Exogenous Indian hedgehog antagonist damages intervertebral discs homeostasis in adult mice.
Exogenous Indian hedgehog antagonist damages intervertebral discs homeostasis in adult mice.
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DOI：
10.1016/j.jot.2022.09.009
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发表时间：
2022-09
影响因子：
6.6
通讯作者：
Zhou, Siru
中科院分区：
文献类型：
--
作者：
Chen, Ran;Tan, Ya;Li, Yang;Huang, Junlan;Kuang, Liang;Ni, Zhenhong;Lan, Haiyang;Long, Rui;Xie, Yangli;Chen, Hangang;Luo, Xiaoqing;Chen, Lin;Tang, Ying;Zhou, Siru
维莫德吉作为外源性Indian hedgehog（Ihh）拮抗剂，已被美国食品药品监督管理局（FDA）批准用于基底细胞癌患者的临床治疗，并且先前的观察暗示了维莫德吉在骨关节炎治疗中的潜在治疗。然而，没有直接证据表明Ihh信号在成年小鼠椎间盘（IVD）内稳态中的作用。本研究的目的是评估全身施用平滑抑制剂（SMOi）-维莫德吉对成人阶段IVD体内平衡的影响。通过免疫组织化学检测接受SMOi全身给药后成年小鼠IVD中胶质瘤相关癌基因同源物1（Gli 1）（Ihh信号传导的下游靶向基因）的表达。通过X线片和显微CT评价SMOi治疗后椎体的病理变化。通过组织学分析来评价SMOi对IVD包括软骨终板（CEP）、生长板（GP）和纤维环（AF）的稳态的影响。免疫组化法检测IVD中聚集蛋白聚糖、基质金属蛋白酶13（MMP 13）和Runt相关转录因子2（Runx 2）的表达。通过末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）法和分析细胞增殖抗原Ki-67的表达来评估IVD中软骨细胞凋亡和增殖的变化。SMOi能显著降低Ihh信号通路中Gli 1的表达。SMOi治疗后椎体骨量减少。此外，在SMOi处理的小鼠中观察到IVD变性（IDD）样缺陷，包括CEP硬化、退行性髓核（NP）和AF内的裂隙，以及GP变窄或融合和椎体的骨量丢失。IDD的严重程度与在2-8周后施用SMOi治疗具有时间依赖性。经SMOi处理的小鼠IVD中聚集蛋白聚糖、MMP 13和Runx 2的表达显著降低。此外，软骨细胞凋亡明显增强，而软骨细胞增殖明显抑制。我们的研究表明，全身给药维莫德吉损害IVD稳态通过抑制Ihh信号在成年小鼠。Ihh信号拮抗剂如维莫德吉的临床应用应慎重考虑这些副作用。维莫德吉作为Ihh信号传导的外源性拮抗剂已被FDA批准用于基底细胞癌患者的临床治疗。然而，vismodegib是否会对IVD软骨稳态的患者或动物模型产生不利影响仍然是未知的。基于我们的研究，全身给药维莫德吉通过抑制Ihh信号通路损害成年小鼠IVD的稳态，应特别注意维莫德吉的临床应用。
Vismodegib, as an exogenous Indian hedgehog (Ihh) antagonist, has been approved by the Food and Drug Administration (FDA) for the clinical treatment of patients with basal cell carcinoma, and previous observations implicate the potential therapeutic of vismodegib in osteoarthritis treatment. However, there is no direct evidence for the role of Ihh signaling in intervertebral discs (IVDs) homeostasis of adult mice. The aim of the present study is to assess the effect of systemic administration of Smoothened inhibitor (SMOi) - vismodegib on IVDs homeostasis during the adult stage. The expression of glioma-associated oncogene homolog 1 (Gli1), the downstream targeting gene of Ihh signaling, in IVDs of adult mice after receiving systemic administration of SMOi was examined by immunohistochemistry. The pathological changes of vertebral bodies after SMOi treatment were evaluated by X-ray and micro-CT. The effects of SMOi on homeostasis of IVDs including cartilaginous endplates (CEP), growth plates (GP) and annulus fibrous (AF) were evaluated by histological analysis. The expressions of Aggrecan, Matrix metalloproteinase 13 (MMP13) and Runt-related transcription factor 2 (Runx2), in IVDs were also investigated by immunohistochemistry. Changes in chondrocyte apoptosis and proliferation in IVDs were evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and analyzing the expression of the cell proliferation antigen Ki-67. Systemic administration of SMOi significantly decreased the expression of Gli1 in IVDs that indicating effective inhibition of Ihh signaling. Bone mass of vertebral bodies was diminished after SMOi treatment. Moreover, IVDs degeneration (IDD) like defects including CEP sclerosis, degenerative nucleus pulposus (NP) and fissure within AF, as well as narrowed or fused GP and loss bone mass of vertebral bodies was observed in SMOi-treated mice. The severity of IDD was time-dependent with the administration of SMOi treatment after 2–8 weeks. The expressions of Aggrecan, MMP13 and Runx2 in IVDs of mice receiving SMOi treatment were significantly decreased. In addition, chondrocyte apoptosis was significantly enhanced, while chondrocyte proliferation was significantly inhibited. Our study propose that systemic administration of vismodegib damages IVDs homeostasis via inhibition of Ihh signaling in adult mice. The clinical application of Ihh signaling antagonists such as vismodegib should be careful considering these side adverse. Vismodegib as an exogenous antagonist of Ihh signaling has been approved by the FDA for the clinical treatment of patients with basal cell carcinoma. However, it is still unknown whether vismodegib will has adverse effects on the patient or animal model of IVDs cartilage homeostasis. Based on our study, systemic administration of vismodegib damages IVDs homeostasis via inhibition of Ihh signaling in adult mice and special attention should be paid to the clinical application of vismodegib.
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影响因子：
3.7
作者：
Melgoza IP;Chenna SS;Tessier S;Zhang Y;Tang SY;Ohnishi T;Novais EJ;Kerr GJ;Mohanty S;Tam V;Chan WCW;Zhou CM;Zhang Y;Leung VY;Brice AK;Séguin CA;Chan D;Vo N;Risbud MV;Dahia CL
通讯作者：
Dahia CL
DOI：
10.1016/j.matbio.2018.02.011
发表时间：
2018-04
期刊：
Matrix biology : journal of the International Society for Matrix Biology
影响因子：
--
作者：
Kurio N;Saunders C;Bechtold TE;Salhab I;Nah HD;Sinha S;Billings PC;Pacifici M;Koyama E
通讯作者：
Koyama E
痛苦的椎间盘退变和炎症：从实验室证据到临床干预
影响因子：
12.7
作者：
Lyu FJ;Cui H;Pan H;Mc Cheung K;Cao X;Iatridis JC;Zheng Z
通讯作者：
Zheng Z
DOI：
10.1007/978-1-61779-860-3_5
发表时间：
2012-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Kyrylkova, Kateryna;Kyryachenko, Sergiy;Kioussi, Chrissa
通讯作者：
Kioussi, Chrissa
影响因子：
4.6
作者：
Mak, Kinglun Kingston;Kronenberg, Henry M.;Yang, Yingzi
通讯作者：
Yang, Yingzi