Longitudinal assessment of synovial, lymph node, and bone volumes in inflammatory arthritis in mice by in vivo magnetic resonance imaging and microfocal computed tomography.
OBJECTIVE
To develop longitudinal 3-dimensional (3-D) measures of outcomes of inflammation and bone erosion in murine arthritis using contrast-enhanced magnetic resonance imaging (CE-MRI) and in vivo microfocal computed tomography (micro-CT) and, in a pilot study, to determine the value of entry criteria based on age versus synovial volume in therapeutic intervention studies.


METHODS
CE-MRI and in vivo micro-CT were performed on tumor necrosis factor-transgenic (TNF-Tg) mice and their wild-type littermates to quantify the synovial and popliteal lymph node volumes and the patella and talus bone volumes, respectively, which were validated histologically. These longitudinal outcome measures were used to assess the natural history of erosive inflammatory arthritis. We also performed anti-TNF versus placebo efficacy studies in TNF-Tg mice in which treatment was initiated according to either age (4-5 months) or synovial volume (3 mm(3) as detected by CE-MRI). Linear regression was performed to analyze the correlation between synovitis and focal erosion.


RESULTS
CE-MRI demonstrated the highly variable nature of TNF-induced joint inflammation. Initiation of treatment by synovial volume produced significantly larger treatment effects on the synovial volume (P = 0.04) and the lymph node volume (P < 0.01) than did initiation by age. By correlating the MRI and micro-CT data, we were able to demonstrate a significant relationship between changes in synovial and patellar volumes (R(2) = 0.75, P < 0.01).


CONCLUSIONS
In vivo CE-MRI and micro-CT 3-D outcome measures are powerful tools that accurately demonstrate the progression of erosive inflammatory arthritis in mice. These methods can be used to identify mice with arthritis of similar severity before intervention studies are initiated, thus minimizing heterogeneity in outcome studies of chronic arthritis seen between genetically identical littermates.
Proulx
Steven T
ST
Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Kwok
Edmund
E
You
Zhigang
Z
Papuga
M Owen
MO
Beck
Christopher A
CA
Shealy
David J
DJ
Ritchlin
Christopher T
CT
Awad
Hani A
HA
Boyce
Brendan F
BF
Xing
Lianping
L
Schwarz
Edward M
EM
D000818:Animals; D001168:Arthritis / Q000000981:diagnostic imaging / Q000473:pathology*; D015415:Biomarkers; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology*; D004195:Disease Models, Animal; D004487:Edema / Q000000981:diagnostic imaging / Q000473:pathology; D007249:Inflammation / Q000000981:diagnostic imaging / Q000473:pathology; D008198:Lymph Nodes / Q000000981:diagnostic imaging / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D010000:Osteitis / Q000000981:diagnostic imaging / Q000473:pathology; D010865:Pilot Projects; D013583:Synovial Membrane / Q000000981:diagnostic imaging / Q000473:pathology*; D014057:Tomography, X-Ray Computed / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics
D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha