The role of ALK4 signaling in skeletal homeostasis and pathogenesis

以信号通路为靶点的新型生物疗法具有巨大的潜力 治疗慢性疾病和经常使人衰弱的疾病的新疗法。一种这样的方法是创建配体陷阱， 它捕获与受体细胞外域高亲和力结合的蛋白质，并随后 阻止这些分子激活靶细胞。使用配体陷阱进行Acvr2A/B的临床前研究 (2A/B-LT)，转化生长因子-β超家族中的2型受体，共同证明减少典型的Smad2/3 在慢性疾病的小鼠模型中，信号传递减少了疾病负担。基于这些发现，正在进行的 计划中的临床试验正在评估2A/B-LT对肥胖、慢性阻塞性疾病患者的疗效 肺部疾病、癌症引起的恶病质、2型糖尿病、类风湿性关节炎和炎症性贫血。 这些慢性病大多也有骨骼的表现，骨量和骨量的有益变化 据报道，用2A/B-LT治疗的小鼠的强度。然而，为什么2A/B-LT治疗有积极的效果 在骨骼上，哪些细胞群直接受到2A/B-LT的影响，以及其作用机制(S) 减少Smad2/3的激活对骨细胞反应的调节在很大程度上是未知的。填补这些空白 对于确定使用2A/B-LT的任何骨骼副作用，知识将是至关重要的。我们实验室的发现表明 在早期的骨祖细胞中，转化生长因子-β超家族中的1型受体ALK4的基因缺失导致 增加小鼠的骨量。此外，来自我们小组和其他人的数据表明，骨骼动态平衡可能 受共享使用Acvr2A/B的Smad2/3和Smad1/5/8信令中相反更改的影响 BMP和Alk4激活配体之间的关系。因此我们假设循环配体发出信号 Alk4通过Smad2/3和Smad2/3之间的竞争调节骨稳态和发病机制 Smad1/5/8信令。完成我们建议中的目标将使我们能够识别骨细胞靶点 这些转化生长因子-β超家族配体陷阱(SA1)决定了配体陷阱Alk4-Fc是否具有治疗潜力 在骨骼(SA2)中，检查Alk4-FC在两种慢性病模型(SA3)中的疗效，并告知 构成对激活Smad2/3信号的配体的骨骼反应的分子事件(SA4)。这个 这项提案中涉及的问题意义重大，因为它们填补了关于潜在脱机的关键知识空白- 当使用2A/B-LT治疗慢性病时，可能会对骨骼产生靶向影响。我们相信 我们通过完成研究而获得的结果是有影响力的，因为它们突出了使用2A/B-LT的潜力 和/或Alk4-FC，以防止/调节随年龄发生的全身性骨丢失，以及增强骨骼 骨折修复。此外，我们的研究将大大促进我们对Smad2/3和Smad2/3的作用的理解 Smad1/5/8信号在成人骨骼中的表达，为理解转化生长因子-β超家族生物学提供了一个框架 作为一种机制，确保骨骼和其他靶组织的动态平衡。

New biologically-based therapeutics that target signaling pathways have tremendous potential to provide novel treatments for chronic and often debilitating diseases. One such approach is the creation of ligand traps, which capture proteins that exhibit high-affinity binding to a receptor extracellular domain, and subsequently prevent these molecules from activating target cells. Preclinical studies employing ligand traps for Acvr2A/B (2A/B-LT), type 2 receptors in the TGF-β superfamily, collectively demonstrate that reducing canonical Smad2/3 signaling reduces the disease burden in mouse models of chronic illnesses. Based on these findings, ongoing and planned clinical trials are evaluating the efficacy of 2A/B-LT in patients with obesity, chronic obstructive pulmonary disease, cancer-induced cachexia, type 2 diabetes, rheumatoid arthritis, and anemia of inflammation. Most of these chronic illnesses also have skeletal manifestations, and beneficial changes in bone mass and strength have been reported in mice treated with 2A/B-LT. However, why 2A/B-LT treatment has positive effects on the skeleton, what cell populations are directly affected by 2A/B-LT, and the mechanism(s) by which decreasing Smad2/3 activation regulates bone cell responses are largely unknown. Filling these gaps in knowledge will be critical to identifying any skeletal side effects of using 2A/B-LT. Findings from our lab suggest that genetic deletion of Alk4, a type 1 receptor within the TGF-β superfamily, in early osteoprogenitors results in increased bone mass in mice. Furthermore, data from our group and others suggests bone homeostasis may be influenced by opposing changes in Smad2/3 and Smad1/5/8 signaling due to shared usage of Acvr2A/B between BMPs and Alk4-activating ligands. We therefore hypothesize that circulating ligands signaling through Alk4 regulate bone homeostasis and pathogenesis by competition between Smad2/3 and Smad1/5/8 signaling. Completion of the aims in our proposal will allow us to identify the bone cell targets of these TGF-β superfamily ligand traps (SA1), determine whether the ligand trap Alk4-FC has therapeutic potential in bone (SA2), examine the efficacy of Alk4-FC in 2 chronic disease models (SA3), and inform about the molecular events that comprise the skeletal response to ligands that activate Smad2/3 signaling (SA4). The questions addressed in this proposal are significant because they fill a critical knowledge gap about potential off- target effects on the skeleton that may occur when 2A/B-LT is used to treat chronic diseases. We believe the results we obtain by completing our studies are impactful because they highlight the potential of using 2A/B-LT and/or Alk4-FC to prevent/modulate the generalized bone loss that occurs with age, as well as to enhance bone fracture repair. Further, our studies will significantly advance our understanding of the role of Smad2/3 and Smad1/5/8 signaling in the adult skeleton, and provide a framework for understanding TGF-β superfamily biology as a mechanism for ensuring homeostasis in bone and other target tissues.