The Nmp4 Anti-Anabolic Bone Axis R01AR070144-01A1

“骨质疏松症治疗的圣杯仍然是......骨量的恢复......“1，以及随之而来的骨折 还原目前的骨质疏松症治疗有明显的局限性2，NIAMS的目标包括 解决“为什么一些治疗药物在长期使用下变得不那么有效“， 发现用于新药治疗的新鉴定的分子靶点的机会“3.小鼠携带a 编码转录因子Nmp 4的基因中的功能丧失突变的人是健康的、长寿的， 表现出不显著的骨骼表型，直到用包括几种 骨质疏松症的治疗，这eliminate增强骨形成4 -8类。缺乏基线 表型，结合对治疗的改善反应，为开发Nmp 4提供了独特的优势 (or其上游/下游组分之一）作为安全靶点，以增强现有疗法的功效， 确定新疗法的分子靶点。我们的目标是确定禁用Nmp 4如何改善 骨合成代谢对药物治疗的反应，以区分可翻译的靶向分子， 给病人。我们已发表的和初步的组学数据5、生物化学数据5 - 7、11和骨力学数据为我们提供了信息。 假设Nmp 4限制了骨祖细胞的数量，并调节了骨祖细胞的组成、产生和分化。 基质的输出和最终的骨机械性能。此外，成骨细胞中Nmp 4的缺失 急剧增强整体mRNA翻译，与未折叠的选择部分的诱导一致， 蛋白质反应（UPR），其用于扩大ER的加工能力并促进蛋白质 分泌，将成骨细胞转化为超分泌细胞11。我们建议这些超级分泌者 释放不成比例的高水平骨钙素和骨桥蛋白5，7，这有助于形成 抗骨折骨87.三个独立的目标将揭示Nmp 4行动的机制。 目的#1：鉴定驱动Nmp 4-/-对合成代谢剂的反应的特定细胞类型。卵巢小鼠 将处理来自MSPC、成骨细胞或破骨细胞的Nmp 4的选择性基因组缺失（flox 单药和联合治疗骨质疏松症。为了靶向Nmp 4途径， 因此，在干预过程中，识别驱动有益效果的细胞类型至关重要。目标#2：确定Nmp 4 调节成骨细胞核糖体生物发生，基质蛋白的整体和基因特异性mRNA翻译速率， 普遍定期审议的战略部分与控制紧急救济扩大相吻合。普遍定期审议途径是一种潜在的 治疗靶点的许多疾病，包括糖尿病21 -27。目标#3：确定矩阵， 在能量耗散机制的背景下，Nmp 4-/-骨的矿物质组成 疲劳和断裂韧性试验28 -33.这一目标的实现将为这种关系提供前景 成骨细胞分泌体和骨材料特性之间的关系。我们有一个强大的方法来放大 现有骨质疏松症疗法的有效性，并为新疗法提供新的分子靶点。

“The holy grail of osteoporosis therapy remains the restoration of … bone mass…”1, and consequent fracture reduction. Current osteoporosis therapies have significant limitations2 and NIAMS objectives include addressing “why some therapeutic agents become less effective with long-term use and “exploring opportunities for discovery of newly identified molecular targets for new drug treatments”3. Mice harboring a loss-of-function mutation in the gene encoding the transcription factor Nmp4 are healthy, long-lived, and exhibit an unremarkable skeletal phenotype until challenged with an anabolic stimulus including several classes of osteoporosis therapies, which elicits enhanced bone formation4-8. The absence of a baseline phenotype, combined with the improved response to therapy, affords a unique advantage for developing Nmp4 (or one of its upstream/downstream components) as a safe target to enhance efficacy of existing therapies and identify molecular targets for new therapies. Our goal is to determine how disabling Nmp4 improves the osteoanabolic response to drug treatments, in order to distinguish targetable molecules that can be translated to patients. Our published and preliminary –omic5, biochemical5-7,11, and bone mechanical data inform our hypothesis that Nmp4 limits the number of osteoprogenitors and regulates the composition, production, and export of the matrix and ultimately bone mechanical properties. Furthermore, loss of Nmp4 in osteogenic cells sharply enhances global mRNA translation, coincident with induction of select portions of the unfolded protein response (UPR), which serve to expand the processing capacity of the ER and facilitate protein secretion, converting the osteoblast into a super-secretory cell11. We propose that these super-secretors release a disproportionately high level of osteocalcin and osteopontin5,7 that contribute to the formation of fracture resistant bone87. Three independent aims will reveal the mechanisms underlying Nmp4 action. Aim #1: identify the specific cell type(s) driving the Nmp4-/- response to anabolic agents. Ovariectomized mice harboring selective genomic deletion (flox) of Nmp4 from MSPCs, osteoblasts, or osteoclasts will be treated with mono- and combination osteoporosis therapies. To target the Nmp4 pathways for pharmacological intervention it is crucial to identify the cell type driving the beneficial effects. Aim #2: determine how Nmp4 regulates osteoblast ribosome biogenesis, global and gene-specific mRNA translation rates of matrix proteins, and strategic portions of the UPR coincident with control of ER expansion. The UPR pathway is a potential therapeutic target for numerous disorders including osteoporosis21-27. Aim #3: determine the matrix and mineral composition of the Nmp4-/- bone in the context of energy dissipation mechanisms subsequent to fatigue and fracture toughness tests28-33. Completion of this aim will provide perspectives into the relationship between the osteoblast secretome and bone material properties. We have a powerful way to magnify the effectiveness of existing osteoporosis therapies and provide novel molecular targets for new therapies.