Activin receptor-based therapies for musculoskeletal disease

描述（由申请人提供）：哺乳动物的峰值骨和骨骼肌质量是高度相关的，这表明在这些解剖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骨骼发育的增加，这种机械信号传导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起作用。虽然后一种概念在直觉上很吸引人，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/肌肉生长抑制素信号通路构成了一种共同机制，以类似于肌肉中该通路的明确活性的方式调节骨量的获取和维持。在肌肉中，肌生长抑制素和相关配体激活激活素受体信号负调控肌肉生长，从而通过基因改变或药物治疗阻断信号传导，从而显著增加肌肉质量。与这一观点一致，我们发现激活素/肌肉生长抑制素受体的功能成分在成骨细胞中大量表达。此外，我们证明了短期治疗（4次IP注射）可溶性ACVR2B受体在野生型小鼠中快速（4周）增加了三倍的小梁骨量，这首次表明激活素信号直接影响骨获取。基于这些观察结果，我们假设激活素/肌肉生长抑制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得，并且这种受体信号的抑制增加了骨量。在本项目中，我们将通过表征骨中的激活素信号成分并将其与骨骼肌中的激活素信号成分区分开来来验证这一假设。我们将利用骨中选择性缺乏ACVR2或ACVR2B的新小鼠模型来明确识别激活素/肌肉生长抑制素信号的骨骼作用。在第二个系列的补充研究中，我们将进一步测试激活素途径对骨和肌肉质量的意义，在野生型小鼠和年龄相关的肌肉减少症和骨质减少症模型中，通过给药可溶性激活素受体。我们期望本申请中提出的研究结果将加速基于激活素受体的生物制剂的临床试验，以治疗人类与年龄相关的骨质和肌肉损失。

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.