The in vivo effect of prophylactic subchondral bone protection of osteoarthritic synovial membrane in bone-specific Ephb4-overexpressing mice.
The in vivo effect of prophylactic subchondral bone protection of osteoarthritic synovial membrane in bone-specific Ephb4-overexpressing mice.
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DOI：
10.1016/j.ajpath.2014.10.004
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发表时间：
2015-02
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通讯作者：
G. Valverde-Franco;D. Hum;K. Matsuo;B. Lussier;J. Pelletier;H. Fahmi;M. Kapoor;J. Martel-Pelletier-J.-Martel-Pell
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作者：
G. Valverde-Franco;D. Hum;K. Matsuo;B. Lussier;J. Pelletier;H. Fahmi;M. Kapoor;J. Martel-Pelletier-J.-Martel-Pell
骨关节炎（OA）的特征是进行性关节破坏，包括滑膜改变。EphB 4及其配体ephrin-B2在体外对OA软骨下骨和软骨有明显的保护作用，在体内过表达骨特异性EphB 4（TgEphB 4）的实验小鼠模型中发现，EphB 4及其配体ephrin-B2对OA软骨下骨和软骨有保护作用。我们在TgEphB 4小鼠模型中研究了OA过程中对滑膜的体内影响。膝关节OA是通过内侧半月板（DMM）不稳定手术诱导的。使用组织学、组织形态计量学、IHC和实时PCR评价滑膜。与DMM野生型（WT）小鼠相比，DMM-TgEphB 4小鼠的滑膜厚度、血管内皮生长因子和促纤维化标志物纤维蛋白、1型前胶原、3型胶原、结缔组织生长因子、平滑肌肌动蛋白-α、软骨寡聚基质蛋白、前胶原-赖氨酸和2-酮戊二酸5-双加氧酶2显著降低。与DMM-WT小鼠相比，DMM-TgEphB 4中已知的转化生长因子-β信号调节因子、转化生长因子受体1/ALK 1、磷酸化Smad-1和热休克蛋白90β的表达显著降低; Ephb 4过表达对老年小鼠（24月龄）滑膜厚度也有保护作用。骨特异性Ephb 4的过表达清楚地证明了预防OA滑膜纤维化的发展和/或进展，加强了在OA过程中保护软骨下骨减少其他关节组织病理变化的假设。
Osteoarthritis (OA) is characterized by progressive joint destruction, including synovial membrane alteration. EphB4 and its ligand ephrin-B2 were foundin vitroto positively affect OA subchondral bone and cartilage.In vivoin an experimental mouse model overexpressing bone-specificEphb4(TgEphB4), a protective effect was found on both the subchondral bone and cartilage during OA. We investigated in the TgEphB4 mouse model thein vivoeffect on synovial membrane during OA. Knee OA was surgically induced by destabilization of the medial meniscus (DMM). Synovial membrane was evaluated using histology, histomorphometry, IHC, and real-time PCR. Compared to DMM-wild-type (WT) mice, DMM-TgEphB4 mice had a significant decrease in synovial membrane thickness, vascular endothelial growth factor, and the profibrotic markers fibrin, type 1 procollagen, type 3 collagen, connective tissue growth factor, smooth muscle actin-α, cartilage oligomeric matrix protein, and procollagen-lysine, and 2-oxoglutarate 5-dioxygenase 2. Moreover, factors known to modulate transforming growth factor-β signaling, transforming growth factor receptor 1/ALK1, phosphorylated Smad-1, and heat shock protein 90β were significantly decreased in DMM-TgEphB4 compared with DMM-WT mice.Ephb4overexpression also exhibited a protective effect on synovial membrane thickness of aged (24-month-old) mice. Overexpression of bone-specificEphb4clearly demonstrated prevention of the development and/or progression of fibrosis in OA synovial membrane, reinforcing the hypothesis that protecting the subchondral bone prophylactically and during OA reduces the pathologic changes in other articular tissues.