UNCOVERING STRUCTURAL DISEASE PATTERNS OF EARLY POST-TRAUMATIC OSTEOARTHRITIS IN A DMM MOUSE MODEL USING CONTRAST-ENHANCED MICRO-COMPUTED TOMOGRAPHY

J.E. Schadow , E.C. Boersma , A.M. Cagnoni , H. Liu , R.A. Davey , K.S. Stok
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Abstract

INTRODUCTION

Contrast-enhanced micro-computed tomography (CECT) is a non-destructive method to assess cartilage degeneration seen in diseases such as OA whilst also allowing for analysis of bone changes [1, 2]. Application has been limited to ex vivo and in situ studies but using CECT in vivo holds the potential to quantify and track structural cartilage and bone changes and illuminate new understanding of disease onset and progression.

OBJECTIVE

The aim of this study was to uncover structural disease patterns of early post-traumatic osteoarthritis in a destabilized medial meniscus (DMM) mouse model using time-lapse CECT.

METHODS

DMM (n=22) or sham surgery (n=22) was performed on ten-week-old C57Bl/6 mice. A further three mice did not undergo surgery but were euthanized at 10 weeks of age and processed for histology. Of the mice that had surgery, three mice per group were euthanised and processed for histology at seven-, 14-, 21- and 28-days post-surgery. The remaining ten mice per group received an intra-articular injection of Dotarem (Guerbet) and were scanned at 10.4 μm, 70 kVp, 114 μA using microCT (vivaCT80, Scanco Medical AG) at one-day pre-surgery and seven-, 14-, 21-, 28-, and 56-days post-surgery. After scanning at the final timepoint, three mice per group were euthanised after scanning at 56-days post-surgery and processed for histology. Safranin-O histology was used to score joints following the OARSI guidelines [3]. Mean attenuation of cartilage, joint alignment, joint space morphometry, subchondral bone morphometry, and osteophyte presence were analysed from microCT images. Mixed-effects analysis was used to investigate effects of osteoarthritis, time, and joint side (medial/lateral) on mean attenuation, joint space, subchondral bone, and osteophytes as well as the effects of osteoarthritis and time on joint alignment.

RESULTS

OARSI score of medial tibia in DMM OA group increased compared to the lateral side in DMM OA group and medial side of sham controls (Figure 1A). Mean attenuation of medial tibial cartilage in DMM OA mice did not change over time whereas that of sham controls increased over time. The number of voxels in the thinnest joint space layer increased on the medial side of DMM OA group post-surgery but did not change on medial side of sham controls or lateral side of either group (Figure 1B). There was increased variability in dorsal axis and midsagittal axis angles α and γ of DMM OA mice at 14-, 21-, and 28-days post-surgery. There was no difference in shape κ and scale θ of osteophyte thickness distribution of DMM OA tibia compared to sham control, despite osteophyte development on the lateral and medial side of DMM OA tibiae and frontal side of both groups. Cortical porosity and trabecular thickness of medial tibia in DMM OA mice increased over time before decreasing at 56-days post-surgery, whereas all other groups steadily decreased.

CONCLUSION

Mean attenuation was not sensitive to cartilage degeneration as intra-articular distribution and diffusion of contrast agent were impacted by joint space narrowing and increased synovial turnover. Bone structure changed as a reaction to altered mechanical loading. Change patterns were non-linear, likely because the mechanical environment changed over the course of disease development.
在DMM小鼠模型中使用增强微计算机断层扫描揭示早期创伤后骨关节炎的结构性疾病模式
对比增强微计算机断层扫描(CECT)是一种非破坏性的评估骨性关节炎等疾病中软骨退变的方法,同时也可以分析骨骼变化[1,2]。应用仅限于离体和原位研究,但在体内使用CECT有可能量化和跟踪结构软骨和骨骼的变化,并阐明疾病发生和进展的新认识。目的:本研究的目的是利用延时CECT揭示不稳定内侧半月板(DMM)小鼠模型早期创伤后骨关节炎的结构性疾病模式。方法对10周龄C57Bl/6小鼠进行sdmm (n=22)或假手术(n=22)治疗。另外3只小鼠没有接受手术,但在10周龄时被安乐死,并进行组织学处理。在接受手术的小鼠中,每组3只小鼠在手术后7天、14天、21天和28天被安乐死并进行组织学处理。每组10只小鼠关节内注射Dotarem (Guerbet),分别于术前1天和术后7、14、21、28、56天使用microCT (vivaCT80, Scanco Medical AG)在10.4 μm、70 kVp、114 μA下进行扫描。在最后时间点扫描后,每组3只小鼠在术后56天扫描后安乐死,并进行组织学处理。根据OARSI指南bbb,采用红花素- o组织学对关节进行评分。从显微ct图像中分析软骨、关节排列、关节间隙形态测定、软骨下骨形态测定和骨赘存在的平均衰减。混合效应分析用于研究骨关节炎、时间和关节侧面(内侧/外侧)对平均衰减、关节间隙、软骨下骨和骨赘的影响,以及骨关节炎和时间对关节对齐的影响。结果DMM OA组胫骨内侧soarsi评分高于DMM OA组外侧及假对照组内侧(图1A)。DMM OA小鼠胫骨内侧软骨的平均衰减不随时间变化,而假手术对照组的平均衰减随时间增加。术后DMM OA组最薄关节间隙层体素数增加,而假对照组的内侧和两组的外侧均无变化(图1B)。术后14、21和28天,DMM OA小鼠背轴和中矢状轴角α和γ的变异性增加。尽管两组DMM OA胫骨外侧、内侧和正面均有骨赘发育,但与假对照组相比,DMM OA胫骨骨赘厚度分布的形状κ和尺度θ无差异。DMM OA小鼠的皮质孔隙度和胫骨内侧小梁厚度随着时间的推移而增加,但在术后56天下降,而其他所有组均稳步下降。结论造影剂的平均衰减对软骨退变不敏感,关节间隙变窄和滑膜周转量增加影响造影剂在关节内的分布和扩散。骨结构随着机械负荷的改变而改变。变化模式是非线性的,可能是因为机械环境在疾病发展过程中发生了变化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Osteoarthritis imaging
Osteoarthritis imaging Radiology and Imaging
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