RT Journal Article
SR Electronic
T1 Aberrant CpG Islands’ Hypermethylation of ABCB1 in Mesenchymal Stem Cells of Patients with Steroid-associated Osteonecrosis
JF The Journal of Rheumatology
JO J Rheumatol
FD The Journal of Rheumatology
SP 1913
OP 1920
DO 10.3899/jrheum.130191
VO 40
IS 11
A1 Zhibo Sun
A1 Shuhua Yang
A1 Shunan Ye
A1 Yukun Zhang
A1 Weihua Xu
A1 Bo Zhang
A1 Xianzhe Liu
A1 Fengbo Mo
A1 Wenbin Hua
YR 2013
UL http://www.jrheum.org/content/40/11/1913.abstract
AB Objective. 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. Methods. 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). Results. 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. Conclusion. These data suggest that aberrant CpG islands’ hypermethylation of ABCB1 gene may be responsible for individual differences in the development of GC-associated ONFH.