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

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.