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.

中文翻译：

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非编码 RNA 的不同子集与 BMD 和骨折密切相关，在负重和非负重人体骨骼中进行了研究。

我们通过比较非负重 (NWB) 髂骨 ( n = 84) 和负重 (WB) 股骨 ( n = 18) BMD 的绝经后骨从正常 ( T分数 > -1.0) 到骨质疏松 ( T-分数≤-2.5）。全球骨 ncRNA 浓度通过 PCR 和微芯片分析确定。使用线性和逻辑回归以及最小绝对收缩和选择算子 (Lasso) 分析计算与 BMD 或骨折的关联，根据年龄和体重指数进行调整。在 10% 的错误发现率 (FDR) 下，75 种髂骨 ncRNA 和 94 种股骨 ncRNA 与总髋骨 BMD 相关。两个位点共有 8 个 ncRNA，但其中 5 个（miR-484、miR-328-3p、miR-27a-5p、miR-28-3p 和 miR-409-3p）与 BMD 呈正相关股骨，但在髂骨中为阴性。在骨代谢中识别的预测途径中，ECM-受体相互作用和癌症中的蛋白聚糖出现在两个部位，而脂肪酸代谢和粘着斑仅在髂骨中发现。Lasso 分析和交叉验证确定了 9 组骨 ncRNA 与股骨和髂骨中调整后的总髋骨 BMD 密切相关。28 个髂骨 ncRNA 与骨折风险相关（FDR < 0.1）。小核仁 RNA，RNU44 和 RNU48，具有稳定核糖体 RNA (rRNA) 的功能，它们与骨折和 BMD 的关联表明 rRNA 的异常加工可能与骨质疏松症的发展有关。髂骨活检的 Cis-eQTL（表达数量性状基因座）分析确定了两个与 microRNA (miRNA) 相关的基因座，一个先前在脚后跟-BMD 全基因组关联研究 (GWAS) 中发现。在这项对绝经后妇女骨骼遗传背景的全面调查中，我们确定了与骨折和 BMD 相关的功能性骨 ncRNA，代表 WB 和 NWB 骨骼部位的不同子集。© 2020 作者。美国骨与矿物质研究学会出版的骨与矿物质研究杂志。