Development and optimization of a high-throughput micro-computed tomography imaging method incorporating a novel analysis technique to evaluate bone mineral density of arthritic joints in a rodent model of collagen induced arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease resulting in joint inflammation, pain, and eventual bone loss. Bone loss and remodeling caused by symmetric polyarthritis, the hallmark of RA, is readily detectable by bone mineral density (BMD) measurement using micro-CT. Abnormalities in these measurements over time reflect the underlying pathophysiology of the bone. To evaluate the efficacy of anti-rheumatic agents in animal models of arthritis, we developed a high throughput knee and ankle joint imaging assay to measure BMD as a translational biomarker. A bone sample holder was custom designed for micro-CT scanning, which significantly increased assay throughput. Batch processing 3-dimensional image reconstruction, followed by automated image cropping, significantly reduced image processing time. In addition, we developed a novel, automated image analysis method to measure BMD and bone volume of knee and ankle joints. These improvements significantly increased the throughput of ex vivo bone sample analysis, reducing data turnaround from 5 days to 24 hours for a study with 200 rat hind limbs. Taken together, our data demonstrate that BMD, as quantified by micro-CT, is a robust efficacy biomarker with a high degree of sensitivity. Our innovative approach toward evaluation of BMD using optimized image acquisition and novel image processing techniques in preclinical models of RA enables high throughput assessment of anti-rheumatic agents offering a powerful tool for drug discovery.

Automated Quantification of Early Bone Alterations and Pathological Bone Turnover in Experimental Arthritis by in vivo PET/CT Imaging

“…PET imaging would therefore be the means of choice when sensitivity is indispensable, even though it does cause additional costs, a logistic overhead and additional radiation dose compared to CT imaging alone. In contrast, our results demonstrate that VOI roughness is much more sensitive to detect early bone erosion than bone volume or surface area measurements, which have been performed previously 10 and which have frequently been used to quantify arthritic processes in animal models 13, 14, 32, 35, 36 . In fact, we found no delay between the onset of increased PET tracer uptake and increased bone surface roughness after arthritis induction, emphasizing the capability of bone surface roughness analysis to quantify pathological alterations of the bones immediately after arthritis onset.…”

Quantification of arthritic bone degradation by analysis of 3D micro-computed tomography data

“…A standard approach to evaluate the effects of experimental arthritis on bones is to measure the bone mineral density (BMD) using μ CT78. BMD measurements require high radiation doses and the density needs to be concurrent with the scanning of a calibration phantom, which means that histological samples are used in most cases79.…”

Meniscal Ossicles as micro-CT Imaging Biomarker in a Rodent Model of Antigen-Induced Arthritis: a Synchrotron-Based X-ray Pilot Study

“…Micro-CT in animal models appears to be particularly well suited for high-resolution characterization of the bones and can be used to define quantitative parameters to assess RA in an experimental context, thereby providing more insights on the disease process and on therapeutic protection from bone erosions 16 , 17 . However, it is important to note that the results obtained from micro-CT datasets strongly depend on a number of technical issues, including selected volumes of interest (VOI), segmentation, thresholding procedures and scanning resolutions.…”