title: 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.
authors.affiliation: Imaging-Boston, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Raquel S
authors.initials: RS
authors.lastname: Sevilla
authors.affiliation: Informatics IT, Merck Research Laboratories, 126 E. Lincoln Avenue, PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cruz
authors.affiliation: Respiratory & Immunology Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Chi-Sung
authors.initials: CS
authors.lastname: Chiu
authors.affiliation: Imaging-West Point, Merck Research Laboratories, Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Dahai
authors.initials: D
authors.lastname: Xue
authors.affiliation: Imaging-Boston, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bettano
authors.affiliation: Imaging-Boston, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Respiratory & Immunology Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Chakravarthy
authors.affiliation: Respiratory & Immunology Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Faltus
authors.affiliation: Biometrics Research, Merck Research Laboratories, RY34-300, 126 Lincoln Avenue, Rahway, NJ 07065, USA.
authors.forename: Shubing
authors.initials: S
authors.lastname: Wang
authors.affiliation: Imaging-Boston, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Vanko
authors.affiliation: Imaging-Boston, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Gain
authors.initials: G
authors.lastname: Robinson
authors.affiliation: Respiratory & Immunology Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Zielstorff
authors.affiliation: Respiratory & Immunology Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: John
authors.initials: J
authors.lastname: Miao
authors.affiliation: Respiratory & Immunology Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Leccese
authors.affiliation: Compound Management and Engineering, Merck Research Laboratories, 126 E. Lincoln Avenue, PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Conway
authors.affiliation: Respiratory & Immunology Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.affiliation: Informatics IT, Merck Research Laboratories, 126 E. Lincoln Avenue, PO Box 2000, Rahway, NJ 07065, USA.
authors.forename: Belma
authors.initials: B
authors.lastname: Dogdas
authors.affiliation: Respiratory & Immunology Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Milenko
authors.initials: M
authors.lastname: Cicmil
authors.affiliation: Imaging-Boston, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: weisheng_zhang@merck.com.
authors.forename: Weisheng
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control; D015519:Bone Density; D003094:Collagen / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D051381:Rats; D011917:Rats, Inbred Lew; D055114:X-Ray Microtomography / Q000379:methods*
chemical_list: D003094:Collagen
keywords: Automatic segmentation; Bone mineral density; CIA; Micro-CT; Polynomial fitting; Rheumatoid arthritis