DKK-1 介导的 Wnt 信号抑制可改善骨关节炎小鼠的骨关节炎。

Dkk-1-mediated inhibition of Wnt signaling in bone ameliorates osteoarthritis in mice.

机构信息

INSERM UMR-1132, Hôpital Lariboisière, and Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

出版信息

Arthritis Rheumatol. 2014 Nov;66(11):3028-39. doi: 10.1002/art.38799.

DOI:10.1002/art.38799

PMID:25080367

Abstract

OBJECTIVE

Wnt signaling is a master regulator of joint homeostasis, but its role in osteoarthritis (OA) remains unclear. This study was undertaken to characterize the activation of Wnt/β-catenin in knee joints of mice with OA and to assess how inhibiting this pathway in bone could affect cartilage.

METHODS

OA was induced by partial meniscectomy in Topgal mice and in transgenic mice overexpressing Dkk-1 under the control of the 2.3-kb Col1a1 promoter (Col1a1-Dkk-1-Tg mice). Wnt/β-catenin activation was assessed by X-Gal staining at baseline and at weeks 4, 6, and 9. Cartilage and bone damage was analyzed in Col1a1-Dkk-1-Tg mice with OA at week 6. Primary chondrocytes and cartilage explants were used to assess the effect of Dkk-1 on cartilage catabolism.

RESULTS

In meniscectomized Topgal mice, Wnt was mainly activated in osteocytes from the subchondral bone at week 6 after OA induction, as well as in osteophytes and synovium at week 4. Chondrocytes from damaged zones expressed X-Gal from week 4. Dkk-1 expression was high in chondrocytes in control mouse knees (mean ± SEM 84.2 ± 3.1%) but decreased greatly in knees of meniscectomized mice from week 4 (mean ± SEM 14.4 ± 3.8%). The OA score was lower in meniscectomized Col1a1-Dkk-1-Tg mice at week 6 compared with wild-type mice (5.1 ± 0.6 versus 8.4 ± 0.6; P = 0.002). Subchondral bone fraction and osteophyte volume were decreased. However, cartilage explants from Col1a1-Dkk-1-Tg mice showed proteoglycan loss and increased NITEGE expression. Expression of vascular endothelial growth factor (VEGF) was reduced in osteoblasts from Col1a1-Dkk-1-Tg mice, thereby decreasing expression of messenger RNA for matrix metalloproteinases in chondrocytes.

CONCLUSION

Wnt activation in OA affects the whole joint, particularly bone. Selective inhibition of this pathway in bone by Dkk-1 decreased OA severity through VEGF inhibition.

摘要

目的

Wnt 信号是关节稳态的主要调节因子，但它在骨关节炎（OA）中的作用尚不清楚。本研究旨在描述 OA 小鼠膝关节中 Wnt/β-连环蛋白的激活情况，并评估在骨中抑制该途径如何影响软骨。

方法

通过半月板部分切除术诱导 Topgal 小鼠和在 Col1a1 启动子（Col1a1-Dkk-1-Tg 小鼠）控制下过表达 Dkk-1 的转基因小鼠发生 OA。在基线和 4、6 和 9 周时通过 X-Gal 染色评估 Wnt/β-连环蛋白的激活。在 6 周时分析 OA 下的 Col1a1-Dkk-1-Tg 小鼠的软骨和骨损伤。使用原发性软骨细胞和软骨外植体评估 Dkk-1 对软骨分解代谢的影响。

结果

在诱导 OA 后 6 周，半月板切除的 Topgal 小鼠中，Wnt 主要在软骨下骨的成骨细胞中激活，在骨赘和滑膜中也在 4 周时激活。从第 4 周开始，损伤区的软骨细胞表达 X-Gal。在对照小鼠膝关节中，Dkk-1 的表达在软骨细胞中很高（平均值±SEM 84.2±3.1%），但在半月板切除的小鼠膝关节中从第 4 周开始大大降低（平均值±SEM 14.4±3.8%）。与野生型小鼠相比，半月板切除的 Col1a1-Dkk-1-Tg 小鼠在第 6 周的 OA 评分较低（5.1±0.6 与 8.4±0.6；P=0.002）。软骨下骨分数和骨赘体积减少。然而，Col1a1-Dkk-1-Tg 小鼠的软骨外植体显示出蛋白聚糖丢失和 NITEGE 表达增加。Col1a1-Dkk-1-Tg 小鼠成骨细胞中血管内皮生长因子（VEGF）的表达减少，从而降低了软骨细胞中基质金属蛋白酶信使 RNA 的表达。