Diverse Response to Local Pharmacological Blockade of Sirt1 Cleavage in Age-Induced versus Trauma-Induced Osteoarthritis Female Mice.
Diverse Response to Local Pharmacological Blockade of Sirt1 Cleavage in Age-Induced versus Trauma-Induced Osteoarthritis Female Mice.
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DOI：
10.3390/biom14010081
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发表时间：
2024-01-08
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
目的：已有研究表明Sirt1裂解参与了骨关节炎的发生发展。事实上，在年轻雌性小鼠的创伤后诱导模型(PTOA)中，通过关节内(IA)注射两种化合物，一种是阻断Sirt1裂解的化合物(CA074me)，另一种是激活Sirt1的化合物(SRT1720)，有效地消除了OA。在这项研究中，我们试图了解这种局部治疗在预防年龄相关性骨性关节炎(AOA)进展和症状方面是否有效。设计：一组17月龄雌性C57BL/6J小鼠接受CA074Me和/或SRT1720或其组合的IA。进行关节组织病理学分析和骨组织形态计量学，评价膝关节机械性痛觉过敏。对NT/CT Sirt1进行血清分析，同时对关节软骨进行免疫组织化学检测p16INK4A或γH2A.X。类似地，监测半月板软骨Lef1和Col1a1的沉积。对接受创伤后骨性关节炎(PTOA)的年轻雌性小鼠的数据进行了比较。结果：与PTOA相似，联合治疗的AOA表现出膝关节痛觉过敏的改善，但结构未见改善，对应于NT/CT Sirt1血清水平的变化。骨性关节炎和骨性关节炎的核p16INK4A或γH_2A.X染色均未见改变，与骨性关节炎的严重程度缺乏相关性。与PTOA相反，AOA联合治疗并未显示Lef1和Col1靶点的局部减少。结论：当以Sirt1裂解为靶点时，PTOA和AOA模型对联合治疗的疼痛反应相似；但是，它们对关节相关损伤的结构结果不同，与Lef1依赖的信号有关。有趣的是，核p16INK4A在两种模型中都没有受到影响，无论治疗的有效性如何。最后，这些发现突出了两个高度研究的骨关节炎临床前模型之间的反应差异，反映了骨关节炎病理生理学的异质性和与性别相关的药物反应机制的差异。
Objective: Previous studies have shown that the cleavage of Sirt1 contributes to the development of osteoarthritis (OA). In fact, OA was effectively abrogated by the intra-articular (IA) administration of two compounds, one blocking Sirt1 cleavage (CA074me) and the other activating Sirt1 (SRT1720), using a post-traumatically induced model (PTOA) in young female mice. In this study, we attempted to understand if this local treatment is effective in preventing age-associated OA (AOA) progression and symptoms. Design: A group of 17-month-old female C57BL/6J mice were IA administered with CA074me and/or SRT1720 or their combination. Joint histopathological analysis and bone histomorphometry were carried out, with an assessment of knee mechanical hyperalgesia. A serum analysis for NT/CT Sirt1 was carried out along with immunohistochemistry for articular cartilage to detect p16INK4A or γH2A.X. Similarly, meniscal cartilage was monitored for Lef1 and Col1a1 deposition. The data were compared for young female mice subjected to post-traumatic OA (PTOA). Results: Similar to PTOA, combination-treated AOA exhibited improved knee hyperalgesia, yet structural improvements were undetected, corresponding to unchanged NT/CT Sirt1 serum levels. Both AOA and PTOA exhibited unchanged staining for nuclear p16INK4A or γH2A.X and lacked a correlation with OA severity. Contrarily to PTOA, the combination treatment with AOA did not exhibit a local reduction in the Lef1 and Col1 targets. Conclusions: When targeting Sirt1 cleavage, the PTOA and AOA models exhibited a similar pain response to the combination treatment; however, they displayed diverse structural outcomes for joint-related damage, related to Lef1-dependent signaling. Interestingly, nuclear p16INK4A was unaffected in both models, regardless of the treatment’s effectiveness. Finally, these findings highlight the variations in the responses between two highly researched OA preclinical models, reflecting OA pathophysiology heterogeneity and variations in gender-related drug-response mechanisms.
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影响因子：
7
作者：
Cake, MA;Appleyard, RC;Ghosh, P
通讯作者：
Ghosh, P
DOI：
10.1016/j.bpobgyn.2013.02.005
发表时间：
2013-10
影响因子：
5.5
作者：
Lunenfeld, Bruno;Stratton, Pamela
通讯作者：
Stratton, Pamela
影响因子：
7
作者：
Hwang, H. S.;Park, I. Y.;Kim, H. A.
通讯作者：
Kim, H. A.
影响因子：
5.6
作者：
Jin, Jing;Yang, Xiaoquan;Gong, Hui;Li, Xiangning
通讯作者：
Li, Xiangning
影响因子：
--
作者：
Loeser, Richard F.;Olex, Amy L.;McNulty, Margaret A.;Carlson, Cathy S.;Callahan, Michael F.;Ferguson, Cristin M.;Chou, Jeff;Leng, Xiaoyan;Fetrow, Jacquelyn S.
通讯作者：
Fetrow, Jacquelyn S.