Impact of Genetic and Pharmacologic Inhibition of Myostatin in a Murine Model of Osteogenesis Imperfecta.
Impact of Genetic and Pharmacologic Inhibition of Myostatin in a Murine Model of Osteogenesis Imperfecta.
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遗传和药理学抑制肌抑制素在成骨的鼠模型模型中。
DOI：
10.1002/jbmr.4223
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Phillips CL
中科院分区：
文献类型：
--
作者：
Omosule CL;Gremminger VL;Aguillard AM;Jeong Y;Harrelson EN;Miloscio L;Mastaitis J;Rafique A;Kleiner S;Pfeiffer FM;Zhang A;Schulz LC;Phillips CL
成骨不全（OI）是一种遗传性结缔组织疾病，其特征是骨骼完整性受损，微结构改变和骨脆性。目前的骨质疏松症治疗策略侧重于骨抗吸收药物和有效性有限的手术干预，因此确定替代治疗方案仍然至关重要。肌肉是骨形成的重要刺激物。肌生长抑制素是TGF-β超家族肌因子，通过ActRIIB起作用以负调节肌肉生长。最近的研究证明了用可溶性ActRIIB融合蛋白抑制肌肉生长抑制素对骨骼特性的潜在益处，尽管各种OI小鼠模型表现出可变的骨骼反应。与OI相关的遗传和临床异质性、ActRIIB诱饵分子对单独的肌生长抑制素缺乏特异性以及人类临床试验中的不良事件进一步需要阐明肌生长抑制素的治疗潜力和在骨骼完整性中的作用。在这项研究中，我们确定了G610 C小鼠（一种轻度-中度I/IV型人类OI模型）中遗传性肌肉生长抑制素缺乏症和出生后抗肌肉生长抑制素单克隆抗体（Regn 647）的药理学肌肉生长抑制素抑制的肌肉骨骼结局。在出生后研究中，5周龄野生型和+/G610 C雄性和雌性同窝仔用Regn 647或对照抗体处理11周或7周，随后是4周的处理假期。抑制肌肉生长抑制素，无论是遗传还是非遗传，增加肌肉质量，无论OI基因型如何，尽管程度不同。遗传性肌肉生长抑制素缺乏使后肢肌肉重量增加6.9%至34.4%，而药物抑制使其增加13.5%至29.6%。雌性+/mglutamine +/G610 C（Dbl.Het）小鼠倾向于具有与Wt相似的小梁和皮质骨参数，显示+/G610 C特征逆转，但雄性小鼠中发生的+/mglutamine影响极小。药理学肌肉生长抑制素抑制未能改善雄性或雌性+/G610 C小鼠的骨骼特性，尽管在雄性野生型小鼠中观察到骨骼微结构和生物力学改善。四周的治疗假期并没有改变骨骼的结果。
Osteogenesis imperfecta (OI) is a genetic connective tissue disorder characterized by compromised skeletal integrity, altered microarchitecture, and bone fragility. Current OI treatment strategies focus on bone antiresorptives and surgical intervention with limited effectiveness, and thus identifying alternative therapeutic options remains critical. Muscle is an important stimulus for bone formation. Myostatin, a TGF-β superfamily myokine, acts through ActRIIB to negatively regulate muscle growth. Recent studies demonstrated the potential benefit of myostatin inhibition with the soluble ActRIIB fusion protein on skeletal properties, although various OI mouse models exhibited variable skeletal responses. The genetic and clinical heterogeneity associated with OI, the lack of specificity of the ActRIIB decoy molecule for myostatin alone, and adverse events in human clinical trials further the need to clarify myostatin’s therapeutic potential and role in skeletal integrity. In this study, we determined musculoskeletal outcomes of genetic myostatin deficiency and postnatal pharmacological myostatin inhibition by a monoclonal anti-myostatin antibody (Regn647) in the G610C mouse, a model of mild–moderate type I/IV human OI. In the postnatal study, 5-week-old wild-type and +/G610C male and female littermates were treated with Regn647 or a control antibody for 11 weeks or for 7 weeks followed by a 4-week treatment holiday. Inhibition of myostatin, whether genetically or pharmacologically, increased muscle mass regardless of OI genotype, although to varying degrees. Genetic myostatin deficiency increased hindlimb muscle weights by 6.9% to 34.4%, whereas pharmacological inhibition increased them by 13.5% to 29.6%. Female +/mstn +/G610C (Dbl.Het) mice tended to have similar trabecular and cortical bone parameters as Wt showing reversal of +/G610C characteristics but with minimal effect of +/mstn occurring in male mice. Pharmacologic myostatin inhibition failed to improve skeletal bone properties of male or female +/G610C mice, although skeletal microarchitectural and biomechanical improvements were observed in male wild-type mice. Four-week treatment holiday did not alter skeletal outcomes.
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影响因子：
3.2
作者：
Elkasrawy, Moataz;Immel, David;Hamrick, Mark W.
通讯作者：
Hamrick, Mark W.
DOI：
10.1152/ajpendo.90696.2008
发表时间：
2009-04-01
影响因子：
5.1
作者：
Brown, Marybeth;Ning, Jie;Lubahn, Dennis B.
通讯作者：
Lubahn, Dennis B.
影响因子：
82.9
作者：
Dankbar, Berno;Fennen, Michelle;Pap, Thomas
通讯作者：
Pap, Thomas
影响因子：
3.4
作者：
Attie, Kenneth M.;Borgstein, Niels G.;Sherman, Matthew L.
通讯作者：
Sherman, Matthew L.
影响因子：
7
作者：
Alves, Rodrigo D. A. M.;Eijken, Marco;van Leeuwen, Johannes P. T. M.
通讯作者：
van Leeuwen, Johannes P. T. M.