Proulx Steven T, Kwok Edmund, You Zhigang, Papuga M Owen, Beck Christopher A, Shealy David J, Calvi Laura M, Ritchlin Christopher T, Awad Hani A, Boyce Brendan F, Xing Lianping, Schwarz Edward M
University of Rochester, Rochester, New York 14642, USA.
Arthritis Rheum. 2008 Jul;58(7):2019-29. doi: 10.1002/art.23546.
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.
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.
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.
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.
虽然磁共振成像（MRI）检测到的骨髓水肿（BME）是关节炎的一种生物标志物，但由于临床研究的局限性，其本质仍知之甚少。在本研究中，利用小鼠关节炎的MRI来阐明其细胞组成和血管受累情况。
使用对比剂前MRI的归一化骨髓强度（NBMI）和静脉注射钆喷酸葡胺后的归一化骨髓对比增强（NMCE）对BME进行定量。对野生型（WT）和肿瘤坏死因子（TNF）转基因小鼠在2至5月龄时进行扫描，随后对骨髓进行组织学或荧光激活细胞分选（FACS）分析。在疗效研究中，对TNF转基因小鼠用抗TNF或安慰剂治疗8周，然后每两个月进行一次MRI和组织学分析。
2个月时WT和TNF转基因小鼠的NBMI值相似。此后WT小鼠的该值稳步下降，在3.5个月时平均值与TNF转基因小鼠有显著差异（平均值±标准差 0.29±0.08 对 0.46±0.13；P<0.05）。如在5个月时组织学观察到的，WT小鼠发生了红髓向黄髓的转变，而TNF转基因小鼠未发生。接受抗TNF治疗的TNF转基因小鼠的骨髓转变为黄髓，在6周时NBMI值低于安慰剂组（平均值±标准差 0.26±0.07 对 0.61±0.22；P<0.05）。骨髓的FACS分析显示NBMI值与CD11b+单核细胞之间存在显著相关性（R2 = 0.91，P = 0.0028）。建立了“正常”红髓与病理性BME的阈值，还发现炎症骨髓对造影剂具有高渗透性。
TNF转基因小鼠中的BME信号是由黄髓向红髓的转变、髓系造血增加和骨髓通透性增加引起的。介导这些变化的因素值得进一步研究。
