Valverde-Franco Gladys, Pelletier Jean-Pierre, Fahmi Hassan, Hum David, Matsuo Koichi, Lussier Bertrand, Kapoor Mohit, Martel-Pelletier Johanne
University of Montreal Hospital Research Centre, Quebec, Canada.
Arthritis Rheum. 2012 Nov;64(11):3614-25. doi: 10.1002/art.34638.
In vitro activation of the receptor EphB4 positively affects human osteoarthritis (OA) articular cell metabolism. However, the specific in vivo role of this ephrin receptor in OA remains unknown. We investigated in mice the in vivo effect of bone-specific EphB4 overexpression on OA pathophysiology.
Morphometric, morphologic, and radiologic evaluations were performed on postnatal day 5 (P5) mice and on 10-week-old mice. Knee OA was induced surgically by destabilization of the medial meniscus (DMM) in 10-week-old male EphB4 homozygous transgenic (EphB4-Tg) and wild-type (WT) mice. Medial compartment evaluations of cartilage were performed using histology and immunohistochemistry, and evaluations of subchondral bone using histomorphometry, osteoclast staining, and micro-computed tomography.
There was no obvious phenotype difference in skeletal development between EphB4-Tg mice and WT mice at P5 or at 10 weeks. At 8 and 12 weeks post-DMM, the EphB4-Tg mice demonstrated significantly less cartilage alteration in the medial tibial plateau and the femoral condyle than did the WT mice. This was associated with a significant reduction of aggrecan and type II collagen degradation products, type X collagen, and collagen fibril disorganization in the operated EphB4-Tg mice. The medial tibial subchondral bone demonstrated a significant reduction in sclerosis, bone volume, trabecular thickness, and number of tartrate-resistant acid phosphatase-positive osteoclasts at both times assessed post-DMM in the EphB4-Tg mice than in the WT mice.
This is the first in vivo evidence that bone-specific EphB4 overexpression exerts a protective effect on OA joint structural changes. The findings of this study stress the in vivo importance of subchondral bone biology in cartilage integrity.
受体EphB4的体外激活对人骨关节炎（OA）关节细胞代谢有积极影响。然而，这种 Ephrin 受体在OA中的具体体内作用仍不清楚。我们在小鼠中研究了骨特异性EphB4过表达对OA病理生理学的体内影响。
对出生后第5天（P5）的小鼠和10周龄的小鼠进行形态计量学、形态学和放射学评估。通过内侧半月板不稳定（DMM）手术诱导10周龄雄性EphB4纯合转基因（EphB4-Tg）和野生型（WT）小鼠的膝关节OA。使用组织学和免疫组织化学对软骨内侧部分进行评估，使用组织形态计量学、破骨细胞染色和微型计算机断层扫描对软骨下骨进行评估。
在P5或10周时，EphB4-Tg小鼠和WT小鼠在骨骼发育方面没有明显的表型差异。在DMM后8周和12周，EphB4-Tg小鼠在内侧胫骨平台和股骨髁的软骨改变明显少于WT小鼠。这与手术的EphB4-Tg小鼠中聚集蛋白聚糖和II型胶原降解产物、X型胶原以及胶原纤维紊乱的显著减少有关。在DMM后评估的两个时间点，EphB4-Tg小鼠的内侧胫骨软骨下骨硬化、骨体积、小梁厚度和抗酒石酸酸性磷酸酶阳性破骨细胞数量均显著低于WT小鼠。
这是首次在体内证明骨特异性EphB4过表达对OA关节结构变化具有保护作用。本研究结果强调了软骨下骨生物学在软骨完整性方面的体内重要性。
