The role of salt inducible kinases in parathyroid hormone action in bone

项目摘要 骨质疏松症是我们老龄化人口中的一个主要公共健康问题。治疗骨合成代谢的新策略 这种疾病是人们迫切需要的。甲状旁腺激素(PTH)是钙的中枢调节因子 动态平衡。通过在骨骼中的快速作用，甲状旁腺素迅速释放骨骼中储存的钙并保持 血钙水平正常。此外，甲状旁腺激素还刺激骨形成，这一特性在 用于治疗骨质疏松症的每日一次注射的形式(特派拉定和阿巴拉定)。广泛使用 甲状旁腺激素的治疗受到每日注射的需要的限制。此外，我们仍然不完全理解为什么 间歇性甲状旁腺激素有效地建立骨骼，而持续的甲状旁腺功能亢进导致骨量丢失和 对成骨细胞活性有一定的抑制作用。在这个研究项目中，我们将了解甲状旁腺素是如何刺激 骨形成，然后利用这些信息开发下一代口服骨合成代谢药物 治疗。为了实现这些目标，我们最近定义了盐诱导蛋白激酶(SIKs)在细胞内的关键作用 骨细胞中甲状旁腺激素作用的介体。环腺苷酸和蛋白激酶介导的甲状旁腺素信号转导 A阻断细胞内SIK2和SIK3的活性。因此，遗传学和药理学实验策略 阻断SIK2/SIK3活性可有效模拟甲状旁腺激素在骨中的作用。在这里，在目标1中，我们将开发、评估 并测试可阻断SIK2/SIK3活性并促进骨形成的“下一代”口服化合物 以及临床前性腺功能减退相关骨质疏松症模型的骨量。在此过程中，我们将合并 遗传学和药理学方法，以确保这些化合物确实通过其预期的靶点发挥作用 (SIK2和SIK3)刺激骨形成。已经证明了新型Small的治疗效果 分子SIK2/SIK3抑制剂，接下来我们将在目标2中定义它们在骨细胞中的作用机制。 磷酸化蛋白质组学研究揭示了肌醇磷脂3-激酶和AKT信号的潜在调控。 PTH/SIK通路。这一观察或许可以解释为什么持续性甲状旁腺功能亢进症不能充分刺激 成骨细胞的成骨作用。在这里，我们将研究PTH/SIK信号如何与AKT通路在 骨细胞在细胞能量学水平上，然后利用这些信息来测试降低AKT的模型 活动有助于解释持续甲状旁腺机能亢进症造成的骨质流失。综上所述，这些相互关联 AIMS将阐明骨细胞中新的信号转导模型，并定义一种 新的口服骨质疏松症骨合成代谢疗法。

Project Abstract Osteoporosis is a major public health problem in our aging population. New bone anabolic strategies to treat this disease are desperately needed. Parathyroid hormone (PTH) is a central regulator of calcium homeostasis. Through its rapid actions in bone, PTH quickly liberates skeletal stores of calcium and maintains normal blood calcium levels. In addition, PTH also stimulates bone formation, and this property is exploited in the form of once daily injections (teriparatide and abaloparatide) for osteoporosis treatment. Widespread use of PTH therapy is limited by the need for daily injections. In addition, we still do not fully understand why intermittent PTH effectively builds bone while continuous hyperparathyroidism leads to loss of bone mass and some suppression of osteoblast activity. In this research program, we will understand how PTH stimulates bone formation and then use that information to develop next generation orally available bone anabolic therapies. Towards those goals, we recently defined a role for salt inducible kinases (SIKs) as key intracellular mediators of the actions of parathyroid hormone in bone cells. PTH signaling via cyclic AMP and protein kinase A blocks SIK2 and SIK3 activity in cells. Accordingly, genetic and pharmacologic experimental strategies that block SIK2/SIK3 activity effectively mimic the actions of PTH in bone. Here, in Aim 1, we will develop, evaluate, and test ‘next generation’ orally available compounds that block SIK2/SIK3 action and boost bone formation and bone mass in preclinical hypogonadism-associated osteoporosis models. In doing so, we will merge genetic and pharmacologic approaches to ensure that these compounds indeed act via their intended targets (SIK2 and SIK3) to stimulate bone formation. Having demonstrated therapeutic efficacy of novel small molecule SIK2/SIK3 inhibitors, next we will define their mechanism of action in bone cells in Aim 2. Unbiased phospho-proteomic profiling revealed potential control of phosphoinositide 3-kinase and AKT signaling by the PTH/SIK pathway. This observation may explain why continuous hyperparathyroidism fails to fully stimulate bone formation by osteoblasts. Here we will study how PTH/SIK signaling intersects with the AKT pathway in bone cells at the level of cellular energetics, and then use this information to test the model that reduced AKT activity helps explain bone loss due to continuous hyperparathyroidism. Taken together, these inter-related Aims will elucidate novel signal transduction models in bone cells and define the mechanism of action of a new, orally-available osteoporosis bone anabolic therapy.