Guo Wen, Pencina Karol M, O'Connell Karyn, Montano Monty, Peng Liming, Westmoreland Susan, Glowacki Julie, Bhasin Shalender
Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
Bone. 2017 Apr;97:209-215. doi: 10.1016/j.bone.2017.01.032. Epub 2017 Jan 26.
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. 10mg∗kg∗week) - 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 (+8g) than in the placebo group (-4g) (p<0.05). BMD also increased significantly more in the ActRIIB.Fc-treated macaques (+0.03g/cm) than in the placebo-treated animals (+0g/cm) (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<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.
尽管病毒得到有效抑制，但感染HIV的个体患骨质疏松症的风险仍会增加。观察到肌肉生长抑制素基因敲除小鼠的骨量增加，这使我们推测，通过阻断肌肉生长抑制素/TGFβ信号通路，可能会减轻猴免疫缺陷病毒（SIV）相关的骨质流失。在这项概念验证研究中，将成对饲养的幼年雄性恒河猴接种SIVmac239。四周后，动物接受载体或Fc偶联的可溶性激活素受体IIB（ActR2B·Fc，静脉注射，10mg·kg·周）治疗，ActR2B·Fc是肌肉生长抑制素和TGFβ超家族相关成员的拮抗剂。在基线和12周的干预期内，使用双能X线吸收法测量肢体和躯干的骨矿物质含量（BMC）和骨密度（BMD），检测骨生长和转换的循环标志物以及血清睾酮水平。ActRIIB.Fc治疗组的BMC增加量（+8g）显著大于安慰剂组（-4g）（p<0.05）。ActRIIB.Fc治疗的猕猴的BMD增加量（+0.03g/cm）也显著高于安慰剂治疗的动物（+0g/cm）（p<0.005）。ActRIIB.Fc治疗组的血清骨钙素水平比安慰剂组高约两倍（p<0.05），但两组之间的血清C端肽和睾酮水平没有显著差异。ActRIIB.Fc治疗组骨髓中TNFalpha（p<0.05）、GADD45（p<0.005）和硬化蛋白（p<0.038）的表达水平显著低于安慰剂组。
在感染SIV的幼年猕猴中施用ActRIIB.FC可显著增加BMC和BMD，并降低骨髓炎症标志物的表达水平。
