Administration of an activin receptor IIB ligand trap protects male juvenile rhesus macaques from simian immunodeficiency virus-associated bone loss.
Administration of an activin receptor IIB ligand trap protects male juvenile rhesus macaques from simian immunodeficiency virus-associated bone loss.
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DOI：
10.1016/j.bone.2017.01.032
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发表时间：
2017-04
期刊：
影响因子：
4.1
通讯作者：
Bhasin S
中科院分区：
文献类型：
--
作者：
Guo W;Pencina KM;O'Connell K;Montano M;Peng L;Westmoreland S;Glowacki J;Bhasin S
尽管有效的病毒抑制，艾滋病毒感染者患骨质疏松症的风险增加。肌生长抑制素缺失小鼠骨量增加的观察结果使我们假设猴免疫缺陷病毒（SIV）相关的骨丢失可能通过阻断肌生长抑制素/TGFβ信号转导而减弱。在该概念验证研究中，成对圈养的幼年雄性恒河猴接种SIVmac 239。四周后，用媒介物或Fc缀合的可溶性激活素受体IIB（ActR 2B·Fc，iv. 10 mg·kg-1·week-1）-肌肉生长抑制素和TGFβ超家族相关成员的拮抗剂。在基线和12周的干预期间，使用双能X射线吸收法测量四肢和躯干骨矿物质含量（BMC）和密度（BMD），骨生长和转换的循环标志物，以及血清睾酮水平。ActRIIB. Fc治疗组（+8 g）BMC的增加显著大于安慰剂组（-4 g）（p < 0.05）。ActRIIB. Fc处理的猕猴（+0.03 g/cm 2）中的BMD也比安慰剂处理的动物（+0 g/cm 2）中显著增加更多（p < 0.005）。ActRIIB. Fc治疗组的血清骨钙蛋白比安慰剂组高约两倍（p < 0.05），但血清C末端肽和睾酮水平在组间没有显著差异。骨髓中TNF α（p < 0.05）、GADD 45（p <B 0.005）和硬化蛋白（p < 0.038）的表达水平在ActRIIB. Fc治疗组中显著低于安慰剂组。在SIV感染的幼年猕猴中施用ActRIIB.FC显著增加BMC和BMD，与骨髓炎症标志物的表达水平降低相关。
HIV-infected individuals are at an increased risk of osteoporosis despite effective viral suppression. Observations that myostatin null mice have increased bone mass led us to hypothesize that simian immunodeficiency virus (SIV)-associated bone loss may be attenuated by blocking myostatin/TGFβ signaling. In this proof-of-concept study, pair-housed juvenile male rhesus macaques were inoculated with SIVmac239. Four weeks later, animals were treated with vehicle or Fc-conjugated soluble activin receptor IIB (ActR2B·Fc, iv. 10 mg ∗ kg−1 ∗ week−1) – an antagonist of myostatin and related members of TGFβ superfamily. Limb and trunk bone mineral content (BMC) and density (BMD) using dual-energy X-Ray absorptiometry, circulating markers of bone growth and turnover, and serum testosterone levels were measured at baseline and during the 12-week intervention period. The increase in BMC was significantly greater in the ActRIIB.Fc-treated group (+8 g) than in the placebo group (−4 g) (p < 0.05). BMD also increased significantly more in the ActRIIB.Fc-treated macaques (+0.03 g/cm2) than in the placebo-treated animals (+0 g/cm2) (p < 0.005). Serum osteocalcin was about two-fold higher in the ActRIIB.Fc-treated group than in the placebo group (p < 0.05), but serum C-terminal telopeptide and testosterone levels did not differ significantly between groups. The expression levels of TNFalpha (p < 0.05), GADD45 (p <b 0.005), and sclerostin (p < 0.038) in the bone-marrow were significantly lower in the ActRIIB.Fc-treated group than in the placebo group. The administration of ActRIIB.FC in SIV-infected juvenile macaques significantly increases BMC and BMD in association with reduced expression levels of markers of bone marrow inflammation.
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影响因子：
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作者：
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