The use of hyperbaric oxygen for avascular necrosis of the femoral head and femoral condyle: a single centre's experience over 30 years.

Introduction: Avascular necrosis (AVN) is a rare progressive degenerative disease leading to bone and joint destruction. Patients often require surgical intervention. Femoral AVN is the most common anatomical location. Hyperbaric oxygen treatment (HBOT) has been shown to be effective in AVN. We present data collected from one centre over a 30-year period and compare the results with other published data. Methods: A retrospective chart review of all patients receiving HBOT for AVN at Fremantle and Fiona Stanley Hospitals since 1989 was performed. The primary outcome was radiological appearance using the Steinberg score, with secondary outcomes being subjective improvement, the need for joint replacement surgery and rates of complications. Results: Twenty-one joints in 14 patients (14 femoral heads and seven femoral condyles) were treated with HBOT since 1989. Two patients were excluded. Within the femoral head group, nine of the 14 joints (64%) had stable or improved magnetic resonance imaging (MRI) scans post treatment and at six months (minimum); 10 joints (71%) had good outcomes subjectively, three joints required surgical intervention, and three patients developed mild aural barotrauma. Within the femoral condyle group, all five joints had stable or improved post-treatment MRI scans (four had visible improvement in oedema and/or chondral stability), four joints reported good outcomes subjectively, none of the patients required surgical intervention (follow-up > six months). Conclusions: This single centre retrospective study observed prevention of disease progression in femoral AVN with the use of HBOT, comparable to other published studies. This adds to the body of evidence that HBOT may have a significant role in the treatment of femoral AVN.

Mesenchymal Stem Cell Therapy for Bone Repair of Human Hip Osteonecrosis with Bilateral Match-Control Evaluation: Impact of Tissue Source, Cell Count, Disease Stage, and Volume Size on 908 Hips.

We investigated the impact of mesenchymal stem cell (MSC) therapy on treating bilateral human hip osteonecrosis, analyzing 908 cases. This study assesses factors such as tissue source and cell count, comparing core decompression with various cell therapies. This research emphasizes bone repair according to pre-treatment conditions and the specificities of cell therapy in osteonecrosis repair, indicating a potential for improved bone repair strategies in hips without femoral head collapse. This study utilized a single-center retrospective analysis to investigate the efficacy of cellular approaches in the bone repair of osteonecrosis. It examined the impact on bone repair of tissue source (autologous bone marrow concentrate, allogeneic expanded, autologous expanded), cell quantity (from none in core decompression alone to millions in cell therapy), and osteonecrosis stage and volume. Excluding hips with femoral head collapse, it focused on patients who had bilateral hip osteonecrosis, both pre-operative and post-operative MRIs, and a follow-up of over five years. The analysis divided these patients into seven groups based on match control treatment variations in bilateral hip osteonecrosis, primarily investigating the outcomes between core decompression, washing effect, and different tissue sources of MSCs. Younger patients (<30 years) demonstrated significantly better repair volumes, particularly in stage II lesions, than older counterparts. Additionally, bone repair volume increased with the number of implanted MSCs up to 1,000,000, beyond which no additional benefits were observed. No significant difference was observed in repair outcomes between different sources of MSCs (BMAC, allogenic, or expanded cells). The study also highlighted that a 'washing effect' was beneficial, particularly for larger-volume osteonecrosis when combined with core decompression. Partial bone repair was the more frequent event observed, while total bone repair of osteonecrosis was rare. The volume and stage of osteonecrosis, alongside the number of injected cells, significantly affected treatment outcomes. In summary, this study provides comprehensive insights into the effectiveness and variables influencing the use of mesenchymal stem cells in treating human hip osteonecrosis. It emphasizes the potential of cell therapy while acknowledging the complexity and variability of results based on factors such as age, cell count, and disease stage.

Human umbilical cord mesenchymal stem cells promote steroid-induced osteonecrosis of the femoral head repair by improving microvascular endothelial cell function.

Recently, there has been growing interest in using cell therapy through core decompression (CD) to treat osteonecrosis of the femoral head (ONFH). Our study aimed to investigate the effectiveness and mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs) in treating steroid-induced ONFH. We constructed a steroid-induced ONFH rabbit model as well as dexamethasone (Dex)-treated bone microvascular endothelial cells (BMECs) model of human femoral head. We injected hUCMSCs into the rabbit femoral head via CD. The effects of hUCMSCs on steroid-induced ONFH rabbit model and Dex-treated BMECs were evaluated via micro-CT, microangiography, histology, immunohistochemistry, wound healing, tube formation, and western blotting assay. Furthermore, we conducted single-cell RNA sequencing (scRNA-seq) to examine the characteristics of endothelial cells, the activation of signaling pathways, and inter-cellular communication in ONFH. Our data reveal that hUCMSCs improved the femoral head microstructure and bone repair and promoted angiogenesis in the steroid-induced ONFH rabbit model. Importantly, hUCMSCs improved the migration ability and angioplasty of Dex-treated BMECs by secreting COL6A2 to activate FAK/PI3K/AKT signaling pathway via integrin α1ß1.

Autologous concentrated bone marrow injection for precollapse osteonecrosis of the femoral head concurrent with contralateral total hip arthroplasty: protocol for a clinical trial.

INTRODUCTION: The femoral head contralateral to the collapsed femoral head requiring total hip arthroplasty (THA) often manifests in the precollapse stage of osteonecrosis of the femoral head (ONFH). It is not yet demonstrated how autologous concentrated bone marrow injection may prevent collapse of the femoral head concurrent with contralateral THA. The primary objective is to evaluate the efficacy of autologous concentrated bone marrow injection for the contralateral, non-collapsed, femoral head in patients with bilateral ONFH, with the ipsilateral collapsed femoral head undergoing THA. METHODS AND ANALYSIS: This is a multicentre, prospective, non-randomised, historical-data controlled study. We will recruit patients with ONFH who are scheduled for THA and possess a non-collapsed contralateral femoral head. Autologous bone marrow will be collected using a point-of-care device. After concentration, the bone marrow will be injected into the non-collapsed femoral head following the completion of THA in the contralateral hip. The primary outcome is the percentage of femoral head collapse evaluated by an independent data monitoring committee using plain X-rays in two directions 2 years after autologous concentrated bone marrow injection. Postinjection safety, adverse events, pain and hip function will also be assessed. The patients will be evaluated preoperatively, and at 6 months, 1 year and 2 years postoperatively. ETHICS AND DISSEMINATION: This protocol has been approved by the Certified Committee for Regenerative Medicine of Tokyo Medical and Dental University and Japan's Ministry of Healthy, Labour and Welfare and will be performed as a class III regenerative medicine protocol, in accordance with Japan's Act on the Safety of Regenerative Medicine. The results of this study will be submitted to a peer-review journal for publication. The results of this study are expected to provide evidence to support the inclusion of autologous concentrated bone marrow injections in the non-collapsed femoral head in Japan's national insurance coverage. TRIAL REGISTRATION NUMBER: jRCTc032200229.

Investigational regenerative medicine for non-traumatic osteonecrosis of the femoral head: a survey of registered clinical trials.

INTRODUCTION: Osteonecrosis of the femoral head (ONFH) is a refractory disease requiring joint replacement in young patients. Regenerative therapies have been developed. AREAS COVERED: This study surveyed clinical trials on regenerative medicine for ONFH. We extracted clinical trials on non-traumatic ONFH from the websites of five publicly available major registries (EuropeanUnion Clinical Trials Register ([EU-CTR],ClinicalTrials.gov, Chinese ClinicalTrial Registry [ChiCTR], University Hospital Medical InformationNetwork - Clinical Trial Registry [UMIN-CTR] and Australian New Zealand Clinical Trials Registry [ANZCTR]).The trials were classified into six categories based on purpose: surgical treatment, non-drug conservative treatment, conservative drug treatment, therapeutic strategy, diagnosis and pathogenesis, and regenerative therapy.) We extracted 169 clinical trials on ONFH. Of these, 37 were on regenerative medicine, including 29 on cell therapy. Surgical treatment was the most common treatment, followed by regenerative therapy.There were 9 clinical trials registered in the EU-CTR, with 5 on regenerative medicine; 79 trials registered on ClinicalTrials.gov, with 24 on regenerativemedicine; 54 trials registered in the ChiCTR, with 6 on regenerative medicine. EXPERT OPINION: The focus of the joint-preserving surgery has shifted to regenerative therapy based on using cell therapy in early-stage ONFH. The global standardisation of regenerative therapy is still ongoing.

Bone marrow edema of the hip: a narrative review.

Bone marrow edema (BME) of the hip is a radiological-clinical condition with symptoms ranging from asymptomatic to severe, and it is characterized by increased interstitial fluid within the bone marrow, usually at the femur. Depending on the etiology it can be classified as primary or secondary. The primary cause of BME is unknown, while the secondary forms include traumatic, degenerative, inflammatory, vascular, infectious, metabolic, iatrogenic, and neoplastic etiologies. BME could be classified as reversible or progressive. Reversible forms include transient BME syndrome and regional migratory BME syndrome. Progressive forms include avascular necrosis of the femoral head (AVNH), subchondral insufficiency fracture, and hip degenerative arthritis. The diagnosis can be difficult, because at the beginning, the outbreak of hip pain, typically acute and disabling without any prior trauma or exceptional physical activity, is poorly supported by radiographic findings. MRI is the gold standard, and it shows an area of intermediate signal on T1-weighted MRI scans and a high signal on T2-weighted scans, usually lacking sharps margins. In the reversible form, BME is typically self-limiting, and it can be managed conservatively by means of pharmacological and physical therapy. Surgery is generally required for progressive forms in patients who failed non-operative treatment, and it ranges from femoral head and neck core decompression to total hip arthroplasty.

Notch-RBPJ Pathway for the Differentiation of Bone Marrow Mesenchymal Stem Cells in Femoral Head Necrosis.

Femoral head necrosis (FHN) is a common leg disease in broilers, resulting in economic losses in the poultry industry. The occurrence of FHN is closely related to the decrease in the number of bone marrow mesenchymal stem cells (BMSCs) and the change in differentiation direction. This study aimed to investigate the function of differentiation of BMSCs in the development of FHN. We isolated and cultured BMSCs from spontaneous FHN-affected broilers and normal broilers, assessed the ability of BMSCs into three lineages by multiple staining methods, and found that BMSCs isolated from FHN-affected broilers demonstrated enhanced lipogenic differentiation, activated Notch-RBPJ signaling pathway, and diminished osteogenic and chondrogenic differentiation. The treatment of BMSCs with methylprednisolone (MP) revealed a significant decrease in the expressions of Runx2, BMP2, Col2a1 and Aggrecan, while the expressions of p-Notch1/Notch1, Notch2 and RBPJ were increased significantly. Jagged-1 (JAG-1, Notch activator)/DAPT (γ-secretase inhibitor) could promote/inhibit the osteogenic or chondrogenic ability of MP-treated BMSCs, respectively, whereas the differentiation ability of BMSCs was restored after transfection with si-RBPJ. The above results suggest that the Notch-RBPJ pathway plays important role in FHN progression by modulating the osteogenic and chondrogenic differentiation of BMSCs.

Runx2 overexpression promotes bone repair of osteonecrosis of the femoral head (ONFH).

BACKGROUND: Runt-related transcription factor-2 (Runx2) has been considered an inducer to improve bone repair ability of mesenchymal stem cells (MSCs). METHODS AND RESULTS: Twenty-four rabbits were used to establish Osteonecrosis of the femoral head (ONFH) and randomly devided into four groups: Adenovirus Runx2 (Ad-Runx2) group, Runx2-siRNA group, MSCs group and Model group. At 1 week after model establishment, the Ad-Runx2 group was treated with 5 × 107 MSCs transfected through Ad-Runx2, the Runx2-siRNA group was treated with 5 × 107 MSCs transfected through Runx2-siRNA, the MSCs group was injected with 5 × 107 untreated MSCs, and the Model group was treated with saline. The injection was administered at 1 week and 3 weeks after model establishment. The expression of bone morphogenetic protein 2 (BMP-2), Runx2 and Osterix from the femoral head was detected at 3 and 6 weeks after MSCs being injected, and Masson Trichrome Staining, Gross Morphology, X-ray and CT images observation were used to evaluate the repair effect of ONFH. The data revealed that the expression of BMP-2, Runx2 and Osterix in the Runx2-siRNA group was reduced at 3 weeks compared with the MSCs group, and then the expression further reduced at 6 weeks, but was still higher than the Model group besides Osterix; The expression of these three genes in the Ad-Runx2 group was higher than in the MSCs group. Masson Trichrome Staining, Gross Morphology and X-ray and CT images observation revealed that necrotic femoral head of the MSCs group was more regular and smooth than the Runx2-siRNA group, which has a collapsed and irregular femoral head. In the Ad-Runx2 group, necrotic femoral head was basically completely repaired and covered by rich cartilage and bone tissue. CONCLUSIONS: Overexpression of Runx2 can improve osteoblastic phenotype maintenance of MSCs and promote necrotic bone repair of ONFH.

LncAABR07053481 inhibits bone marrow mesenchymal stem cell apoptosis and promotes repair following steroid-induced avascular necrosis.

The osteonecrotic area of steroid-induced avascular necrosis of the femoral head (SANFH) is a hypoxic microenvironment that leads to apoptosis of transplanted bone marrow mesenchymal stem cells (BMSCs). However, the underlying mechanism remains unclear. Here, we explore the mechanism of hypoxic-induced apoptosis of BMSCs, and use the mechanism to improve the transplantation efficacy of BMSCs. Our results show that the long non-coding RNA AABR07053481 (LncAABR07053481) is downregulated in BMSCs and closely related to the degree of hypoxia. Overexpression of LncAABR07053481 could increase the survival rate of BMSCs. Further exploration of the downstream target gene indicates that LncAABR07053481 acts as a molecular "sponge" of miR-664-2-5p to relieve the silencing effect of miR-664-2-5p on the target gene Notch1. Importantly, the survival rate of BMSCs overexpressing LncAABR07053481 is significantly improved after transplantation, and the repair effect of BMSCs in the osteonecrotic area is also improved. This study reveal the mechanism by which LncAABR07053481 inhibits hypoxia-induced apoptosis of BMSCs by regulating the miR-664-2-5p/Notch1 pathway and its therapeutic effect on SANFH.

Prognostic factors in the management of osteonecrosis of the femoral head: A systematic review.

BACKGROUND: Several hip preserving techniques have been described for the management of osteonecrosis of the femoral head (ONFH). This systematic review identified prognostic factors in the treatment of ONFH that are associated with treatment failure and conversion to total hip arthroplasty (THA). MATERIAL AND METHODS: This study followed the PRISMA guidelines. The literature search was conducted in November 2021. All clinical trials comparing two or more treatments for femoral head osteonecrosis were accessed. A multivariate analysis was performed to investigate the association between baseline characteristics and the surgical outcome. A multiple linear model regression analysis through the Pearson Product-Moment Correlation Coefficient (r) was used. RESULTS: Data from 88 articles (6112 procedures) were retrieved. Female gender was associated with increased time to THA (P = 0.03) and reduced rate of THA (P = 0.03). Longer symptom duration before treatment was associated with shorter time to failure (P = 0.03). Increased pre-treatment VAS was associated with reduced time to failure (P = 0.03) and time to THA (P = 0.04). Reduced pre-treatment hip function was associated with increased rate of THA (P = 0.02) and failure (P = 0.005). Patient age and BMI, aetiology, time from surgery to full weight bearing and the side did not show evidence of a statistically significant association with the surgical outcome. CONCLUSION: Male gender, longer symptom duration before treatment, higher VAS scores, and lower HHS scores were negative prognostic factors after treatment for osteonecrosis of the femoral head.

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.

[Expert consensus on clinical diagnosis and treatment technique of osteonecrosis of the femoral head (2022 version)].

Osteonecrosis of the femoral head (ONFH) is a common and refractory disease in the clinic. Although the exact pathophysiological mechanism is not fully understood, it is believed to be closely related to the interruption of intra-bone circulation and eventual bone tissue death. The prevention and treatment of ONFH is always a great challenge for orthopedists. The diagnostic level of ONFH has been continuously improved with the development of imaging techniques such as MRI and the in-depth understanding of the disease in recent years.There are many treatment methods for ONFH, which are generally considered individually and comprehensively according to factors such as the patient's age, osteonecrosis stage, classification, and compliance with joint-sparing treatment. There is currently no unified standard. ONFH staging and classification play an important reference value for doctors to choose treatment options. In recent years, based on the characteristics of ONFH in Chinese people, the academic community has proposed Chinese staging and China-Japan Friendship Hospital (CJFH) classification. The consensus also introduces them together with the international Association Research Circulation Osseous (ARCO) staging to provide guidance for individualized treatment of ONFH. In order to further standardize the diagnosis of ONFH and expand the treatment of ONFH, the Association Related to Circulation Osseous, Chinese Microcirculation Society (CSM-ARCO) organized domestic experts in the field of ONFH to jointly formulate the expert consensus, in order to provide reference for the standardized diagnosis of ONFH and the selection of individualized diagnosis and treatment techniques.

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

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

Clinical Outcome of Surgical Hip Dislocation Combined with Impacting Bone Grafts and Implanting Iliac Bone Flaps in the Treatment of Osteonecrosis of the Femoral Head: A Mid-term Retrospective Study.

OBJECTIVE: To report the medium-term outcomes of surgical hip dislocation (SHD) combined with impacting bone grafts and implanting iliac bone flaps in the treatment of osteonecrosis of the femoral head (ONFH) and to define the indications for this treatment. METHODS: This was a single-center retrospective study. In total, 64 patients (70 hips) with ONFH treated from January 2014 to December 2017 were included in this study. There were 51 males and 13 females aged 18-55 years with an average age of 32 years. All patients underwent surgery for SHD combined with impacting bone grafts and implanting iliac bone flaps. Preoperative and postoperative clinical outcomes were assessed. The clinical outcome was assessed using the Harris hip score (HHS) and the conversion rate of total hip arthroplasty (THA). Univariate and multivariate logistic regression analyses were performed to identify risk factors affecting the clinical outcome. Kaplan-Meier (K-M) analysis was applied to calculate the survival rate of the femoral head. RESULTS: At the last follow-up (60 ± 15.08 months), the HHS was excellent for 41 hips, good for 17 hips, fair for three hips, and poor for nine hips. All nine hips with poor HHS underwent THA, including five in the first 2 years following the index surgery and four between three and 5 years. The conversion rate of total hip arthroplasty was 12.86%. Univariate and multivariate logistic regression analyses showed that the duration of hip pain and JIC classification type were significantly associated with clinical outcomes. Elderly age and advanced ONFH stage tended to lead to worse surgical outcomes. The overall survival rate of JIC classification type C1 and duration of pain ≤6 months was 98.1% and 97.8% at 72 months, respectively, as estimated by the Kaplan-Meier method. CONCLUSION: Surgical hip dislocation combined with impacting bone grafts and implanting iliac bone flaps in the treatment of ONFH had a good mid-term clinical outcome, especially for patients with retention of the lateral column of the femoral head and hip pain less than 1 year.

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

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

Bone Regeneration and Angiogenesis by Co-transplantation of Angiotensin II-Pretreated Mesenchymal Stem Cells and Endothelial Cells in Early Steroid-Induced Osteonecrosis of the Femoral Head.

Mesenchymal stem cells (MSCs) have been shown to exert a positive impact on osteonecrosis of the femoral head (ONFH) in preclinical experiments and clinical trials. After the femoral head suffers avascular necrosis, the transplanted MSCs undergo a great deal of stress-induced apoptosis and senescence in this microenvironment. So, survival and differentiation of MSCs in osteonecrotic areas are especially important in ONFH. Although MSCs and endothelial cells (ECs) co-culture enhancing proliferation and osteogenic differentiation of MSCs and form more mature vasculature in vivo, it remains unknown whether the co-culture cells are able to repair ONFH. In this study, we explored the roles and mechanisms of co-transplantation of angiotensin II (Ang II)-MSCs and ECs in repairing early ONFH. In vitro, when MSCs and ECs were co-cultured in a ratio of 5:1, both types of cells managed to proliferate and induce both osteogenesis and angiogenesis. Then, we established a rabbit model of steroid-induced ONFH and co-transplantation of Ang II-MSCs and ECs through the tunnel of core decompression. Four weeks later, histological and Western blot analyses revealed that ONFH treated with Ang II-MSCs and ECs may promote ossification and revascularization by increasing the expression of collagen type I, runt-related transcription factor 2, osteocalcin, and vascular endothelial growth factor in the femoral head. Our data suggest that co-transplantation of Ang II-MSCs and ECs was able to rescue the early steroid-induced ONFH via promoting osteogenesis and angiogenesis, which may be regarded as a novel therapy for the treatment of ONFH in a clinical setting.

Bone Marrow Mesenchymal Stem Cells Overexpressing HIF-1α Prevented the Progression of Glucocorticoid-Induced Avascular Osteonecrosis of Femoral Heads in Mice.

Glucocorticoid (GC)-induced avascular osteonecrosis of femoral head (AOFH) is a devastating complication, and no cures are currently available for it. Previous studies have demonstrated that implantation of bone marrow mesenchymal stem cells (BMMSCs) may prevent the progression of pre-collapse AOFH. Based on previous observations, we hypothesized that GCs induce AOFH via the COX-2 (cyclooxygenase-2)-PGE-2 (prostaglandin E2)-HIF-1α (hypoxia-inducible factor-1α) axis, and that modification of BMMSCs may improve the efficacy of their implantation. BMMSCs isolated from wild-type (WT) mice were treated with dexamethasone (Dex) and the results showed that Dex repressed the expression of COX-2. Femoral head samples harvested from both WT and COX-2 knock-out (COX-2-/-) mice were subjected to micro-computed tomography and histological examinations. Compared with their WT littermates, COX-2-/- mice had larger trabecular separations, diminished microvasculature, and reduced HIF-1α expression in their femoral heads. In vitro angiogenesis assays with tube formation and fetal metatarsal sprouting demonstrated that Dex repressed angiogenesis and PGE-2 antagonized its effects. An AOFH model was successfully established in C57BL/6J mice. In vitro experiment showed that BMMSCs infected with Lentivirus encoding HIF-1α (Lenti-HIF-1α) resulted in a robust increase in the production of HIF-1α protein. Implantation of BMMSCs overexpressing HIF-1α into femoral heads of AOFH mice significantly reduced osteonecrotic areas and enhanced bone repair, thus largely preserving the structural integrity of femoral heads. Our studies provide strong rationales for early intervention with core decompression and implantation of modified BMMSCs for GC-induced AOFH, which may spare patients from expensive and difficult surgical procedures.

Extracorporeal shockwave relieves endothelial injury and dysfunction in steroid-induced osteonecrosis of the femoral head via miR-135b targeting FOXO1: in vitro and in vivo studies.

Injury and dysfunction of endothelial cells (ECs) are closely related to the pathogenesis of steroid-induced osteonecrosis of the femoral head (ONFH), while MicroRNAs (miRNAs) play an essential role in the processes. Extracorporeal shockwave treatment (ESWT) has been used in the non-invasive treatment of various diseases including musculoskeletal and vascular disorders. In particular, ESWT with low energy levels showed a beneficial effect in ischemic tissues. However, there has been no comprehensive assessment of the effect of ESWT and miRNAs on steroid-induced ONFH. In the present study, we investigated the role and mechanism of ESWT and miRNAs both in vitro and in vivo. Using a steroid-induced ONFH rat model, we found that ESWT significantly enhances proliferation and angiogenesis as well as alleviates apoptosis. In two types of ECs, ESWT can promote cell proliferation and migration, enhance angiogenesis, and inhibit apoptosis. Notably, our study demonstrates that miR-135b is downregulated and modulated forkhead box protein O1 (FOXO1) in ECs treated with dexamethasone. Remarkably, both miR-135b knockdown and FOXO1 overexpression reversed the beneficial effect of ESWT on ECs. Additionally, our data suggest that ESWT activates the FOXO1-related pathway to impact proliferation, apoptosis, and angiogenesis. Taken together, this study indicates that ESWT relieves endothelial injury and dysfunction in steroid-induced ONFH via miR-135b targeting FOXO1.

Combination use of core decompression for osteonecrosis of the femoral head: A systematic review and meta-analysis using Forest and Funnel Plots.

OBJECTIVE: This study evaluated the efficacy and safety of CD combined with bone marrow stem cells in the treatment of femoral head necrosis by systematic review and meta-analysis. Methodology. PubMed, The Cochrane Library, Embase, CNKI, Google Scholar and MEDLINE, etc. databases were searched for clinical randomized controlled trials (RCTs) comparing core decompression combined with autologous bone marrow mesenchymal stem cells versus core decompression alone in the treatment of femoral head necrosis. The retrieval period is from the establishment of each database to May 20, 2021. After literature was extracted and literature quality was evaluated, meta-analysis was conducted by using RevMan5.3 software. RESULTS: A total of 420 osteonecrosis of the femoral head 452 patients' data were collected from all studies. Compared with the core decompression alone group, the CD combined with bone marrow stem cell showed marked reduction in the Visual analog scale (VAS), enhanced Harris hip score (HHS) at 12 months and 24 months, slowed down the progression of the disease, decreased the number of hips conversed to total hip arthroplasty (THA) in the future. CONCLUSION: Core decompression therapy is a very effective and safe treatment process used for ONFH. Moreover, CD combined autologous bone marrow stem cell transplantation can improve the survival rate of the necrotic head, reduce hip pain and delay the disease progression, the rate of THA postoperatively.

Core Decompression with Local Administration of Zoledronate and Enriched Bone Marrow Mononuclear Cells for Treatment of Non-Traumatic Osteonecrosis of Femoral Head.

OBJECTIVE: To investigate the efficacy and safety of core decompression (CD) with local administration of zoledronate and enriched bone marrow mononuclear cells (BMMCS) for the treatment of non-traumatic osteonecrosis of femoral head (ONFH). METHODS: A total of 17 patients (30 hips) diagnosed with stage II and III ONFH according to the 2019 revised Association for Research on Osseous Circulation (ARCO) staging criteria from 2012 to 2014 were retrospectively reviewed. The patients received the following therapy: the BMMCs and zoledronate were injected into the necrotic zone, respectively, along with CD. The mean age of the patients was 36.8 years; 14 were men and three were women. All patients included had non-traumatic ONFH and a minimum follow-up of 5 years, which ended when total hip arthroplasty (THA) was performed. Imaging modalities, including plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI) were taken pre- and postoperatively. Harris hip score (HHS) was used to evaluate the functional outcomes of femoral head necrosis. Kaplan-Meier analysis was adopted to determine the probability of survivorship with THA as the end point in this series of patients. The correlation between radiological progression or THA and related risk factors were further analyzed. All complications were recorded. RESULTS: With THA as the follow-up endpoint, All patients were followed up for an average of 69.1 ± 20.5 months (range, 18-95 months). Preoperative imaging found six hips (20%) at ARCO stage II, 14 hips (46.7%) at stage IIIA, 10 hips (33.3%) at stage IIIB. Fourteen hips (46.7%) shown progression radiologically, while six hips (20%) underwent TKA among these patients with hip preservation. The cumulative survival was 80% (95% CI, 0.608-905) at 5 years with THA as the end point. HHS improved from 63.3 ± 8.7 preoperatively to 74.6 ± 20.6 postoperatively (P = 0.000). Radiological progression was found to be associated with ARCO stage, Japanese Investigation Committee (JIC) type, and corticosteroid exposure (P = 0.047; P = 0.012; P = 0.031). However, no correlation was found between conversion to THA and the known risk factors. No major complication was reported, with only four patients complaining about general weakness and muscle soreness, and all disappeared within 2-3 days. CONCLUSIONS: The novel treatment modality could relieve pain, delay the progression of collapse, which might be an effective and safe method for hip preservation of early and mid-term ONFH. However, the effect of this method may be related to ARCO stage, JIC type, and corticosteroid exposure.