Osteonecrosis of the femoral head (ONFH) is a devastating disease affecting young adults, resulting in significant pain, articular surface collapse, and disabling dysfunction. ONFH can be divided into two broad categories: traumatic and non-traumatic. It has been established that ONFH results from an inadequate blood supply that causes the death of osteocytes and bone marrow cells. Nonetheless, the precise mechanism of ONFH remains to be elucidated. In this regard, preclinical animal and cell models to study ONFH have been established to assess the efficacy of various modalities for preventing and treating ONFH. Nevertheless, it should be borne in mind that many models do not share the same physiologic and metabolic characteristics as humans. Therefore, it is necessary to establish a reproducible model that better mimics human disease. We systematically reviewed the literatures in regard to ONFH experimental models over the past 30 years. The search was performed in PubMed and Web of Science. Original animal, cell studies with available full-text were included. This review summarizes different methods for developing animal and cell experimental models of ONFH. The advantages, disadvantages and success rates of ONFH models are also discussed. Finally, we provide experimental ONFH model schemes as a reference. According to the recent literatures, animal models of ONFH include traumatic, non-traumatic and traumatic combined with non-traumatic models. Most researchers prefer to use small animals to establish non-traumatic ONFH models. Indeed, small animal-based non-traumatic ONFH modeling can more easily meet ethical requirements with large samples. Otherwise, gradient concentration or a particular concentration of steroids to induce MSCs or EPCs, through which researchers can develop cell models to study ONFH. Glucocorticoids in combination with LPS to induce ONFH animal models, which can guarantee a success rate of more than 60% in large samples. Traumatic vascular deprivation combines with non-traumatic steroids to induce ONFH, obtaining success rates ranging from 80% to 100%. However, animals that undergo vascular deprivation surgery may not survive the glucocorticoid induction process. As for cell models, 10-6mol/L Dexamethasone (Dex) to treat bone marrow stem cells, which is optimal for establishing cell models to study ONFH. This review aims to summarize recent development in experimental models of ONFH and recommended the modeling schemes to verify new models, mechanisms, drugs, surgeries, and biomaterials of ONFH to contribute to the prevention and treatment of ONFH.

Osteonecrosis of the femoral head (ONFH) is a disabling disease characterized by the disruption of the blood supply to the femoral head, leading to the apoptosis and necrosis of bone cells and subsequent joint collapse. Total hip arthroplasty is not optimal since most patients are young. Multiple risk factors contribute to osteonecrosis, including glucocorticoid (GC) usage, excessive alcohol intake, hypercholesterolemia, and smoking. Continuous stimulation by many variables causes a chronic inflammatory milieu, with clinical repercussions including endothelial dysfunction, leading to thrombosis, coagulopathy, and poor angiogenesis. Immune cells are the primary regulators of inflammation. Innate and adaptive immune cells interact with endothelial cells to hinder the regeneration and repair of bone lesions. An in-depth examination of the pathological drivers of ONFH reveals that endothelial dysfunction may be a major cause of osteonecrosis. Understanding the involvement of endothelial dysfunction in the chronic inflammation of osteonecrosis could aid in the development of possible therapies. This review summarizes the role of endothelial cells in osteonecrosis and further explains the pathophysiological mechanism of endothelial dysfunction in this disease from the perspective of inflammation to provide new ideas for the treatment of osteonecrosis.

Background: The purpose of this study was to compare total complications, complications stratified by type, readmissions, and reoperations at 30 and 90 days after outpatient and standard inpatient total knee and total hip arthroplasty (TKA, THA).Methods: A literature search was conducted from the PubMed, Cochrane Library, and Embase databases for articles published before 20 August 2021. The types of studies included prospective randomized controlled trials, prospective cohort studies, retrospective comparative studies, retrospective reviews of THA and TKA registration databases, and observational case-control studies. Comparisons of interest included total complications, complications stratified by type, readmissions, and reoperations at 30 and 90 days. The statistical analysis was performed using Review Manager 5.3.Results: Twenty studies with 582,790 cases compared relevant postoperative indicators of outpatient and inpatient total joint arthroplasty (TJA) (TKA and THA). There was a significant difference in the total complications at 30 days between outpatient and inpatient THA (p = 0.001), readmissions following TJA (p = 0.03), readmissions following THA (p = 0.001), stroke/cerebrovascular incidents following TJA (p = 0.01), cardiac arrest following TJA (p = 0.007), and blood transfusions following TJA (p = 0.003). The outcomes showed an obvious difference in 90-day total complications between outpatient and inpatient TJA (p = 0.01), readmissions following THA (p = 0.002), and surgical-related pain following TJA (p < 0.001). We did not find significant differences in the remaining parameters.Conclusion: Outpatient procedures showed comparable and even better outcomes in total complications, complications stratified by type, readmissions, and reoperations at 30 and 90 days compared with inpatient TJA for selected patients.

: Osteonecrosis of the femoral head (ONFH) is a common complication of glucocorticoid (GC) therapy. Recent advances demonstrate that sympathetic nerves regulate bone homeostasis, and GCs lower the sympathetic tone. Here, we show that the dramatically decreased sympathetic tone is closely associated with the pathogenesis of GC-induced ONFH. GCs activate the glucocorticoid receptor (GR) but hinder the activation of the mineralocorticoid receptor (MR) on neurons in the hypothalamic paraventricular nucleus (PVN). This disrupts the balance of corticosteroid receptors (GR/MR) and subsequently reduces the sympathetic outflow in the PVN. Vascular endothelial cells rapidly react to inhibition of sympathetic tone by provoking endothelial apoptosis in adult male mice treated with methylprednisolone (MPS) daily for 3 days, and we find substantially reduced H-type vessels in the femoral heads of MPS-treated ONFH mice. Importantly, treatment with a GR inhibitor (RU486) in the PVN promotes the activation of MR and rebalances the ratio of GR and MR, thus effectively boosting sympathetic outflow, as shown by an increase in tyrosine hydroxylase expression in both the PVN and the sympathetic postganglionic neurons and an increase in norepinephrine levels in both the serum and bone marrow of the femoral head of MPS-treated mice. Rebalancing the corticosteroid receptors mitigates GC-induced endothelial impairment and ONFH and promotes angiogenesis coupled with osteogenesis in the femoral head, while these effects are abolished by chemical sympathectomy with 6-OHDA or adrenergic receptor-β2 (Adrb2) knockout. Furthermore, activating Adrb2 signaling in vivo is sufficient to rescue the GC-induced ONFH phenotype. Mechanistically, norepinephrine increases the expression of the key glycolytic gene 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) via Adrb2-cyclic AMP response element-binding protein (CREB) signaling. Endothelial-specific overexpression of PFKFB3 attenuates endothelial impairment and prevents severe osteonecrosis in MPS-treated Adrb2 knockout mice. Thus, GC inhibits sympathetic tone via the hypothalamic descending pathway, which, in turn, acts as a mediator of GC-induced ONFH.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a progressive disease that leads to an increased disability rate. This study aimed to ascertain biomarkers, infiltrating immune cells, and therapeutic drugs for SONFH. The gene expression profile of the GSE123568 dataset was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the NetworkAnalyst platform. Functional enrichment, protein-protein interaction network (PPI), and module analyses were performed using Metascape tools. An immune cell abundance identifier was used to explore immune cell infiltration. Furthermore, hub genes were identified based on maximal clique centrality (MCC) evaluation using cytoHubba application and confirmed by qRT-PCR using clinical samples. Finally, the L1000 platform was used to determine potential drugs for SONFH treatment. The SONFH mouse model was used to determine the therapeutic effects of aspirin. In total, 429 DEGs were identified in SONFH samples. Functional enrichment analysis showed that these DEGs were enriched in myeloid leukocyte activation and osteoclast differentiation processes. A set of nine immune cell types was confirmed to be markedly different between the SONFH and control samples. All 10 hub genes were significantly highly expressed in the serum of SONFH patients, as shown by qRT-PCR. Finally, the therapeutic effect of aspirin on SONFH was examined in animal experiments. Taken together, our data revealed the hub genes and infiltrating immune cells in SONFH, and we also screened potential drugs for use in SONFH treatment.