden ONFH and the normally healed FNF groups in terms of the Garden type (P < 0.001). A large number of cases with hidden ONFH were confirmed using MRI following healed FNF, and most of them were initially displaced FNF. Thus, the treatment method between internal fixation and hip arthroplasty should be carefully selected, particularly with displaced FNF.

Glucocorticoids induce femoral head necrosis in rats through the ROS/JNK/c-Jun pathway.

Osteonecrosis of the femoral head (ONFH) is a common clinical disease with a high disability rate. Apoptosis of osteoblasts caused by high-dose short-term or low-dose long-term glucocorticoid (GC) administration is the biological basis of steroid-induced avascular necrosis of the femoral head (SANFH). The pathogenesis of SANFH has not yet been fully elucidated, and there is currently a lack of effective clinical treatments. Here, we investigated the role of the reactive oxygen species (ROS)/JNK/c-Jun signaling pathway in SANFH. Dexamethasone (Dex) was used to induce apoptosis in osteoblasts, and this resulted in a significant increase in levels of p-JNK, p-c-Jun, Bax, caspase-3, caspase-9, cytochrome C, Beclin-1, and LC3, and a decrease in levels of P62 and Bcl-2. In addition, intracellular ROS levels were increased and mitochondrial membrane potential was decreased. Administration of 3-MA, an autophagy inhibitor, attenuated Dex-mediated changes in autophagy and apoptosis. A rat model of ONFH exhibited severe bone trabecular hollow bone pits along with a significant increase in femoral head cell apoptosis compared with the control group. Additionally, micro-CT analysis showed that both bone tissue content and femoral head integrity were significantly reduced in the ONFH group. Furthermore, 3-MA treatment decreased the effect of Dex on GC-induced ONFH and osteoblast apoptosis in rats and could counteract microstructure destruction due to femoral head necrosis. In summary, our data suggest that GC can induce osteoblast apoptosis and autophagy through the ROS/JNK/c-Jun signaling pathway, which contributes to ONFH.

MiR-155-5p regulates mesenchymal stem cell osteogenesis and proliferation by targeting GSK3B in steroid-associated osteonecrosis.

microRNAs (miRNAs) have recently been recognized as playing an important role in bone-associated diseases. This study investigated whether the reduced miR-155-5p in steroid-associated osteonecrosis of the femoral head (ONFH) attenuated osteogenic differentiation and cell proliferation by targeting GSK3B. Bone marrow was collected from the proximal femurs of patients with steroid-associated ONFH (n = 10) and patients with new femoral neck fracture (n = 10) and mesenchymal stem cells (MSCs) were isolated. The expression profile, the biological function of miR-155-5p, and the interaction between miR-155-5p and GSK3B were investigated by cell viability measurement, western blot, real-time polymerase chain reaction, luciferase reporter assay, and Alizarin Red S (ARS) staining of MSCs. The MSCs that were obtained from the femoral neck fracture group and from the steroid-associated ONFH group were transfected with or without miR-155-5p. We found that, in ONFH samples, the level of mature miR-155-5p was significantly lower than that of control samples. By inhibiting GSK3B, miR-155-5p promoted the nuclear translocation of β-catenin, increased the expression of osteogenesis-related genes, and facilitated the proliferation and differentiation of MSCs. Restoring the expression of GSK3B in MSCs partially reversed the effect of miR-155-5p. These findings suggest that reduced miR-155-5p in steroid-associated ONFH attenuates osteogenic differentiation and cell proliferation by increased levels of GSK3B and inhibition of Wnt signaling.