Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK.
Dis Model Mech. 2022 Apr 1;15(4). doi: 10.1242/dmm.049318. Epub 2022 Apr 26.
Paget's disease of bone (PDB) is characterized by focal increases in bone remodelling. Genome-wide association studies identified a susceptibility locus for PDB tagged by rs5742915, which is located within the PML gene. Here, we have assessed the candidacy of PML as the predisposing gene for PDB at this locus. We found that the PDB-risk allele of rs5742915 was associated with lower PML expression and that PML expression in blood cells from individuals with PDB was lower than in controls. The differentiation, survival and resorptive activity of osteoclasts prepared from Pml-/- mice was increased compared with wild type. Furthermore, the inhibitory effect of IFN-γ on osteoclast formation from Pml-/- was significantly blunted compared with wild type. Bone nodule formation was also increased in osteoblasts from Pml-/- mice when compared with wild type. Although microCT analysis of trabecular bone showed no differences between Pml-/- mice and wild type, bone histomorphometry showed that Pml-/- mice had high bone turnover with increased indices of bone resorption and increased mineral apposition rate. These data indicate that reduced expression of PML predisposes an individual to PDB and identify PML as a novel regulator of bone metabolism. This article has an associated First Person interview with the first author of the paper.
佩吉特氏骨病（PDB）的特征是骨重建的局部增加。全基因组关联研究确定了 PDB 的易感性位点，该位点由 rs5742915 标记，位于 PML 基因内。在这里，我们评估了 PML 作为该位点 PDB 易感基因的候选基因。我们发现，rs5742915 的 PDB 风险等位基因与 PML 表达降低有关，并且 PDB 患者血液中的 PML 表达低于对照组。与野生型相比，来自 Pml-/- 小鼠的破骨细胞的分化、存活和吸收活性增加。此外，与野生型相比，IFN-γ 对 Pml-/- 破骨细胞形成的抑制作用明显减弱。与野生型相比，来自 Pml-/- 小鼠的成骨细胞的骨结节形成也增加。尽管小梁骨的 microCT 分析显示 Pml-/- 小鼠与野生型之间没有差异，但骨组织形态计量学显示 Pml-/- 小鼠具有高骨转换，骨吸收指数增加，矿化沉积率增加。这些数据表明，PML 表达降低使个体易患 PDB，并确定 PML 为骨代谢的新调节因子。本文附有该论文第一作者的第一人称采访。
