Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
PLoS One. 2013 May 10;8(5):e63565. doi: 10.1371/journal.pone.0063565. Print 2013.
Bone is constantly formed and resorbed throughout life by coordinated actions of osteoblasts and osteoclasts. However, the molecular mechanisms involved in osteoblast function remain incompletely understood. Here we show, for the first time, that the peptidyl-prolyl isomerase PIN1 controls the osteogenic activity of osteoblasts. Pin1 null mice exhibited an age-dependent decrease in bone mineral density and trabecular bone formation without alteration in cortical bone. Further analysis identified a defect in BMP signaling in Pin1 null osteoblasts but normal osteoclast function. PIN1 interacted with SMAD5 and was required for the expression by primary osteoblasts of osteoblast specific transcription factors (CBFA1 and OSX), ECM (collagen I and OCN) and the formation of bone nodules. Our results thus uncover a novel aspect of the molecular underpinning of osteoblast function and identify a new therapeutic target for bone diseases.
骨骼在一生中不断地通过成骨细胞和破骨细胞的协调作用进行形成和吸收。然而，成骨细胞功能所涉及的分子机制仍不完全清楚。在这里，我们首次表明，肽基脯氨酰顺反异构酶 PIN1 控制着成骨细胞的成骨活性。Pin1 敲除小鼠表现出骨密度和小梁骨形成的年龄依赖性下降，而皮质骨没有改变。进一步的分析确定了 Pin1 敲除成骨细胞中 BMP 信号的缺陷，但破骨细胞功能正常。PIN1 与 SMAD5 相互作用，是成骨细胞特异性转录因子（CBFA1 和 OSX）、细胞外基质（胶原 I 和 OCN）的表达以及骨结节形成所必需的。因此，我们的研究结果揭示了成骨细胞功能的分子基础的一个新方面，并确定了治疗骨疾病的一个新的治疗靶点。
