Exosomes derived from M2 macrophages prevent steroid-induced osteonecrosis of the femoral head by modulating inflammation, promoting bone formation and inhibiting bone resorption.

Inflammatory reactions are involved in the development of steroid-induced osteonecrosis of the femoral head(ONFH). Studies have explored the therapeutic efficacy of inhibiting inflammatory reactions in steroid-induced ONFH and revealed that inhibiting inflammation may be a new strategy for preventing the development of steroid-induced ONFH. Exosomes derived from M2 macrophages(M2-Exos) display anti-inflammatory properties. This study aimed to examine the preventive effect of M2-Exos on early-stage steroid-induced ONFH and explore the underlying mechanisms involved. In vitro, we explored the effect of M2-Exos on the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells(BMMSCs). In vivo, we investigated the role of M2-Exos on inflammation, osteoclastogenesis, osteogenesis and angiogenesis in an early-stage rat model of steroid-induced ONFH. We found that M2-Exos promoted the proliferation and osteogenic differentiation of BMMSCs. Additionally, M2-Exos effectively attenuated the osteonecrotic changes, inhibited the expression of proinflammatory mediators, promoted osteogenesis and angiogenesis, reduced osteoclastogenesis, and regulated the polarization of M1/M2 macrophages in steroid-induced ONFH. Taken together, our data suggest that M2-Exos are effective at preventing steroid-induced ONFH. These findings may be helpful for providing a potential strategy to prevent the development of steroid-induced ONFH.

Risk factor analysis of femoral avascular necrosis after operation for Tönnis grade IV developmental dysplasia of the hip.

PURPOSE: We explored the risk factors for avascular necrosis (AVN) after surgery using open reduction, pelvic osteotomy, and femoral osteotomy for Tönnis grade IV developmental dysplasia of the hip (DDH). METHODS: In this retrospective study, we collected data of patients with Tönnis grade IV DDH treated with open reduction and pelvic osteotomy combined with femoral osteotomy from January 2012 to May 2020. The patients were divided into the AVN group and non-AVN group using the Kalamchi-MacEwen classification system. The clinical and imaging data of the two groups were collected, and the possible risk factors were included in the analysis. Univariate and multivariate logistic regression analyses were used to identify the independent risk factors and odds ratios of AVN. RESULTS: In all, 254 patients (mean age; 2.6±0.9 years, 278 hips) were included. The mean follow-up time was 3.8±1.5 years. A total of 89 hips (32%) were finally classified as AVN (Kalamchi-MacEwen II-IV). Univariate analysis showed significant associations with AVN for age (p=0.006), preoperative femoral neck anteversion (FAV) (p<0.001), femoral osteotomy length to dislocation height ratio (FDR) <1 (p<0.001), and the epiphyseal ossific nucleus diameter to the neck diameter ratio (ENR) <50% (p=0.009). Multivariate logistic regression analysis showed that only excessive preoperative FAV (OR: 1.04; 95% CI: 1.02-1.05; p<0.001) and FDR<1 (OR: 3.58; 95% CI: 2.03-6.31; p<0.001) were independent risk factors for femoral head necrosis. CONCLUSION: Excessive preoperative FAV and FDR<1 are important risk factors for femoral AVN after open reduction, pelvic osteotomy, and femoral osteotomy for Tönnis grade IV DDH. For children with DDH with high dislocation and excessive FAV, clinicians should fully evaluate their condition and design more personalized treatment programs to prevent AVN.

The protective role of vitamins C and E in steroid-induced femoral head osteonecrosis: An experimental study in rats.

OBJECTIVES: This study aimed to determine whether vitamin C (VC) and vitamin E (VE) can effectively protect the femoral head and reduce the risk of developing osteonecrosis in rats that have been treated with steroids. MATERIALS AND METHODS: The study was conducted on 30 young adult male Sprague-Dawley rats (mean weight: 356±18 g; range, 330 to 375 g), which were randomly assigned to one of five groups. The control group received saline solution, while the other groups were given lipopolysaccharide/methylprednisolone (LPS/MPS) to induce osteonecrosis. Three groups in which osteonecrosis was induced were also intraperitoneally administered either VC, VE, or both once a day for four weeks. Intracardiac blood samples were taken at the end of the fourth week for biochemical examination, and the rats were then sacrificed under general anesthesia. After sacrification, right femurs were removed for histopathological, immunohistochemical, and radiologic examinations. RESULTS: The results showed that the mean trabecular number increased significantly in the VC+VE group. There was a substantial decrease observed in the mean trabecular separation within the LPS/MPS group compared to the control group, although trabecular separation decreased in all three vitamin groups compared to the LPS/MPS group. The surface area/bone volume was significantly increased in the VC+VE group compared to the LPS/MPS group. Histological, immunohistochemical, and radiological examinations showed that the administration of VC and VE significantly reduced oxidative stress, inflammation, and microvascular dysfunction in rats with steroid-induced femoral head osteonecrosis. CONCLUSION: This study suggests that VC, VE, and particularly VC+VE have a protective effect on the femoral head in rats with steroid-induced femoral head osteonecrosis. These findings may lead to new treatment options for patients.

The effects of prophylactic tadalafil use on VEGF expression in the rabbit model of steroid-induced femoral head avascular necrosis.

OBJECTIVE: The purpose of this study was to examine the effect of prophylactic tadalafil use on a steroid-induced femoral head avascular necrosis model in terms of microscopic, imaging, and molecular biological changes. METHODS: Twenty-four New Zealand rabbits were divided into 3 equal groups. Eight rabbits were designated as the control group and did not receive treatment. Rabbits in group 1 (G1) received 0.1 mg/kg Escherichia coli lipopolysaccharide (LPS) intravenously and 40 mg/ kg methylprednisolone sodium succinate (MP) was administered intramuscularly for 3 days consecutively. Rabbits in group 2 (G2) were given 5 mg/kg tadalafil orally for 10 consecutive days. Starting on the eighth day, 0.1 mg/kg LPS was given, and following this 40 mg/kg MP injections were administered for 3 days. All animals were sacrificed 3 weeks after the final MP injection. Magnetic resonance imaging was performed, and bilateral femora were harvested. Half of the femoral head was stored for Vascular Endothelial Growth Factor (VEGF) examination with Western blot analysis. The other half was examined microscopically for the presence of osteonecrosis. RESULTS: In G1, 15 out of 16 hips (93%) of the 8 rabbits had osteonecrosis compared to 8 out of 12 hips (67%) of 6 rabbits in G2 (P > .05). The VEGF expression in G2 was significantly higher than in the control group and G1 (P < .05 and P < .001, respectively). There was no significant difference in VEGF expression between the control group and G1 (P > .05). CONCLUSION: This study has shown us that femoral head osteonecrosis can be reliably induced with LPS and corticosteroid, as described in the literature. Prophylactic tadalafil use did not decrease the occurrence of osteonecrosis significantly. However, it significantly increased VEGF expression in the femoral head independent of the effects of steroids and LPS.

[Expert consensus on clinical drug prevention and treatment of osteonecrosis of the femoral head(2022)].

With the in-depth understanding of osteonecrosis of femoral head (ONFH), and more and more patients seeking medical treatment in the early stage of the disease, surgical treatment of femoral head necrosis alone is no longer sufficient for the current treatment of patients' demand, how to rationally and effectively apply drugs to strengthen the early prevention and treatment of femoral head necrosis and delay the progression of disease is becoming more and more important. This article combines the latest expert consensus and evidence-based medical evidence on the principles of ONFH diagnosis and treatment in Chinese and Western medicine at home and abroad, combined with domestic actual clinical application experience, and is organized by experts from Association Related to Circulation Osseous Chinese Microcirculation Society (CSM-ARCO) to write this consensus, focusing on the types of ONFH drugs, the characteristics, safety, rationality and basic principles of drug use provide reference opinions for the safe, reasonable, standardized and effective drug use of medical institutions at all levels. This consensus is only an expert guideline based on literature and clinical experience, not as a requirement for mandatory implementation, let alone as a legal basis. The clinical practice could be tailored to the actual local conditions to develop appropriate prevention and treatment measures for patients.

Extracellular vesicles from human umbilical cord mesenchymal stem cells prevent steroid-induced avascular necrosis of the femoral head via the PI3K/AKT pathway.

Extracellular vesicles (EVs) secreted by human umbilical cord mesenchymal stem cells (hucMSC) have excellent therapeutic potential for many diseases. The aim of this study was to define the role of hucMSC-EVs in the prevention and treatment of steroid-induced avascular necrosis of the femoral head (SANFH). After establishing the SANFH rat model, the effects of hucMSC-EVs were assessed by measuring the microstructure of the femoral head using HE staining, micro-computed tomography (micro-CT), and TUNEL staining. The administration of hucMSC-EVs caused a significant reduction to glucocorticoids (GCs)-induced osteoblast apoptosis and empty lacuna of the femoral head, while effectively improving the microstructure. HucMSC-EVs rescued the deactivation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway induced by GCs, and reversed the proliferation and migration of osteoblasts inhibited by GCs. In addition, hucMSC-EVs attenuated the inhibitory effects of GCs on rat osteoblast osteogenesis, angiogenesis of endothelial cells, and prevented osteoblast apoptosis. However, the promoting effects of hucMSC-EVs were abolished following the blockade of PI3K/AKT on osteoblasts. hucMSC-EVs were found to prevent glucocorticoid-induced femoral head necrosis in rats through the PI3K/AKT pathway.

Effects of Puerarin-Loaded Tetrahedral Framework Nucleic Acids on Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is recognized as a common refractory orthopedic disease that causes severe pain and poor quality of life in patients. Puerarin (Pue), a natural isoflavone glycoside, can promote osteogenesis and inhibit apoptosis of bone mesenchymal stem cells (BMSCs), demonstrating its great potential in the treatment of osteonecrosis. However, its low aqueous solubility, fast degradation in vivo, and inadequate bioavailability, limit its clinical application and therapeutic efficacy. Tetrahedral framework nucleic acids (tFNAs) are promising novel DNA nanomaterials in drug delivery. In this study, tFNAs as Pue carriers is used and synthesized a tFNA/Pue complex (TPC) that exhibited better stability, biocompatibility, and tissue utilization than free Pue. A dexamethasone (DEX)-treated BMSC model in vitro and a methylprednisolone (MPS)-induced ONFH model in vivo is also established, to explore the regulatory effects of TPC on osteogenesis and apoptosis of BMSCs. This findings showed that TPC can restore osteogenesis dysfunction and attenuated BMSC apoptosis induced by high-dose glucocorticoids (GCs) through the hedgehog and Akt/Bcl-2 pathways, contributing to the prevention of GC-induced ONFH in rats. Thus, TPC is a promising drug for the treatment of ONFH and other osteogenesis-related diseases.

Denosumab Can Prevent Collapse in Patients with Early-Stage Steroid-Induced Osteonecrosis of the Femoral Head by Inhibiting Osteoclasts and Autophagy.

OBJECTIVE: The osteoclastic bone resorption inhibitors might have positive effect in preventing femoral head collapse in patients with osteonecrosis of the femoral head (ONFH). However, as a novel osteoclastic inhibitor, whether denosumab can prevent collapse in steroid-induced ONFH remains unknown. This study aims to evaluate the treatment effect of denosumab and the potential protective mechanism. METHODS: This was a retrospective study. A total of 161 patients with steroid-induced ONFH who underwent denosumab treatment were reviewed, and 209 untreated patients were selected as controls. Their clinical characteristics and radiological exam results were obtained. Patients were treated with 60 mg denosumab every 6 months for 2 years. The primary outcome was the incidence of femoral head collapse at 2 years after the initial diagnosis of ONFH. Secondary outcomes included the Harris hip score, progression of osteosclerosis, increase in necrotic area, bone marrow oedema relief, and bone mineral density increase in the femoral head. The Mann-Whitney U test and chi-square tests were performed to identify the differences between the continuous and categorical variables, respectively. A multivariate logistic regression model was built to identify the factors associated with the treatment effect of denosumab. RESULTS: The incidence of femoral head collapse was 42.24% (68/161) in the denosumab group and 54.07% (113/209) in the control group (χ2  = 5.094, p = 0.024; relative risk = 0.787, 95% CI = 0.627-0.973). The excellent-good rates of the Harris hip score were 63.98% (103/161) in the denosumab group and 44.98% (94/209) in the control group (χ2  = 13.186, p < 0.001). The incidence of osteosclerosis progression in the denosumab group was 55.28% (89/161), which was significantly higher than that in the control group (43.54%, 91/209, χ2  = 5.016, p = 0.025). Meanwhile, a significant increase in bone mineral density was identified in 29.19% (47/161) and 7.18% (15/209) of patients in the denosumab and control groups, respectively (χ2  = 31.600, p < 0.001). The osteoclastic cytoplasm expression of LC3-II was more positive in the control group than in the denosumab group (immunohistochemistry scoring: 3.58 ± 2.27 vs 6.33 ± 2.64, Z = -2.684, p = 0.007). A total of three independent factors were considered to be associated with the positive treatment effect of denosumab, the time of first denosumab administration (OR = 2.010, 95% CI = 1.272-3.177), osteosclerosis (OR = 1.583, 95% CI = 1.024-2.445), and the necrotic area before denosumab administration (medium necrotic area: OR = 2.084, 95% CI = 1.245-3.487; large necrotic area: OR = 2.211, 95% CI = 1.255-3.893). CONCLUSIONS: The current study demonstrated that denosumab had a positive effect on preventing femoral head collapse in patients with steroid ONFH. This effect might be closely associated with the inhibition of osteoclasts and their autophagy.

Modified Smith-Petersen approach with rectus-sparing reduces severe avascular necrosis for developmental dysplasia of the hip at walking age: minimum 5-year follow-up.

BACKGROUND: Developmental dysplasia of the hip (DDH) is one of the most common orthopedic malformations in children. Open reduction for DDH at walking age remains a major concern. The goal of this study is to evaluate the mid-term effect of a modified Smith-Petersen approach which preserves the rectus femoris on DDH at walking age, in particular avascular necrosis (AVN). METHODS: A retrospective review of DDH patients aged between 12 and 24 months was carried out between January 2010 and June 2016. Open reduction through the Smith-Petersen approach (Group A) and modified Smith-Petersen approach, which preserves the rectus femoris (Group B), were both used. Measurement of hip geometry included acetabular index, the International Hip Dysplasia Institute classification, and AVN degree. Clinical records included operation time, bleeding volume, and abduction angle. RESULTS: There were 101 children (119 hips) with DDH who met the inclusion criteria. There were 66 hips in Group A and 53 in Group B. The mean surgical age at open reduction was 17.0 ± 2.4 months, with a mean 104.9 ± 19.5 months at last follow-up. There was no statistical difference in surgical age between the two groups (17.2 vs. 16.4 months). There was no significant difference in the incidence of all types of clinically significant AVN between group A and group B (27.3 vs. 18.9%), but the incidence of severe AVN was lower in group B (19.7 vs. 5.7%, P = 0.026). In addition, the lower the age at the time of open reduction, the lower the severity of AVN (P = 0.002). CONCLUSIONS: These mid-term data suggest that the modified Smith-Petersen approach with rectus-sparing could reduce severe AVN more than the classical Smith-Peterson approach in open reduction in DDH at walking age. In addition, early open reduction can reduce the postoperative degree of AVN.

Ginkgo biloba L. extract prevents steroid-induced necrosis of the femoral head by rescuing apoptosis and dysfunction in vascular endothelial cells via the PI3K/AKT/eNOS pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. extract (EGb) is one of the world's most extensively used herbal medicines. Due to the diverse pharmacological properties of EGb, it has been used in the treatment of neurological illnesses, as well as cardiovascular and cerebrovascular ailments. However, the effect and pharmacological mechanism of EGb on steroid-induced necrosis of the femoral head (SINFH) are still unclear. AIM OF THE STUDY: SINFH remains a challenging problem in orthopedics. Previous investigations have shown that EGb has the potential to reduce the occurrence of SINFH. The goal was to determine the effect and mechanism of EGb in preventing SINFH by inhibiting apoptosis and improving vascular endothelial cells (VECs) functions. MATERIALS AND METHODS: CCK-8, nitric oxide (NO) production and flow cytometry were used to determine the cell apoptosis and function. The scratch and angiogenesis tests assessed migration and tube formation. Western blot analysis detected the expressions of apoptosis-related proteins and PI3K/AKT/eNOS pathway-related proteins. Apoptosis and angiogenesis were also detected treated with the inhibitors. A mouse model of SINFH was established. Paraffin section was used to determine the necrotic pathology and apoptosis. Vessels in the femoral heads were assessed by immunofluorescence staining. RESULTS: When stimulated by methylprednisolone (MPS), cell viability, NO generation and tube formation were decreased, the apoptotic rate increased. Simultaneously, MPS decreased the expression levels of p-PI3K, p-AKT, and p-eNOS. EGb increased the expression levels of these proteins, restrained apoptosis, and restored cell functions. The addition of the inhibitors decreased anti-apoptotic effect and angiogenesis. In addition, when compared to the model mice, there were fewer empty lacunae and normal trabecular arrangement after taking different doses of EGb. The protective effect was also confirmed by the vascular quantitative analysis in vivo. CONCLUSION: This study established that EGb increased endothelial cell activity and inhibited apoptosis and function loss induced by MPS, elucidating the effect and molecular mechanism of EGb on early SINFH.

Activation of aldehyde dehydrogenase 2 protects ethanol-induced osteonecrosis of the femoral head in rat model.

OBJECTIVES: Osteonecrosis of the femoral head (ONFH) is a devastating disease characterized by destructive bone structures, enlarged adipocyte accumulation and impaired vascularization. The aldehyde dehydrogenase 2 (ALDH 2) is the limiting enzyme for ethanol metabolism with many physiological functions. The aim was investigated the potential protective role of activated ALDH 2 by Alda-1 for ethanol-induced ONFH. MATERIALS AND METHODS: The ethanol-induced ONFH in rat was performed to explore the protective of Alda-1 by various experimental methods. Subsequently, the effect of Alda-1 and ethanol on the osteogenic and adipogenic differentiation was investigated via multiple cellular and molecular methods. Finally, the effect of Alda-1 and ethanol on the neo-vascularization was detected in Human umbilical vein endothelial cells (HUVECs) and ONFH model. RESULTS: Firstly, radiographical and pathological measurements indicated that alda-1 protected ethanol-induced ONFH. Moreover, ethanol significantly inhibited the proliferation and osteogenic differentiation of BMSCs, whereas Alda-1 could distinctly rescue it by PI3K/AKT signalling. Secondly, ethanol remarkably promoted the lipid vacuoles formation of BMSCs, while Alda-1 significantly retarded it on BMSCs by AMPK signalling pathway. Finally, ethanol significantly inhibited proliferation and growth factor level resulting in reduced angiogenesis, whereas Alda-1 could rescue the effect of ethanol. Additionally, Alda-1 significantly reduced the occurrence of ONFH and promoted vessel number and distribution in alcoholic ONFH. CONCLUSIONS: Alda-1 activation of ALDH 2 was highly demonstrated to protect ethanol-induced ONFH by triggering new bone formation, reducing adipogenesis and stimulating vascularization.

Core Decompression Prevents Progression of Asymptomatic Type C Osteonecrosis of Femoral Head According to the Japanese Investigation Committee Classification: A Retrospective Study.

OBJECTIVE: To evaluate whether core decompression could prevent progression of asymptomatic type C osteonecrosis of the femoral head (ONFH) according to the Japanese Investigation Committee (JIC) classification. METHODS: This retrospective cohort study included 124 hips (117 patients) with asymptomatic type C ONFH. Seventy-one hips (67 patients) received core decompression (core decompression group) and 53 hips (50 patients) received no surgical treatment (control group). Clinical and radiological follow-up was conducted at 6 and 12 months, then annually until 5 years. Clinical outcomes were evaluated in terms of the Oxford hip score and UCLA Activity Level rating. Radiological outcomes were evaluated using X-ray and magnetic resonance imaging. Survival analysis was performed based on collapse of the femoral head as the first endpoint and total hip arthroplasty (THA) as the second endpoint. RESULTS: There were no significant differences in clinical outcomes between the core decompression group and the control group within 2 years after surgery. Patients in the core decompression group had significantly better Oxford hip score and UCLA Activity Level from year 3 to the end of follow-up (P < 0.05). In year 5, the absolute difference in Oxford hip score (5.3 points) exceeded the reported minimal clinically important difference (MCID, 5.2 points). In years 3-5, the absolute difference in UCLA Activity Level rating (0.95 points, 0.95 points, and 0.99 points, respectively) exceeded the reported MCID (0.92 points). By 5-year follow-up, significantly fewer patients in the core decompression group had experienced femoral head collapse (40.8% vs 62.3%, P = 0.011) or received THA (26.8% vs 45.3%, p = 0.022). CONCLUSIONS: Core decompression can prevent progression of asymptomatic type C ONFH according to the JIC classification, leading to better medium-term hip function and activity levels than no surgical treatment. Core decompression is recommended for early intervention against asymptomatic type C ONFH.

Lycium barbarum polysaccharide protects against osteonecrosis of femoral head via regulating Runx2 expression.

BACKGROUND: Osteonecrosis of femoral head (ONFH) is a pathological state caused by lack of blood supply in femoral head. This study aimed to explore the function of Lycium barbarum polysaccharide (LBP), an antioxidant agent extracted from L. barbarum, on ONFH. METHODS: Osteonecrosis rat model was generated using lipopolysaccharide (LPS) and methylprednisolone followed by examination of body weight, blood glucose, morphology, and BMSC osteoblast differentiation. The effect and underlying mechanism of LBP on the proliferation, apoptosis, and osteoblast differentiation of BMSC were determined with or without LPS or hypoxia treatment using CCK-8. Alizarin Red S staining, flow cytometry, and western blot, respectively. RESULT: LBP could protect against glucocorticoid-induced ONFH in rats, resulting in improved sparse trabecular bone, empty lacunae and bone cell coagulation. Moreover, LBP promoted the proliferation and osteoblast differentiation of bone mesenchymal-derived stem cells (BMSCs) in a dose-dependent manner. Furthermore, LBP enhanced osteoblast differentiation of BMSCs under hypoxia condition. Mechanistically, we found that LBP treatment enhanced Runx2 and ALP expression in BMSCs. LBP restored the expression of Runx2 and ALP under hypoxia, suggesting that LBP might be involved in regulating Runx2/ALP expression and contributed to osteoblast differentiation. Knockdown of Runx2 significantly inhibited BMSCs proliferation, while LBP treatment did not rescue the osteoblast differentiation ability of BMSCs with Runx2 knockdown. CONCLUSION: Our findings suggested that LBP protects against ONFH via regulating Runx2 expression, which could be utilized to treat patients suffering ONFH.

Evaluation of avascular necrosis risk factors after closed reduction for developmental dysplasia of the hip before walking age.

Avascular necrosis (AVN) of the femoral head is one of the most important complications after closed reduction and spica cast application in developmental dysplasia of the hip (DDH) treatment. This study aims to put forth the impact of closed reduction age and other factors which can cause AVN. Inclusion criteria of the study were: closed reduction and spica cast application before walking age (12 months) and minimum 2 years duration of follow-up. The presence of femoral head ossific nucleus, International Hip Dysplasia Institute (IHDI) score, acetabular indices and AVN were evaluated from radiographies. Hip abduction angles were evaluated on CT images. The absence of the ossific nucleus at the closed reduction time and preoperative IHDI grade were not significant risk factors for AVN (respectively OR = 2.83; 95% CI, 0.99-8.07; P = 0.052; OR = 2.5; 95% CI, 0.85-7.32; P = 0.094). For the patients older than 10 months, (1) the absence of the ossific nucleus was a significant risk factor for grade 2 or higher AVN according to the Bucholz Ogden criteria (P = 0.020) and (2) the higher preoperative IHDI grade (IHDI 3-4) was a significant risk factor for AVN (P = 0.032). AVN of the femoral head was a significant risk factor for fair or poor clinical outcome (P = 0.001). It is not reasonable to wait for radiological visibility of the ossific nucleus to prevent femoral head AVN before applying closed reduction and spica cast, irrespective of the age interval.

Soluble epoxide hydrolase inhibitor can protect the femoral head against tobacco smoke exposure-induced osteonecrosis in spontaneously hypertensive rats.

Exposure to tobacco smoke (TS) has been considered a risk factor for osteonecrosis of the femoral head (ONFH). Soluble epoxide hydrolase inhibitors (sEHIs) have been found to reduce inflammation and oxidative stress in a variety of pathologies. This study was designed to assess the effect of sEHI on the development of ONFH phenotypes induced by TS exposure in spontaneously hypertensive (SH) rats. SH and normotensive Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or TS (80 mg/m3 particulate concentration) 6 h/day, 3 days/week for 8 weeks. During this period, sEHI was delivered through drinking water at a concentration of 6 mg/L. Histology, immunohistochemistry, and micro-CT morphometry were performed for phenotypic evaluation. As results, TS exposure induced significant increases in adipocyte area, bone specific surface (BS/BV), and trabecular separation (Tb.SP), as well as significant decreases in bone mineral density (BMD), percent trabecular area (Tb.Ar), HIF-1a expression, bone volume fraction (BV/TV), trabecular numbers (Tb.N), and trabecular thickness (Tb.Th) in both SH and WKY rats. However, the protective effects of sEHI were mainly observed in TS-exposed SH rats, specifically in the density of osteocytes, BMD, Tb.Ar, HIF-1a expression, BV/TV, BS/BV, Tb.N, and Tb.SP. Our study confirms that TS exposure can induce ONFH especially in SH rats, and suggests that sEHI therapy may protect against TS exposure-induced osteonecrotic changes in the femoral head.

Can formation of avascular necrosis really be prevented in Delbet type 2 femoral neck fractures?

BACKGROUND: Fractures of proximal femur are rarely seen in childhood. These fractures can result in serious complications such as avascular necrosis (AVN), coxa vara, and early closure of the femoral epiphysis. The aim of this study is to investigate retrospectively the Delbet type 2 fractures that are commonly seen and has high rates of AVN. METHODS: Forty-two patients whose Delbet type 2 fractures were treated in our hospital between January 2009 and June 2018 were analyzed. The patients' mechanism of fracture formation, displacement of the fracture, presence of accompanying injuries, timing of surgery, open or closed reduction, whether the screws cross the epiphyseal growth plate epiphyseal line, and AVN data were analyzed retrospectively. RESULTS: Of the 42 screened patients, 34 patients with complete follow-up graphs and files were included in the study. The mean age of the patients was 11.02 years (1-17 years old), and the mean follow-up time was 40.82 months (range 24 to 98 months). When the follow-up radiographs of the patients were examined, it was found that AVN in 9 patients (26.5%), coxa vara in 2 patients (5.9%), and non-union in 1 patient (2.9%). The AVN rate was significantly higher in patients with high-energy injuries and high fracture displacement at baseline (p=0.034 and p=0.047, respectively). CONCLUSION: According to our findings in Delbet type 2 fractures, other than the severity of the trauma and the initial displacement of the fracture, factors related to the treatment process do not have a significant effect on the development of AVN. Age was not determined as a risk factor for the development of AVN in these patients.

Hyper-activated platelet lysates prevent glucocorticoid-associated femoral head necrosis by regulating autophagy.

Platelet Rich Plasma (PRP) can activate angiogenic and osteogenic pathways, making it a highly promising therapeutic agent for bone growth. Super active platelet lysate (sPL) is derived from platelet-rich plasma (PRP) through ultra-low temperature freeze-thawing. The aim of this study was to evaluate the potential therapeutic effect of sPL on glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). sPL increased the proliferation of GC-treated osteoblasts and endothelial cells, and inhibited apoptosis in vitro. Furthermore, sPL promoted healing of necrotic bone tissues in a rat ONFH model by restraining GC-induced apoptosis and increase autophagy of the osteoblasts. Overall, the results of this study provide a theoretical basis for the clinical application of sPL in ONFH.

The effectiveness of preliminary traction in the treatment of congenital dislocation of the hip.

BACKGROUND: Historical papers on the treatment of congenital dislocation of the hip suggest the use of preliminary traction to facilitate closed reduction or to decrease the risk of avascular necrosis (AVN) of the femoral head. In the 1980s, some authors questioned the role of preliminary traction and suspended its use, yielding satisfactory results. Since then, several studies called into question this method, and some authors have continued to recommend preliminary traction while other authors have discouraged its use. MATERIALS AND METHODS: We reanalysed the full set of radiographs of 71 hips (52 patients) surgically treated by a medial approach after 4 weeks of preoperative longitudinal traction. The mean age at operation was 16 months. Before and after traction, the height of the dislocation was graded according to the Gage and Winter method. The hips were divided into two groups: group 1, in which the traction was effective, and group 2, in which the traction was not effective. These two groups were statistically analysed regarding the severity of the dislocation, the age of the patient at surgery and the incidence of AVN. RESULTS: Preliminary traction was effective in 48 hips (68%, group 1), while it was not effective in the remaining 23 (32%, group 2). The effectiveness of preliminary traction was statistically related to the height of the dislocation and to the age of the patient at surgery, with traction being less effective in more severe dislocations and in older children. The incidence of AVN was statistically lower in group 1 than in group 2. CONCLUSIONS: In our study population, despite not having a control group, preliminary traction-when effective-seemed to reduce the incidence of AVN in patients surgically treated for congenital dislocation of the hip. The effectiveness of the traction was influenced by the severity of the dislocation and the age of the patient; it worked better for less severe dislocations and in younger children. To reduce hospital costs, traction should be applied at home. LEVEL OF EVIDENCE: 3.

Exosomes Secreted from Hypoxia-Preconditioned Mesenchymal Stem Cells Prevent Steroid-Induced Osteonecrosis of the Femoral Head by Promoting Angiogenesis in Rats.

Recent studies have suggested that exosomes exert similar therapeutic effects to those of mesenchymal stem cells (MSCs) in regenerative medicine and MSCs-derived exosomes exhibit therapeutic effects on steroid-induced osteonecrosis of the femoral head (ONFH). Furthermore, reparative functions of exosomes from MSCs are enhanced by hypoxia treatment of the cells. However, there are no related reports about whether exosomes derived from hypoxia-preconditioned MSCs could show better therapeutic effects on steroid-induced ONFH. In vitro, we investigated the effects of hypoxia precondition on exosomes derived from bone marrow mesenchymal stem cells (BMMSCs) from rats and the proangiogenic ability of exosomes derived from hypoxia-preconditioned BMMSCs. In vivo, we investigated the role of exosomes from hypoxia-preconditioned BMMSCs on angiogenesis and protecting osteonecrosis in a rat ONFH model. We found that the potential of the proangiogenic ability of exosomes derived from hypoxia-preconditioned BMMSCs was higher than exosomes derived from BMMSCs cultured under normoxia. Exosomes derived from hypoxia-preconditioned BMMSCs significantly promoted proliferation, migration, vascular endothelial growth factor (VEGF) expression, and tube formation of human umbilical vein endothelial cells (HUVECs) compared with exosomes derived from BMMSCs cultured under normoxia. Administration of exosomes derived from hypoxia-preconditioned BMMSCs significantly prevented bone loss and increased vessel volume in the femoral head compared with exosomes derived from BMMSCs cultured under normoxia. Taken together, our data suggest that exosomes derived from hypoxia-preconditioned BMMSCs exert better therapeutic effects on steroid-induced ONFH by promoting angiogenesis and preventing bone loss.