Li Jau-Yi, Walker Lindsey D, Tyagi Abdul Malik, Adams Jonathan, Weitzmann M Neale, Pacifici Roberto
Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, GA, USA.
J Bone Miner Res. 2014 Jan;29(1):43-54. doi: 10.1002/jbmr.2044.
Both blunted osteocytic production of the Wnt inhibitor sclerostin (Scl) and increased T-cell production of the Wnt ligand Wnt10b contribute to the bone anabolic activity of intermittent parathyroid hormone (iPTH) treatment. However, the relative contribution of these mechanisms is unknown. In this study, we modeled the repressive effects of iPTH on Scl production in mice by treatment with a neutralizing anti-Scl antibody (Scl-Ab) to determine the contribution of T-cell-produced Wnt10b to the Scl-independent modalities of action of iPTH. We report that combined treatment with Scl-Ab and iPTH was more potent than either iPTH or Scl-Ab alone in increasing stromal cell production of OPG, osteoblastogenesis, osteoblast life span, bone turnover, bone mineral density, and trabecular bone volume and structure in mice with T cells capable of producing Wnt10b. In T-cell-null mice and mice lacking T-cell production of Wnt10b, combined treatment increased bone turnover significantly more than iPTH or Scl-Ab alone. However, in these mice, combined treatment with Scl-Ab and iPTH was equally effective as Scl-Ab alone in increasing the osteoblastic pool, bone volume, density, and structure. These findings demonstrate that the Scl-independent activity of iPTH on osteoblasts and bone mass is mediated by T-cell-produced Wnt10b. The data provide a proof of concept of a more potent therapeutic effect of combined treatment with iPTH and Scl-Ab than either alone.
Wnt抑制剂硬化蛋白（Scl）的骨细胞生成减弱以及Wnt配体Wnt10b的T细胞生成增加，均有助于间歇性甲状旁腺激素（iPTH）治疗的骨合成代谢活性。然而，这些机制的相对贡献尚不清楚。在本研究中，我们通过用中和性抗Scl抗体（Scl-Ab）处理来模拟iPTH对小鼠Scl产生的抑制作用，以确定T细胞产生的Wnt10b对iPTH不依赖Scl的作用方式的贡献。我们报告，在能够产生Wnt10b的T细胞的小鼠中，Scl-Ab和iPTH联合治疗在增加基质细胞骨保护素（OPG）生成、成骨细胞生成、成骨细胞寿命、骨转换、骨矿物质密度以及小梁骨体积和结构方面比单独使用iPTH或Scl-Ab更有效。在无T细胞的小鼠和缺乏T细胞产生Wnt10b的小鼠中，联合治疗比单独使用iPTH或Scl-Ab更显著地增加骨转换。然而，在这些小鼠中，Scl-Ab和iPTH联合治疗在增加成骨细胞池、骨体积、密度和结构方面与单独使用Scl-Ab同样有效。这些发现表明，iPTH对成骨细胞和骨量的不依赖Scl的活性是由T细胞产生的Wnt10b介导的。数据提供了iPTH和Scl-Ab联合治疗比单独使用更有效治疗效果的概念验证。
