芳香化酶抑制剂相关绝经前乳腺癌症骨丢失模型的建立及骨丢失机制的实验研究

IF 1.7 4区 医学 Q4 ENDOCRINOLOGY & METABOLISM
Meiling Chu (Primary Author), Yulian Yin (Contributing Author), Hongfeng Chen (Contributing Author)
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引用次数: 0

摘要

目的/目的建立绝经前乳腺癌手术后芳香化酶抑制剂相关性骨质流失(AIBL)裸鼠模型,探讨来曲唑诱导骨质流失的可能机制。目前,AIBL的临床和实验研究主要集中在绝经后乳腺癌患者,忽略了绝经前AIs合并卵巢功能抑制人群。AIBL的发生机制除了众所周知的雌激素急剧下降外,还缺乏对骨代谢相关的细胞机制和因素的探索。h型血管在骨微环境中促进血管生成和骨形成。裂隙引导配体3 (slit guided ligand 3, SLIT3)是一种由成骨细胞分泌的血管生成因子。敲除SLIT3会导致骨内h型血管内皮细胞减少,导致骨量减少。在此基础上,有助于建立AIBL动物模型,探讨骨质流失机制,优化内分泌治疗方案。方法采用乳腺癌异种移植物接种切除、双侧卵巢切除术和来曲唑灌胃法建立绝经前乳腺癌术后AIBL模型。将BALB/c裸鼠随机分为5组:对照组(Control group)、术后组(MX组)、去势组(MX+OVX组)、模型组A (MX+OVX+Le组)、模型组B (OVX+Le组)。取小鼠眼球血,ELISA法检测相关骨代谢及骨相关激素水平。采用micro - ct检测股骨、胫骨骨密度和骨小梁微观结构,HE染色检测骨组织结构,OCN免疫组化检测成骨细胞活性,TRAP免疫组化检测破骨细胞活性。采用H型血管(CD31hiEmcnhi)免疫荧光染色,探讨AIBL的可能机制及相关靶点。结果A、B模型组大鼠血清E2、P1NP、CTX-1、GH、SLIT3与对照组比较,差异均有统计学意义(p < 0.05);0.05)。显微ct (P<0.05),模型A组降低更为显著。在HE染色中,A模型组骨小梁数量明显减少。此外,TRAP和OCN免疫组化染色显示,A模型组骨小梁周围破骨细胞较多,成骨细胞较少。与对照组相比,A模型组免疫荧光下h型血管变小。结论A组更适合作为绝经前乳腺癌手术后的AIBL动物模型。显微CT结合病理染色有助于优化和评价动物模型骨密度和骨微结构的变化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Experimental study on the establishment of Aromatase inhibitor associated bone loss model after premenopausal breast cancer and the mechanism of bone loss

Purpose/Aims

To construct a nude mouse model of aromatase inhibitor-associated bone loss (AIBL) after premenopausal breast cancer surgery, and to explore the possible mechanism of letrozole-induced bone loss.

Rationale/Background

At present, clinical and experimental research on AIBL mainly focuses on postmenopausal breast cancer patients, ignoring the premenopausal population of AIs combined with Ovarian Function Suppression. The mechanism of AIBL is not only the well-known sharp decline of estrogen, but also the lack of exploration of the cellular mechanism and factors related to bone metabolism. H-type blood vessels contribute to angiogenesis and bone formation in the bone microenvironment. It is a sensitive indicator for evaluating bone mass andSlit guided ligand 3 (SLIT3) is a type of angiogenic factor secreted by osteoblasts. Knocking out SLIT3 will lead to the reduction of H-type vascular endothelial cells in bone and resulting in a decrease in bone mass. Based on this, it will be helpful to establish AIBL animal model and explore the mechanism of bone loss, which will help optimize the endocrine therapy regimen.

Methods

The postoperative AIBL model of premenopausal breast cancer was established by inoculation and resection of breast cancer xenografts, bilateral ovariectomy and letrozole gavage. BALB/c nude mice were randomly divided into 5 groups: Control group (Control group), postoperative group (MX group), castration group (MX+OVX group), model group A (MX+OVX+Le group), model group B (OVX+Le group). The eyeball blood of mice was collected to detect the related bone metabolism and bone-related hormones by ELISA. The bone mineral density and trabecular microstructure of the femur and tibia were evaluated by mirco-CT, the bone tissue was evaluated by HE staining, the activity of osteoblasts was evaluated by OCN immunohistochemistry, and the activity of osteoclasts was evaluated by TRAP immunohistochemistry. Immunofluorescence staining of type H blood vessel (CD31hiEmcnhi) was used to explore the potential mechanism and related targets of AIBL.

Results

Compared with the control group, there were significant differences in serum E2, P1NP, CTX-1, GH and SLIT3 in model A and model B groups (P< 0.05). Bone mineral density was significantly reduced by mirco-CT (P< 0.05), and the decrease in model group A was more significant. In HE staining, the number of bone trabeculae in the model A group was significantly reduced. In addition, TRAP and OCN immunohistochemical staining showed that the trabeculae of model A group were surrounded by more osteoclasts and fewer osteoblasts. Compared to the control group, H-type blood vessels in model A group were smaller under immunofluorescence.

Implications

Model group A is more suitable as an AIBL animal model after premenopausal breast cancer surgery. Mirco- CT combined with pathological staining is helpful in optimizing and evaluating changes in bone mineral density and bone microstructure in animal models.

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来源期刊
Journal of Clinical Densitometry
Journal of Clinical Densitometry 医学-内分泌学与代谢
CiteScore
4.90
自引率
8.00%
发文量
92
审稿时长
90 days
期刊介绍: The Journal is committed to serving ISCD''s mission - the education of heterogenous physician specialties and technologists who are involved in the clinical assessment of skeletal health. The focus of JCD is bone mass measurement, including epidemiology of bone mass, how drugs and diseases alter bone mass, new techniques and quality assurance in bone mass imaging technologies, and bone mass health/economics. Combining high quality research and review articles with sound, practice-oriented advice, JCD meets the diverse diagnostic and management needs of radiologists, endocrinologists, nephrologists, rheumatologists, gynecologists, family physicians, internists, and technologists whose patients require diagnostic clinical densitometry for therapeutic management.
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