Objective

One driving factor in the progression to posttraumatic osteoarthritis (PTOA) is the perpetuation of the inflammatory response to injury into chronic inflammation. Molecular imaging offers many opportunities to complement the sensitivity of current imaging modalities with molecular specificity. The goal of this study was to develop and characterize agents to image hyaluronan (HA)-mediated inflammatory signaling.

Design

We developed optical (Cy5.5-P15-1) and magnetic resonance contrast agents (Gd-DOTA-P15-1) based in a hyaluronan-binding peptide (P15-1) that has shown anti-inflammatory effects on human chondrocytes, and validated them in vitro and in vivo in two animal models of PTOA.

Results

In vitro studies with a near infrared (NIR) Cy5.5-P15-1 imaging agent showed a fast and stable localization of Cy5.5-P15-1 on chondrocytes, but not in synovial cells. In vivo NIR showed significantly higher retention of imaging agent in PTOA knees between 12 and 72 h (n = 8, Cohen's d > 2 after 24 h). NIR fluorescence accumulation correlated with histologic severity in cartilage and meniscus (ρ between 0.37 and 0.57, P < 0.001). By using in vivo magnetic resonance imaging with a Gd-DOTA-P15-1 contrast agent in 12 rats, we detected a significant decrease of T1 on injured knees in all cartilage plates at 48 h (−15%, 95%-confidence interval (CI) = [-18%,-11%]) while no change was observed in the controls (−2%, 95%-CI = [-5%,+1%]).

Conclusions

This study provides the first in vivo evidence that hyaluronan-related inflammatory response in cartilage after injury is a common finding. Beyond P15-1, we have demonstrated that molecular imaging can provide a versatile technology to investigate and phenotype PTOA pathogenesis, as well as study therapeutic interventions.

中文翻译：

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透明质酸介导的关节软骨炎症反应的体内多模态成像

客观的

创伤后骨关节炎 (PTOA) 进展的一个驱动因素是对损伤的炎症反应持续存在慢性炎症。分子成像提供了许多机会来补充具有分子特异性的当前成像方式的灵敏度。本研究的目的是开发和表征对透明质酸 (HA) 介导的炎症信号进行成像的试剂。

设计

我们开发了基于透明质酸结合肽 (P15-1) 的光学 (Cy5.5-P15-1) 和磁共振造影剂 (Gd-DOTA-P15-1)，对人类软骨细胞具有抗炎作用，并且在 PTOA 的两种动物模型中体外和体内验证了它们。

结果

用近红外 (NIR) Cy5.5-P15-1 显像剂进行的体外研究表明，Cy5.5-P15-1 在软骨细胞上快速而稳定地定位，但在滑膜细胞中却没有。体内NIR 在 12 到 72 小时之间显示显像剂在 PTOA 膝盖中的保留显着更高（n  = 8，24 小时后 Cohen's d  > 2）。NIR 荧光积累与软骨和半月板的组织学严重程度相关（ρ 介于 0.37 和 0.57 之间，P  < 0.001）。通过体内使用在 12 只大鼠中使用 Gd-DOTA-P15-1 造影剂进行磁共振成像，我们检测到 48 小时时所有软骨板中受伤膝关节的 T1 显着降低（-15%，95% 置信区间 (CI) = [ -18%,-11%])，而在对照组中没有观察到变化 (-2%, 95%-CI = [-5%,+1%])。

结论

这项研究提供了第一个体内证据，表明损伤后软骨中与透明质酸相关的炎症反应是一个常见的发现。除了 P15-1，我们已经证明分子成像可以提供一种通用技术来研究和表型 PTOA 发病机制，以及研究治疗干预。