Activin receptor-based therapies for musculoskeletal disease

描述(申请人提供)：哺乳动物的骨骼和骨骼肌峰值质量高度相关，表明在这些解剖学上相邻的组织中存在共同的合成代谢信号网络，促进了它们的发育。人们普遍认为，较大的肌肉通过力产生的机械信号间接刺激增加的骨骼获得，从而传递邻近骨骼的合成代谢活动。或者，这些控制肌肉质量的信号网络可能直接在骨骼中发挥作用。虽然后一种概念直观上很吸引人，但很少有基础研究试图描述这种途径。本应用中的研究直接针对这一问题，并提出激活素/肌肉抑制素信号通路构成了一种共同的机制，以类似于该通路在肌肉中明确定义的活动的方式来调节骨骼质量的获得和维持。在肌肉中，由肌肉抑制素和相关配体激活的激活素受体信号对肌肉生长具有负面调节作用，从而通过基因改变或药物治疗来阻止信号传递，从而显著增加肌肉质量。与这一观点一致，我们发现激活素/肌肉生长抑素受体的功能成分在成骨细胞中大量表达。此外，我们还证明了短期治疗(4次ip注射)野生型小鼠的一种可溶的ACVR2B受体可以迅速(4周)使骨小梁数量增加两倍，这首次表明激活素信号直接影响骨获得。基于这些观察，我们假设激活素/肌肉生长抑素分子的一个子集通过成骨细胞中的特定受体直接抑制骨获取，而抑制这种受体信号转导会增加骨量。在这个项目中，我们将通过表征骨骼中的激活素信号成分并将它们与骨骼肌中的激活素信号成分区分开来来检验这一假说。我们将利用在骨骼中选择性缺乏ACVR2或ACVR2B的新小鼠模型来明确识别激活素/肌肉生长抑素信号的骨骼作用。在第二系列补充性研究中，我们将通过注射可溶性激活素受体，进一步测试激活素通路在野生型小鼠和年龄相关性骨量减少和骨量减少模型中对骨骼和肌肉质量的意义。我们预计，这项申请中提出的研究结果将加快激活素受体生物制剂的临床试验，以治疗人类与年龄相关的骨骼和肌肉损失。 公共卫生相关性：该项目将使用新的遗传小鼠模型来明确定义激活素受体信号在骨骼发育和维护中的直接作用。此外，我们将在一种与年龄相关的骨骼和肌肉丢失的小鼠模型中评估药物操纵这一途径的治疗效果。我们预计，这些研究的结果将加快激活素受体生物制剂的临床试验，以治疗人类的骨骼和肌肉丢失。

DESCRIPTION (provided by applicant): Peak bone and skeletal muscle mass in mammals is highly correlated, suggesting the existence of common anabolic signaling networks in these anatomically adjacent tissues that promote their development. It has been widely assumed, that larger muscles stimulate increased skeletal acquisition indirectly, through force- generated mechanical signals, which transduce anabolic activity in the adjacent bone. Alternatively, these same signaling networks that control muscle mass might function directly in bone. While this latter concept is intuitively appealing, few basic studies have attempted to describe such a pathway. The studies in this application take direct aim at this problem and propose that the activin/myostatin signaling pathway constitutes a common mechanism that regulates the acquisition and maintenance of skeletal mass in a manner analogous to the well-defined activity of this pathway in muscle. In muscle, activation of activin receptor signaling by myostatin and related ligands negatively regulates muscle growth such that blocking signaling via genetic alterations or pharmacologic treatments profoundly increases in muscle mass. Consistent with this idea, we have found that functional components of the activin/myostatin receptors are abundantly expressed in osteoblasts. Further, we demonstrated that short-term treatment (4 IP injections) of a soluble ACVR2B receptor in wild-type mice rapidly (4 weeks) tripled trabecular bone mass, suggesting for the first time that activin signaling directly influences bone acquisition. Based upon these observations, we hypothesize that a subset of activin/myostatin molecules function through specific receptors in osteoblasts to directly inhibit bone acquisition, and that inhibition of such receptor signaling increases bone mass. In this project, we will test this hypothesis by characterizing the activin signaling components in bone and distinguishing them from those that operate in skeletal muscle. We will exploit new mouse models that lack selectively either ACVR2 or ACVR2B in bone to unambiguously identify skeletal actions of activin/myostatin signaling. In a second series of complementary studies, we will further test the significance of the activin pathway on bone and muscle mass, in wild type mice and models of age-related sarcopenia and osteopenia, by administration of soluble activin receptors. We expect the results from the studies proposed in this application will expedite clinical trials of activin receptor-based biologics to treat age-related bone and muscle loss in humans. PUBLIC HEALTH RELEVANCE: This project will use novel genetic mouse models to unambiguously define the direct actions of activin receptor signaling in skeletal development and maintenance. Further, we will evaluate the therapeutic efficacy of pharmacologically manipulating this pathway in a mouse model of age related bone and muscle loss. We anticipate that results from these studies will expedite clinical trials of activin receptor-based biologics to treat bone and muscle loss in humans.