Lrp5 and Lrp6 signaling in bone mechanotransduction and metabolism

寻找可被操纵以改善骨骼特性的分子靶点和途径是一项非常重要的工作 调查的活跃区域。最近，人们对靶向生物分子表示了特别的兴趣，这些生物分子可以 增强骨骼中的机械信号；下一代骨质疏松药物可能在 结合身体活动/负荷，以不成比例地将新骨形成引导到骨骼 最需要它的基因座(即那些承受最大压力和最大失败风险的基因座)。这个 WNT信号通路是骨量和强度的关键调节因子，也是骨细胞的重要调节因子 机械转导。骨质疏松症治疗药物EvenityTM(即Romosozumab- AQQG)强调了靶向WNT途径以改善骨骼特性和 抗断裂性。然而，FDA发布了该产品的黑盒标签，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 形成可以从心血管功能上分离出来，但驱动这些的分子机制 完全不同的过程是完全未知的。现在的目标是应用，就是要准确地理解 LRP5和LRP6-两种结构上相关的细胞表面蛋白，作为WNT共同受体-有何不同 在骨骼和非骨骼环境中，目的是利用信号差异来改善临床 基于WNT治疗结果(例如，硬化素抑制)。涉及的关键问题包括：(1)做 LRP5和LRP6在体内对骨细胞中不同WNT配体表现出不同的偏好或选择性？(2) 激活LRP5是否会触发与激活LRP6不同的下行信令网络？(3) 已知的规范的WNTs，只激活LRP5，只激活LRP6，或两者都参与？(4)LRP6参与 骨骼中的机械转导(过度使用和/或废弃)？(5)LRP5单独激活(通过硬化素) 抗体介导的抑制或通过受体功能获得突变)将骨性能改善到 比单独激活LRP6的程度更大吗？和(6)心血管效应受以下因素的影响不同 LRP5与LRP6信号(单独)？我们将使用尖端的老鼠模型，显微技术，单一的 细胞和空间转录方法、机械转导模型和放射学/组织学/ 用生物化学方法揭示LRP5和LRP5的潜在生物学和治疗潜力/差异 骨组织中LRP6的表达。该项目是罗布林(印第安纳州)之间密切合作的延续 大学。)和Warman(哈佛大学)实验室，17年多来卓有成效的合作伙伴关系。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LRP5和LRP6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.