Maternal Anti-myostatin (GDF8) Therapy to Enhance Offspring Musculoskeletal Health in Mouse Models of Osteogenesis Imperfecta

摘要 成骨不全(OI)是一种遗传性和临床异质性的结缔组织疾病 导致肌肉无力、骨骼畸形和脆性增加，主要是由于I型胶原 基因突变。目前还没有治愈的方法。遗传和临床异质性(&gt；1500突变)和 越来越多的证据表明，突变特定的致病机制进一步挑战了药物发现。不足之处 肌肉生长抑制素是一种循环中的肌肉生长负调节因子，它会导致肌肉质量增加和 骨骼上的生理负荷伴随着骨量和生物力学的增加 正直。出生前环境的发育规划被认为起着重要的作用 在终身骨骼健康中的作用，并承诺为治疗干预提供一种新的方式。 先天性肌肉生长抑制素基因缺失的小鼠表现为肌纤维增生和肥大，而小鼠 出生后肌肉抑制素缺乏症仅表现为肥大，表明成人生理的某些方面 是在产前发育过程中不可逆转地决定的。以前，通过三种独立的方法 我们证明，在怀孕期间减少母亲的肌肉生长抑素可以改善骨骼几何形状和 子代的生物力学完整性：1)野生型(Wt)母鼠所生的子代肌肉生长抑制素降低 (/MSTN)比Wt Dam所生的Wt后代骨骼更强壮；2)成骨不全的小鼠 (/OIM)出生在/MSTN水坝比出生在/OIM水坝时骨骼更坚固；和3)/OIM 移植到/MSTN受体母鼠的囊胚成年后骨骼比移植的要坚固 /OIM大坝。重要的是，最后一种方法通过胚胎移植实验证明 母体/MSTN对子代骨骼的影响是由子宫胎盘环境在 怀孕了。基于这些发现，我们将测试药物抑制母体的疗效。 母抗肌抑制素(GDF8)单抗和妊娠期间胎儿肌抑制素 使用两种分子上不同的OI小鼠模型作为OI的产前治疗方法。这个 疗效的主要结果、措施和指标是改善肌肉骨骼健康(骨骼 Wt和Oi子代在骨量峰值年龄(4月龄)的肌肉、骨量和功能)。 OI可以在产前诊断，无论是通过遗传还是通过超声波，但我们没有产前诊断。 治疗选择和，因此错过了一个关键的治疗窗口。这项高风险研究代表了一项 在建立产前治疗的翻译潜力方面迈出了更大的一步 OI，这是理解和治疗OI的范式转变；从只相信遗传和 出生后因素控制骨骼健康，以包括产前/围产期为重要因素 和可修改的窗口，用于控制成人骨骼健康。

Summary Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous connective tissue disorder resulting in muscle weakness, bone deformity and increased fragility, primarily due to type I collagen gene mutations. Currently there is no cure. Genetic and clinical heterogeneity (> 1500 mutations) and growing evidence of mutation specific pathogenesis further challenges drug discovery. Deficiency in myostatin, a circulating negative regulator of muscle growth, results in increased muscle mass and physiological loading on the skeleton with concomitant increases in bone mass and biomechanical integrity. Developmental programming by the prenatal environment is hypothesized to play a significant role in lifelong bone health and promises to provide a novel modality for therapeutic intervention. Congenital myostatin null mice demonstrate both myofiber hyperplasia and hypertrophy, while mice with postnatal myostatin deficiency exhibit only hypertrophy, indicating some aspects of adult physiology are irreversibly determined during prenatal development. Previously, by three independent approaches we demonstrated that reduced maternal myostatin during pregnancy improves bone geometry and biomechanical integrity in offspring: 1) Wildtype (Wt) offspring born to dams with reduced myostatin (+/mstn) had stronger bones than Wt offspring born to Wt dams; 2) Mice with osteogenesis imperfecta (+/oim) had stronger bones when born to +/mstn dams than when born to +/oim dams; and 3) +/oim blastocysts transferred to +/mstn recipient dams had stronger bones as adults than those transferred to +/oim dams. Importantly, the last approach through embryo transfer experiments demonstrated that the maternal +/mstn effect on offspring bone was conferred by the uteroplacental environment during pregnancy. Based on these findings, we will test the efficacy of pharmacological inhibition of maternal and fetal myostatin during pregnancy via maternal anti-myostatin (GDF8) monoclonal antibody treatment as a prenatal therapeutic approach for OI using two molecularly distinct OI mouse models. The primary outcomes measures and indicators of efficacy are improved musculoskeletal health (skeletal muscle and bone mass and function) of Wt and OI offspring at the age of peak bone mass (4 month old). OI can be diagnosed prenatally, whether genetically or by ultrasound, yet we have no prenatal treatment options and, are thus missing a critical therapeutic window. This high risk study represents a more than incremental leap towards establishing the translational potential of a prenatal treatment for OI, it is a paradigm shift in understanding and treating OI; a shift from believing only genetic and postnatal factors control bone health, to the inclusion of the prenatal/perinatal period as an important and modifiable window for controlling adult bone health.