Lrp5 and Lrp6 signaling in bone mechanotransduction and metabolism

寻找可以被操纵以改善骨特性的分子靶点和途径是一个高度复杂的问题。 积极开展调查。最近，已经表达了对靶向生物分子的特别兴趣，所述生物分子可以 增强骨骼中的机械信号;下一代骨质疏松症药物可能会在 结合身体活动/负荷，以便不成比例地将新骨形成引导到骨骼 最需要它的位点（即，那些承受最大压力并处于最大失败风险的基因座）。的 WNT信号通路已成为骨质量和强度的关键调节因子，也是骨细胞的关键调节因子。 机械传导最近临床批准的骨质疏松症治疗EvenityTM（即，Romosozumab- aqqg）已经强调了靶向WNT途径以改善骨骼特性的效用和效力， 抗断裂性然而，FDA对该产品发布了一个黑盒标签，因为它对 心血管功能和健康。最近的研究表明，WNT刺激对骨骼的影响 形成可以从那些对心血管功能，但分子机制驱动这些 完全不同的过程是完全未知的。现在的目标是应用， LRP 5和LRP 6--两种结构相关的细胞表面蛋白，充当WNT共受体--有何不同 在其骨骼和非骨骼背景下，目的是利用信号差异来改善临床 基于WNT的治疗结果（例如，sclerostin抑制）。主要问题包括：（1） LRP 5和LRP 6在体内骨细胞中对不同的WNT配体表现出不同的偏好性或选择性？（二） LRP 5激活是否触发与激活的LRP 6不同的下游信令网络？(3)中 已知的典型WNT，仅激活LRP 5，仅激活LRP 6或两者都激活？(4)LRP 6是否参与 骨机械传导（过度使用和/或废用）？(5)单独激活LRP 5（通过硬化蛋白） 抗体介导的抑制或通过受体中的功能获得性突变）将骨性质改善至 比单独激活LRP6的程度更大？和（6）心血管效应是否受以下因素的不同影响 LRP5与LRP6信号传导（孤立）？我们将使用尖端的小鼠模型，显微技术，单 细胞和空间转录组学方法，机械转导模型，以及放射学/组织学/ 生物化学方法来揭示LRP 5的潜在生物学和治疗潜力/差异， 骨组织中的LRP 6。该项目是罗布林（印第安纳州）与 大学）和沃曼（哈佛大学）实验室，一个非常富有成效的合作伙伴关系超过17年。我们有 汇集了专业知识、资源、生物模型和工具以及技术创新的独特组合 阐明和区分LRP 5和LRP 6在骨生物学中的作用。

The search for molecular targets and pathways that can be manipulated to improve bone properties is a highly active area of investigation. Recently, particular interest has been expressed in targeting biomolecules that can augment mechanical signaling in bone; the next generation of osteoporosis drugs is likely to work in conjunction with physical activity/loading in order to disproportionately direct new bone formation to the skeletal loci that need it most (i.e., those loci that endure the greatest strains and are at the greatest risk of failure). The WNT signaling pathway has emerged as a key regulator of bone mass and strength, but also of bone cell mechanotransduction. Recent clinical approval of the osteoporosis therapy EvenityTM (i.e., Romosozumab- aqqg) has highlighted the utility and potency of targeting the WNT pathway to improve skeletal properties and fracture resistance. However, the FDA issued a black-box label to the product because of its side effects on cardiovascular function and health. Recent work suggests that the effects of WNT stimulation on bone formation can be isolated from those on cardiovascular function, but the molecular mechanisms driving these disparate processes are completely unknown. The goal of the present is application is to understand precisely how LRP5 and LRP6—two structurally related cell surface proteins that function as WNT co-receptors—differ in their skeletal and non-skeletal contexts, with the goal of exploiting signaling differences to improve clinically based WNT therapeutic outcomes (e.g., sclerostin inhibition). Among the key questions addressed are: (1) Do LRP5 and LRP6 exhibit different predilection, or selectivity, to different WNT ligands in bone cells in vivo? (2) Does LRP5 activation trigger different downstream signaling networks than activated LRP6? (3) Among the known canonical WNTs, which activate only LRP5, only LRP6 or both? (4) Is LRP6 involved in mechanotransduction in bone (overuse and/or disuse)? (5) Can activation of LRP5 alone (through sclerostin antibody-mediated inhibition or by gain-of-function mutation in the receptor) improve bone properties to a greater extent than activation of LRP6 alone? And (6) are cardiovascular effects differentially affected by LRP5 vs LRP6 signaling (in isolation)? We will use cutting-edge mouse models, microscopic techniques, single cell and spatial transcriptomic approaches, mechanotransduction models, and radiographic/histologic/ biochemical approaches to reveal the underlying biology and therapeutic potential/differences of LRP5 and LRP6 in bone tissue. The project is a continuation of the close collaboration between the Robling (Indiana Univ.) and Warman (Harvard Univ.) labs, an extremely fruitful partnership for more than 17 yrs. We have assembled a unique combination of expertise, resources, biological models and tools, and technical innovation to elucidate and distinguish the roles of LRP5 and LRP6 in bone biology.