Impairment of two types of circulating endothelial progenitor cells in patients with glucocorticoid-induced avascular osteonecrosis of the femoral head
Department of Orthopedics, Union Hospital, Tongji Medical College, Science and Technology of Huazhong University, Wuhan 430022, China.Joint, bone, spine: revue du rhumatisme (Impact Factor: 2.9). 04/2012; 80(1). DOI: 10.1016/j.jbspin.2012.02.015
OBJECTIVES: This study examined whether abnormalities of early EPCs and endothelial colony forming cells (ECFCs) are present and compared their functions in glucocorticoid (GC)-induced avascular osteonecrosis of the femoral head (ANFH). METHODS: Early EPCs and endothelial colony forming cells (ECFCs) were obtained from 33 patients with glucocorticoid-induced ANFH and 33 age- and sex-matched control subjects. Cells were isolated, in vitro cultured and studied by Flow Cytometry and Immunofluorescence. Colony-forming unit counts were observed from 33 patients and 33 healthy controls. Growth kinetics, migratory capacity to multiple chemo-attractants, in vitro tube formation capacity and cytokine (vascular endothelial growth factor and stromal cell-derived factor-1) levels in supernatants of two types of EPCs were assayed in ANFH patients and matched controls (n=4). RESULTS: Mean numbers of colonies formed by both types of EPCs were decreased in ANFH patients (Early EPCs: 2.42±1.46 versus 4.52±2.00, p<0.05; ECFCs: 0.62±0.55 versus 1.12±0.82, p<0.05,). Early EPCs from ANFH patients showed impaired migratory capacity (63.8±11.7 versus 152.3±12.4, p<0.001) and VEGF secretion (50.8±7.2pg/ml versus 62.8±10.1pg/ml, p<0.05). ECFCs from ANFH patients showed decreased tube formation capacity (7.1±2.7 versus 23.8±4.3, p<0.001) and proliferation. DISCUSSION: Early EPCs and ECFCs were impaired in number and function in GC-induced ANFH, and their distinct reduced capacity profiles might reflect different roles they played in endothelial dysfunction of GC-induced ANFH.
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ABSTRACT: Patients carrying an ABCB1 polymorphism have a higher risk of developing osteonecrosis of the femoral head (ONFH). We investigated whether aberrant dinucleotide CpG islands' hypermethylation of ABCB1 gene existed in mesenchymal stem cells (MSC) of patients with ONFH, which results in cell dysfunction. Bone marrow was collected from the proximal femur of patients with glucocorticoid (GC)-associated ONFH (n = 22) and patients with new femoral neck fractures (n = 25). MSC were isolated by density gradient centrifugation. We investigated cell viability, intracellular reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), the amount of P-glycoprotein (P-gp) and ABCB1 transcripts, and methylation at CpG islands of ABCB1 promoter from both the femoral neck fractures group and the GC-associated ONFH group treated with or without the DNA methyltransferase inhibitor, 5'-Aza-2-deoxycytidine (5'-Aza-dC). We observed that MSC from GC-associated ONFH groups showed reduced proliferation ability, elevated ROS levels, and depressed MMP when compared with the other 2 groups. Low levels of P-gp and ABCB1 transcript, as well as ABCB1 gene hypermethylation, in patients with GC-associated ONFH were also noted. Treatment with 5'-Aza-dC rapidly restored ABCB1 expression. Analysis of general expression revealed that aberrant CpG islands' hypermethylation of ABCB1 caused sensitivity to GC and induced changes in the proliferation and oxidative stress of MSC under GC administration. These data suggest that aberrant CpG islands' hypermethylation of ABCB1 gene may be responsible for individual differences in the development of GC-associated ONFH.
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ABSTRACT: In this study, we found out a previously undefined function of icariin which restored the dynamic balance between osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) in patients with osteonecrosis of femoral head (ONFH) via ABCB1-promoter demethylation. These findings provided important information regarding potential implication of icariin targeting epigenetic changes for the treatment of steroid -associated ONFH. Here, we investigated whether icariin can also exert a beneficial role in the reactivation of MSCs in the patients with steroid-associated ONFH via ABCB1-promoter demethylation. Bone marrow was collected from the proximal femur in patients with steroid-associated ONFH (n = 20) and patients with new femoral neck fractures (n = 22), and then MSCs were isolated. We investigated cell viability, intracellular reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), P-glycoprotein (P-gp) activity, the transcript levels of ABCB1 and oxidative stress-related genes, methylation extent at CpG islands of ABCB1 promoter, and osteogenic and adipogenic differentiation ability of MSCs from the femoral neck fractures group and from the steroid-associated ONFH group treated with or without icariin. We observed that MSCs from the steroid-associated ONFH group showed reduced proliferation ability, elevated ROS level, depressed MMP, weakened osteogenesis, and enhanced adipogenesis while low P-gp activity, transcription level of ABCB1, and oxidative stress-related genes as well as aberrant CpG islands hypermethylation of ABCB1 were also noted in steroid-associated ONFH group. Treatment with icariin obviously induced de novo P-gp expression, decreased oxidative stress, and promoted osteogenesis. Icariin may be a potential drug targeting epigenetic changes for the treatment of steroid-associated ONFH.
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ABSTRACT: Background The results of studies on association between ABCB1 gene polymorphisms and glucocorticoid-induced avascular necrosis of the femoral head (GANFH) are controversial. This study aimed to assess the association of ABCB1 gene polymorphisms with the risk of GANFH by conducting a meta-analysis. Material/Methods The PubMed, Cochrane Library, and Embase databases were searched for papers that describe the association between ABCB1 polymorphisms and GANFH risk. Summary odds ratios and 95% confidence intervals (CI) were estimated based on a fixed-effects model or random-effects model, depending on the absence or presence of significant heterogeneity. Results A total of 5 studies and 833 patients were included in the final analysis. Significant differences were found for rs1045642 polymorphism in the comparisons of CC vs. CT+TT (OR, 1.462; 95% CI, 1.066–2.007; P=0.019), and rs2032582 polymorphism in the comparisons of GG vs. G(TA)+(TA)(TA) (OR, 1.548; 95% CI,1.063–2.255; P=0.023). Conclusions The study demonstrated that the ABCB1 polymorphisms (rs1045642 and rs2032582) significantly reduced the risk of GANFH.