MicroRNA (miRs) are small, non-coding RNA that post-transcriptionally regulate DNA expression. We hypothesized that specific miR profiles may be a feature of overactive osteoclasts in Paget's disease of bone (PDB), a disorder characterized by an increased and disorganized bone remodeling that typically begins with excessive bone resorption. We compared the expression profile of 13 miRs in human osteoclasts differentiated in vitro from peripheral blood mononuclear cells (PBMCs) of patients with PDB (n = 10) or age- and sex- matched healthy subjects (n = 10). We selected 13 miRs for testing, on the basis of their previously reported roles either in human osteoclast differentiation, in bone diseases, or in osteoclast important signaling pathways. From those expression results, 3 miRNAs were further selected for in-vitro studies aiming at modulating miR expression in human cord blood monocyte derived osteoclasts: 2 miRs (miR-146a-3p and miR-155-5p) whose expression was significantly reduced in pagetic osteoclasts, as well as miRNA-133a-3p, stable in PDB relative to controls, but with known regulatory importance within osteoclasts. We demonstrated a positive (miR-133a-3p) or negative (miR-155-5p, miR-146a-3p) impact of those miRs on the formation of osteoclasts and/or their bone resorption capacity in this human model. Signaling pathways were significantly affected, including p38 MAP-kinase (miR-133a-3p), RANKL-induced TRAF6/NFκB signaling (miR-146a-3p), and MITF expression (miR-155-5p). Osteoclast miRNA profiles might have an important value to yield significant new insights into the osteoclast phenotype in PDB and in other bone diseases with hyperactive osteoclasts.

MicroRNA（miRs）是小的非编码RNA，可转录后调节DNA表达。我们假设特定的miR谱可能是Paget骨病（PDB）中过度活跃的破骨细胞的特征，这种疾病的特征是骨骼重塑增加和紊乱，通常始于过度的骨吸收。我们比较了在体外与PDB患者外周血单个核细胞（PBMC）分化的人类破骨细胞中13 miRs的表达谱（n = 10）或年龄和性别匹配的健康受试者（n = 10）。根据先前报道的13种miR在人类破骨细胞分化，骨病或破骨细胞重要信号通路中的作用，我们选择了13种miR。从这些表达结果中，进一步选择了3个miRNA用于体外研究，目的是调节人脐血单核细胞来源的破骨细胞中miR的表达：2个miR（miR-146a-3p和miR-155-5p）在分页中的表达明显降低破骨细胞以及miRNA-133a-3p在PDB中相对于对照稳定，但在破骨细胞中具有已知的调控重要性。我们在这些人模型中证明了这些miR对破骨细胞形成和/或骨吸收能力的正面（miR-133a-3p）或负面（miR-155-5p，miR-146a-3p）影响。信号通路受到显着影响，包括p38 MAP激酶（miR-133a-3p），RANKL诱导的TRAF6 /NFκB信号通路（miR-146a-3p）和MITF表达（miR-155-5p）。破骨细胞miRNA谱图可能具有重要价值，可为PDB和其他伴有高活性破骨细胞的骨病中的破骨细胞表型产生重要的新见解。