Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy.
Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy.
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DOI：
10.1038/s41413-018-0017-8
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发表时间：
2018
期刊：
影响因子：
12.7
通讯作者：
Virshup DM
中科院分区：
文献类型：
--
作者：
Madan B;McDonald MJ;Foxa GE;Diegel CR;Williams BO;Virshup DM
Wnt 信号传导失调与癌症、纤维化和血管疾病的发病机制有关。 Wnt 信号传导的抑制已在这些疾病的各种临床前模型中显示出功效。开发靶向抗癌药物的关键挑战之一是平衡疗效与靶向毒性。鉴于 Wnt 在成骨细胞和破骨细胞分化中发挥的关键作用，Wnt 信号传导的急性抑制可能会影响骨稳态。在这项研究中，我们评估了邻酰基转移酶豪猪 (PORCN) 小分子抑制剂的骨骼效应，该抑制剂通过阻断所有 Wnt 的分泌来阻止 Wnt 信号传导。微型计算机断层扫描和组织形态学评估显示，用两种结构不同的 PORCN 抑制剂 LGK974 和 ETC-1922159 (ETC-159) 治疗的小鼠骨骼在暴露后 4 周内出现骨体积和密度损失。骨量的减少与骨髓内脂肪细胞的显着增加有关。值得注意的是，同时给予临床批准的抗骨吸收剂阿仑膦酸盐（双膦酸盐家族的成员），通过调节破骨细胞的活性和阻止骨髓脂肪细胞的积累，减轻了 ETC-159 治疗时出现的骨量损失。我们的结果支持在使用 PORCN 抑制剂治疗患者时添加骨保护剂。减轻骨毒性可以扩展 Wnt 通路抑制剂的治疗效用。通过使用现有的骨质疏松症药物可以减轻癌症药物引起的潜在骨质流失。 Wnt 信号通路的过度激活有助于维持健康组织和骨骼发育，常见于癌症中。科学家正在试验阻断关键酶 PORCN 从而抑制 Wnt 信号传导的抗癌药物，但这些药物也可能对患者的骨骼结构产生不利影响。新加坡杜克-新加坡国立大学医学院的 David Virshup 和美国密歇根州 Van Andel 研究所的 Bart Williams 及其同事发现，接受 PORCN 抑制癌症药物治疗的小鼠在暴露后 4 周内骨量和密度下降。研究小组随后将这种抗癌药物与另一种药物阿仑膦酸钠结合使用，阿仑膦酸钠已用于治疗骨质疏松症。这种组合针对小鼠的异常 Wnt 信号传导和有限的骨毒性。
Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine (PORCN) that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159 (ETC-159) had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably, simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family, mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors. Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors. Potential bone loss caused by cancer drugs could be mitigated by administering an existing osteoporosis drug. Over-activation of the Wnt signaling pathway, which helps maintain healthy tissues and bone development, is often found in cancer. Scientists are trialing cancer drugs that block a key enzyme PORCN and therefore inhibit Wnt signaling, but these drugs may also adversely affect patients’ bone structure. David Virshup at Duke-NUS Medical School in Singapore and Bart Williams at the Van Andel Research Institute in Michigan, US, and co-workers found that mice treated with PORCN -inhibiting cancer drugs lost bone volume and density within four weeks of exposure. The team then combined the cancer drug with another drug, alendronate, which is already used to treat osteoporosis. This combination targeted aberrant Wnt signaling and limited bone toxicity in the mice.
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DOI：
10.1074/jbc.m112.381970
发表时间：
2012-10-05
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Proffitt KD;Virshup DM
通讯作者：
Virshup DM
影响因子：
12.4
作者：
Chen Q;Shou P;Zheng C;Jiang M;Cao G;Yang Q;Cao J;Xie N;Velletri T;Zhang X;Xu C;Zhang L;Yang H;Hou J;Wang Y;Shi Y
通讯作者：
Shi Y
影响因子：
19.6
作者：
Madan B;Patel MB;Zhang J;Bunte RM;Rudemiller NP;Griffiths R;Virshup DM;Crowley SD
通讯作者：
Crowley SD
影响因子：
64.5
作者：
Gong, YQ;Slee, RB;Warman, ML
通讯作者：
Warman, ML
DOI：
10.1056/nejmoa0802633
发表时间：
2009-01-01
期刊：
The New England journal of medicine
影响因子：
--
作者：
Weinstein RS;Roberson PK;Manolagas SC
通讯作者：
Manolagas SC