透明质酸注射治疗小鼠骨关节炎通过 CD44 依赖机制预防 TGFβ1 诱导的滑膜新生血管形成和纤维化，并维持关节软骨完整性。

Hyaluronan injection in murine osteoarthritis prevents TGFbeta 1-induced synovial neovascularization and fibrosis and maintains articular cartilage integrity by a CD44-dependent mechanism.

机构信息

Department of Internal Medicine (Rheumatology), Rush University Medical Center, 1611 West Harrison Street Suite 510, Chicago, IL 60612, USA.

出版信息

Arthritis Res Ther. 2012 Jun 21;14(3):R151. doi: 10.1186/ar3887.

DOI:10.1186/ar3887

PMID:22721434

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3446537/

Abstract

INTRODUCTION

The mechanism by which intra-articular injection of hyaluronan (HA) ameliorates joint pathology is unknown. Animal studies have shown that HA can reduce synovial activation, periarticular fibrosis and cartilage erosion; however, its specific effects on the different cell types involved remain unclear. We have used the TTR (TGFbeta1 injection and Treadmill Running) model of murine osteoarthritis (OA), which exhibits many OA-like changes, including synovial activation, to examine in vivo tissue-specific effects of intra-articular HA.

METHODS

The kinetics of clearance of fluorotagged HA from joints was examined with whole-body imaging. Naïve and treated knee joints were examined macroscopically for cartilage erosion, meniscal damage and fibrosis. Quantitative histopathology was done with Safranin O for cartilage and with Hematoxylin & Eosin for synovium. Gene expression in joint tissues for Acan, Col1a1, Col2a1, Col3a1, Col5a1, Col10a1, Adamts5 and Mmp13 was done by quantitative PCR. The abundance and distribution of aggrecan, collagen types I, II, III, V and X, ADAMTS5 and MMP13 were examined by immunohistochemistry.

RESULTS

Injected HA showed a half-life of less than 2 h in the murine knee joint. At the tissue level, HA protected against neovascularization and fibrosis of the meniscus/synovium and maintained articular cartilage integrity in wild-type but not in Cd44 knockout mice. HA injection enhanced the expression of chondrogenic genes and proteins and blocked that of fibrogenic/degradative genes and proteins in cartilage/subchondral bone, whereas it blocked activation of both groups in meniscus/synovium. In all locations it reduced the expression/protein for Mmp13 and blocked Adamts5 expression but not its protein abundance in the synovial lining.

CONCLUSIONS

The injection of HA, 24 h after TGFbeta1 injection, inhibited the cascade of OA-like joint changes seen after treadmill use in the TTR model of OA. In terms of mechanism, tissue protection by HA injection was abrogated by Cd44 ablation, suggesting that interaction of the injected HA with CD44 is central to its protective effects on joint tissue remodeling and degeneration in OA progression.

摘要

简介

关节内注射透明质酸（HA）改善关节病理的机制尚不清楚。动物研究表明，HA 可以减少滑膜激活、关节周围纤维化和软骨侵蚀；然而，其对涉及的不同细胞类型的具体影响尚不清楚。我们使用了 TTR（TGFbeta1 注射和跑步机跑步）模型的骨关节炎（OA），该模型表现出许多 OA 样变化，包括滑膜激活，以检查关节内 HA 的体内组织特异性作用。

方法

通过全身成像检查荧光标记 HA 从关节中的清除动力学。对未经处理和处理的膝关节进行大体检查，以检查软骨侵蚀、半月板损伤和纤维化。用番红 O 对软骨进行定量组织病理学检查，用苏木精和伊红对滑膜进行定量组织病理学检查。通过定量 PCR 检测关节组织中的 Acan、Col1a1、Col2a1、Col3a1、Col5a1、Col10a1、Adamts5 和 Mmp13 的基因表达。通过免疫组织化学检查聚集蛋白聚糖、胶原 I、II、III、V 和 X、ADAMTS5 和 MMP13 的丰度和分布。

结果

在鼠膝关节中，注射的 HA 的半衰期不到 2 小时。在组织水平上，HA 可防止半月板/滑膜的新生血管形成和纤维化，并维持关节软骨的完整性，但在 Cd44 敲除小鼠中则不然。HA 注射可增强软骨形成基因和蛋白的表达，并阻断软骨/软骨下骨中纤维形成/降解基因和蛋白的表达，而在半月板/滑膜中则阻断两组的激活。在所有部位，它均降低了 Mmp13 的表达/蛋白水平，并阻断了滑膜衬里中 Adamts5 的表达，但不阻断其蛋白丰度。