Elucidating bone marrow edema and myelopoiesis in murine arthritis using contrast-enhanced magnetic resonance imaging.
OBJECTIVE
While bone marrow edema (BME) detected by magnetic resonance imaging (MRI) is a biomarker of arthritis, its nature remains poorly understood due to the limitations of clinical studies. In this study, MRI of murine arthritis was used to elucidate its cellular composition and vascular involvement.


METHODS
BME was quantified using normalized bone marrow intensity (NBMI) from precontrast MRI and normalized marrow contrast enhancement (NMCE) following intravenous administration of gadopentate dimeglumine. Wild-type (WT) and tumor necrosis factor (TNF)-transgenic mice were scanned from 2 to 5 months of age, followed by histologic or fluorescence-activated cell sorting (FACS) analysis of marrow. In efficacy studies, TNF-transgenic mice were treated with anti-TNF or placebo for 8 weeks, and then were studied using bimonthly MRI and histologic analysis.


RESULTS
NBMI values were similar in WT and TNF-transgenic mice at 2 months. The values in WT mice steadily decreased thereafter, with mean values becoming significantly different from those of TNF-transgenic mice at 3.5 months (mean +/- SD 0.29 +/- 0.08 versus 0.46 +/- 0.13; P < 0.05). Red to yellow marrow transformation occurred in WT but not TNF-transgenic mice, as observed histologically at 5 months. The marrow of TNF-transgenic mice that received anti-TNF therapy converted to yellow marrow, with lower NBMI values versus placebo at 6 weeks (mean +/- SD 0.26 +/- 0.07 versus 0.61 +/- 0.22; P < 0.05). FACS analysis of bone marrow revealed a significant correlation between NBMI values and CD11b+ monocytes (R2 = 0.91, P = 0.0028). Thresholds for "normal" red marrow versus pathologic BME were established, and it was also found that inflammatory marrow is highly permeable to contrast agent.


CONCLUSIONS
BME signals in TNF-transgenic mice are caused by yellow to red marrow conversion, with increased myelopoiesis and increased marrow permeability. The factors that mediate these changes warrant further investigation.
Proulx
Steven T
ST
University of Rochester, Rochester, New York 14642, USA.
Kwok
Edmund
E
You
Zhigang
Z
Papuga
M Owen
MO
Beck
Christopher A
CA
Shealy
David J
DJ
Calvi
Laura M
LM
Ritchlin
Christopher T
CT
Awad
Hani A
HA
Boyce
Brendan F
BF
Xing
Lianping
L
Schwarz
Edward M
EM
D000818:Animals; D001168:Arthritis / Q000175:diagnosis* / Q000188:drug therapy; D001853:Bone Marrow / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000175:diagnosis*; D003287:Contrast Media; D004487:Edema / Q000175:diagnosis*; D019786:Gadolinium DTPA; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D038042:Myelopoiesis / Q000187:drug effects; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
D003287:Contrast Media; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D019786:Gadolinium DTPA