The Polycomb Protein Bmi1 Plays a Crucial Role in the Prevention of 1,25(OH) 2 2 D Deficiency‐Induced Bone Loss

摘要

ABSTRACT We analyzed the skeletal phenotypes of heterozygous null Cyp27b1 ( Cyp27b1 +/? ) mice and their wild‐type (WT) littermates to determine whether haploinsufficiency of Cyp27b1 accelerated bone loss, and to examine potential mechanisms of such loss. We found that serum 1,25‐dihydroxyvitamin D [1,25(OH) 2 D] levels were significantly decreased in aging C yp27b1 +/? mice, which displayed an osteoporotic phenotype. This was accompanied by a reduction of expression of the B lymphoma Moloney murine leukemia virus (Mo‐MLV) insertion region 1 (Bmi1) at both gene and protein levels. Using chromatin immunoprecipitation (ChIP)‐PCR, electrophoretic mobility shift assay (EMSA) and a luciferase reporter assay, we then showed that 1,25(OH) 2 D 3 upregulated Bmi1 expression at a transcriptional level via the vitamin D receptor (VDR). To determine whether Bmi1 overexpression in mesenchymal stem cells (MSCs) could correct bone loss induced by 1,25(OH) 2 D deficiency, we overexpressed Bmi1 in MSCs using Prx1 ‐driven Bmi1 transgenic mice ( Bmi1 Tg ) mice. We then compared the bone phenotypes of Bmi1 Tg mice on a Cyp27b1 +/? background, with those of Cyp27b1 +/? mice and with those of WT mice, all at 8?months of age. We found that overexpression of Bmi1 in MSCs corrected the bone phenotype of C yp27b1 +/? mice by increasing osteoblastic bone formation, reducing osteoclastic bone resorption, increasing bone volume, and increasing bone mineral density. Bmi1 overexpression in MSCs also corrected 1,25(OH) 2 D deficiency‐induced oxidative stress and DNA damage, and cellular senescence of C yp27b1 +/? mice by reducing levels of reactive oxygen species (ROS), elevating serum total superoxide dismutase levels, reducing the percentage of γH 2 A.X, p16, IL‐1β, and TNF‐α–positive cells and decreasing γH2A.X, p16, p19, p53, p21, IL‐1β, and IL‐6 expression levels. Furthermore, 1,25(OH) 2 D stimulated the osteogenic differentiation of MSCs, both ex vivo and in vitro, from WT mice but not from Bmi1 ?/? mice and 1,25(OH) 2 D administration in vivo increased osteoblastic bone formation in WT, but not in Bmi1 ?/? mice. Our results indicate that Bmi1, a key downstream target of 1,25(OH) 2 D, plays a crucial role in preventing bone loss induced by 1,25(OH) 2 D deficiency. ? 2019 American Society for Bone and Mineral Research.