Genetic and pharmacologic suppression of PPARγ enhances NELL-1-stimulated bone regeneration.
Genetic and pharmacologic suppression of PPARγ enhances NELL-1-stimulated bone regeneration.
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PPARγ的基因和药物抑制增强了Nell-1刺激的骨再生。
DOI：
10.1016/j.biomaterials.2022.121609
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发表时间：
2022-08
期刊：
影响因子：
14
通讯作者：
中科院分区：
文献类型：
--
作者：
最近对骨质疏松症发生机制的研究表明，抑制PPARγ介导的脂肪生成可以改善骨形成和骨密度。在这项研究中，我们研究了一种联合治疗策略，通过将NELL-1与两种抑制PPARγ的方法相结合来增强骨形成，NELL-1是一种成骨分子，已被广泛研究其作为骨质疏松症治疗的潜在用途。首先，我们在免疫功能低下的小鼠中使用慢病毒PPARγ-shRNA基因抑制PPARγ，以证明概念。第二，我们使用了一种PPARγ拮抗剂来抑制免疫活性老年骨质减少小鼠的PPARγ β，以获得临床转基因。我们发现，与单药治疗组相比，联合治疗策略显著增加了骨形成，增加了增殖期细胞群，降低了原代小鼠BMSCs的晚期凋亡，并增加了成骨标志物mRNA水平。在NELL-1治疗中加入PPARγ抑制，通过上调合成代谢过程增强了NELL-1对骨形成的作用，而不改变NELL-1对骨形成和脂肪形成活性的抑制作用。我们的研究结果表明，将抑制PPARγ与治疗性NELL-1结合可能是一种可行的方法，可以进一步开发为逆转骨丢失和减少年龄相关性骨质疏松症中骨髓脂肪的新策略。
Recent investigations into mechanisms behind the development of osteoporosis suggest that suppressing PPARγ-mediated adipogenesis can improve bone formation and bone mineral density. In this study, we investigated a co-treatment strategy to enhance bone formation by combining NELL-1, an osteogenic molecule that has been extensively studied for its potential use as a therapeutic for osteoporosis, with two methods of PPARγ suppression. First, we suppressed PPARγ genetically using lentiviral PPARγ-shRNA in immunocompromised mice for a proof of concept. Second, we used a PPARγ antagonist to suppress PPARγ pharmacologically in immunocompetent senile osteopenic mice for clinical transability. We found that the co-treatment strategy significantly increased bone formation, increased the proliferation stage cell population, decreased late apoptosis of primary mouse BMSCs, and increased osteogenic marker mRNA levels in comparison to the single agent treatment groups. The addition of PPARγ suppression to NELL-1 therapy enhanced NELL-1’s effects on bone formation by upregulating anabolic processes without altering NELL-1’s inhibitory effects on osteoclastic and adipogenic activities. Our findings suggest that combining PPARγ suppression with therapeutic NELL-1 may be a viable method that can be further developed as a novel strategy to reverse bone loss and decrease marrow adiposity in age-related osteoporosis.
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影响因子：
4.1
作者：
James, Aaron W.;Shen, Jia;Soo, Chia
通讯作者：
Soo, Chia
影响因子：
4
作者：
James, Aaron W.;Pang, Shen;Soo, Chia
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影响因子：
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作者：
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Nakayama K
影响因子：
4.1
作者：
Fehlberg, S;Trautwein, S;Göke, R
通讯作者：
Göke, R
影响因子：
4.9
作者：
Farmer, SR
通讯作者：
Farmer, SR