Gautvik Kaare M, Günther Clara-Cecilie, Prijatelj Vid, Medina-Gomez Carolina, Shevroja Enisa, Rad Leila Heidary, Yazdani Mazyar, Lindalen Einar, Valland Haldor, Gautvik Vigdis T, Olstad Ole K, Holden Marit, Rivadeneira Fernando, Utheim Tor P, Reppe Sjur
Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
Department of Molecular Medicine, University of Oslo, Oslo, Norway.
J Bone Miner Res. 2020 Jun;35(6):1065-1076. doi: 10.1002/jbmr.3974. Epub 2020 Mar 2.
We investigated mechanisms resulting in low bone mineral density (BMD) and susceptibility to fracture by comparing noncoding RNAs (ncRNAs) in biopsies of non-weight-bearing (NWB) iliac (n = 84) and weight bearing (WB) femoral (n = 18) postmenopausal bone across BMDs varying from normal (T-score > -1.0) to osteoporotic (T-score ≤ -2.5). Global bone ncRNA concentrations were determined by PCR and microchip analyses. Association with BMD or fracture, adjusted by age and body mass index, were calculated using linear and logistic regression and least absolute shrinkage and selection operator (Lasso) analysis. At 10% false discovery rate (FDR), 75 iliac bone ncRNAs and 94 femoral bone ncRNAs were associated with total hip BMD. Eight of the ncRNAs were common for the two sites, but five of them (miR-484, miR-328-3p, miR-27a-5p, miR-28-3p, and miR-409-3p) correlated positively to BMD in femoral bone, but negatively in iliac bone. Of predicted pathways recognized in bone metabolism, ECM-receptor interaction and proteoglycans in cancer emerged at both sites, whereas fatty acid metabolism and focal adhesion were only identified in iliac bone. Lasso analysis and cross-validations identified sets of nine bone ncRNAs correlating strongly with adjusted total hip BMD in both femoral and iliac bone. Twenty-eight iliac ncRNAs were associated with risk of fracture (FDR < 0.1). The small nucleolar RNAs, RNU44 and RNU48, have a function in stabilization of ribosomal RNAs (rRNAs), and their association with fracture and BMD suggest that aberrant processing of rRNAs may be involved in development of osteoporosis. Cis-eQTL (expressed quantitative trait loci) analysis of the iliac bone biopsies identified two loci associated with microRNAs (miRNAs), one previously identified in a heel-BMD genomewide association study (GWAS). In this comprehensive investigation of the skeletal genetic background in postmenopausal women, we identified functional bone ncRNAs associated to fracture and BMD, representing distinct subsets in WB and NWB skeletal sites. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
我们通过比较非负重（NWB）髂骨（n = 84）和负重（WB）股骨（n = 18）绝经后骨活检中的非编码RNA（ncRNA），研究了导致低骨矿物质密度（BMD）和骨折易感性的机制，这些骨活检样本的BMD范围从正常（T评分＞ -1.0）到骨质疏松（T评分≤ -2.5）。通过PCR和微芯片分析确定整体骨ncRNA浓度。使用线性和逻辑回归以及最小绝对收缩和选择算子（Lasso）分析计算经年龄和体重指数调整后的与BMD或骨折的关联。在10%的错误发现率（FDR）下，75种髂骨ncRNA和94种股骨ncRNA与全髋BMD相关。其中8种ncRNA在两个部位都存在，但其中5种（miR - 484、miR - 328 - 3p、miR - 27a - 5p、miR - 28 - 3p和miR - 409 - 3p）在股骨中与BMD呈正相关，而在髂骨中呈负相关。在骨代谢中公认的预测通路中，ECM - 受体相互作用和癌症中的蛋白聚糖在两个部位都出现了，而脂肪酸代谢和粘着斑仅在髂骨中被识别。Lasso分析和交叉验证确定了9种骨ncRNA与股骨和髂骨中经调整的全髋BMD密切相关。28种髂骨ncRNA与骨折风险相关（FDR＜0.1）。小核仁RNA，RNU44和RNU48，在核糖体RNA（rRNA）的稳定中起作用，它们与骨折和BMD的关联表明rRNA的异常加工可能参与骨质疏松的发展。对髂骨活检样本进行顺式表达数量性状位点（cis - eQTL）分析确定了两个与微小RNA（miRNA）相关的位点，其中一个是先前在足跟BMD全基因组关联研究（GWAS）中确定的。在这项对绝经后女性骨骼遗传背景的全面研究中，我们确定了与骨折和BMD相关的功能性骨ncRNA，它们在WB和NWB骨骼部位代表不同的子集。© 2020作者。由美国骨与矿物质研究学会出版的《骨与矿物质研究杂志》
