Polycystins/TAZ as a novel therapeutic target to treat osteoporosis

成骨细胞（Obs）由间充质干细胞（MSCs）分化而来，并在骨表面形成成骨细胞， 填充破骨细胞介导的骨吸收所产生的空腔的新骨。多囊蛋白1和2（Pkd 1/Pkd 2） TAZ和TAZ在成熟的Obs中形成机械感觉复合物，在骨的维持中起重要作用 马萨诸塞州小鼠成熟Obs中Pkd 1/TAZ基因缺失导致Obs介导的骨代谢减少引起的骨量减少 骨形成（Ob-BF）和骨髓脂肪（MAT）的意外增加。这种反向关系 在复合Pkd 1/TAZ缺陷小鼠中，Ob-BF和骨髓脂肪细胞之间的关系类似于某些形式的 人骨质疏松症（OP）。OP中MAT的增加被认为是由于MSC分化向 脂肪细胞以Obs为代价，脂肪细胞释放旁分泌因子据称可以抑制Ob， BF.然而，成熟Ob中Pkd 1/TAZ的破坏导致MAT增加并不容易解释为 对血统承诺的影响相反，Pkd 1/TAZ在Obs中的直接影响提高了其他可能性。 机制负责将Obs转化为脂肪细胞。一个未被探索的可能性是脂肪细胞产生于 我们提出了新的假设，即骨骼中的物理力 微环境通过激活Pkd 1/Pkd 2/TAZ调控Ob向脂肪细胞（OAT）的转分化。 R61阶段将：1）探索Obs中Pkd 1/Pkd 2/TAZ反向调节Ob-BF的机制， MAT在骨中的作用，以及2）开发药理学工具来改变这一过程。在目标1中，小鼠遗传方法 将用于有条件地删除成骨细胞中的Pkd 1和TAZ，并定义 PKD 1和TAZ在调节骨量中的作用。在目标2中，谱系追踪研究将确定OAT各自的作用 或在这些小鼠中Ob-BF和MAT的相互调节中改变谱系定型。在目标3中，我们 进行治疗前先导物设计和优化新型小分子，“钉合”C-末端区域 Pkd 1/Pkd 2/TAZ的表达，促进成骨细胞的生成，抑制成脂细胞的生成 cultures.确定Pkd 1/Pkd 2/TAZ在体内调节OAT将是一个范式转变，挑战了 关于骨量在健康和疾病中如何维持的流行概念。优化铅类似物， 激活这种复合物可能会为OP提供一种新的治疗方法。 只有在达到目标1-3的预期结果的情况下，我们才能合成足够的数量， 以表征体内药代动力学（PK）特性和安全性特征，并测试 最有希望的化合物在OP的临床前小鼠模型中预防骨丢失的能力。 机械感应复合物Pkd 1/Pkd 2/TAZ调节Ob向脂肪细胞转化提供了一个新的视角 了解骨形成和MAT之间相互关系的病理意义 并为开发治疗OP的药物定义了一个新的治疗靶点， 通过激活成熟成骨细胞中的Pkd 1/Pkd 2/TAZ抑制MAT。

Osteoblasts (Obs) differentiate from mesenchymal stem cells (MSCs) and polarize on bone surfaces to produce new bone that fills in cavities created by osteoclast-mediated bone resorption. Polycystins 1 and 2 (Pkd1/Pkd2) and TAZ form a mechanosening complex in mature Obs that plays an important role in the maintenance of bone mass. Genetic loss of Pkd1/TAZ in mature Obs of mice results in osteopenia caused by decreased Ob-mediated bone formation (Ob-BF) and an unexpected increase in bone marrow fat (MAT). This inverse relationship between Ob-BF and marrow adipocytes in compound Pkd1/TAZ deficient mice resembles certain forms of human osteoporosis (OP). Increased MAT in OP is thought to be due to a shift of MSC differentiation to adipocytes at the expense of Obs, and the release of paracrine factors by adipocytes are purported to inhibit Ob- BF. However, increased MAT resulting from disruption of Pkd1/TAZ in mature Ob is not readily explained by effects on lineage commitment. Rather, the direct effects of Pkd1/TAZ in Obs raises the possibility that other mechanisms are responsible for converting Obs to adipocytes. An unexplored possibility is that adipocytes arise from transdifferentiation of Obs. We propose the novel hypothesis that physical forces in the bone microenvironment regulate Ob transdifferentiation to adipocytes (OAT) through activation of Pkd1/Pkd2/TAZ. The R61 phase will: 1) explore the mechanisms whereby Pkd1/Pkd2/TAZ in Obs inversely regulate Ob-BF and MAT in bone, and 2) develop pharmacological tools to modify this process. In Aim 1, mouse genetic approaches will be used to conditionally delete Pkd1 and TAZ in osteoblasts and define the functional interdependence of Pkd1 and TAZ in regulating bone mass. In Aim 2, lineage tracing studies will determine the respective roles OAT or altered lineage commitment in the reciprocal regulation of Ob-BF and MAT in these mice. In Aim 3, we will pursue pre-therapeutic lead design and optimization of novel small molecules that “staple” the C-terminal regions of Pkd1 and Pkd2, and stimulate Pkd1/Pkd2/TAZ to promote osteoblastogenesis and inhibit adipogenesis in Ob cultures. Establishing that Pkd1/Pkd2/TAZ regulates OAT in vivo would be a paradigm shift that challenges prevailing concepts of how bone mass is maintained in health and disease. Optimizing lead analogues that activate this complex would potentially provide a novel treatment for OP. In Aim 4, which will be undertaken in the R33 phase only if the expected outcomes of Aims 1-3 are achieved, we will synthesize sufficient quantities of the lead compounds to characterize in vivo pharmacokinetic (PK) properties and safety profiles, and test the ability of the most promising compounds to prevent bone loss in preclinical mouse models of OP. A role of the mechanosensing complex Pkd1/Pkd2/TAZ to regulate Ob to adipocyte conversion provides a new perspective for understanding the pathological significance of the reciprocal relationship between bone formation and MAT in OP and defines a new therapeutic target for developing drugs to treat OP that uniquely stimulate Ob-mediated bone formation and inhibit MAT through activation of Pkd1/Pkd2/TAZ in mature osteoblasts.