Dkk-1-Mediated Inhibition of Wnt Signaling in Bone Ameliorates Osteoarthritis in Mice
Dkk-1-Mediated Inhibition of Wnt Signaling in Bone Ameliorates Osteoarthritis in Mice
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DOI：
10.1002/art.38799
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发表时间：
2014-11-01
影响因子：
13.3
通讯作者：
Cohen-Solal, Martine
中科院分区：
文献类型：
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作者：
Funck-Brentano, Thomas;Bouaziz, Wafa;Cohen-Solal, Martine
Objective. Wnt信号是关节内稳态的主要调节因子，但其在骨关节炎（OA）中的作用仍不清楚。本研究旨在表征OA小鼠膝关节中Wnt/β-连环蛋白的激活，并评估抑制骨中该途径如何影响软骨。在Topgal小鼠和在2.3-kb Col 1a 1启动子控制下过表达Dkk-1的转基因小鼠（Col 1a 1-Dkk-1-Tg小鼠）中通过部分睾丸切除术诱导OA。在基线和第4、6和9周通过X-Gal染色评估Wnt/β-连环蛋白活化。在第6周时，在患有OA的Col 1a 1-Dkk-1-Tg小鼠中分析了软骨和骨损伤。采用原代软骨细胞和软骨外植体来评估Dkk-1对软骨分解代谢的影响。在骨切除的Topgal小鼠中，Wnt主要在OA诱导后第6周的软骨下骨的骨细胞中活化，以及在第4周的骨赘和滑膜中活化。从第4周起，受损区的软骨细胞表达X-Gal。Dkk-1在对照小鼠膝关节的软骨细胞中表达较高（平均值+/- SEM 84.2 +/- 3.1%），但在切除软骨的小鼠膝关节中从第4周开始显著降低（平均值+/- SEM 14.4 +/- 3.8%）。在第6周，与野生型小鼠相比，切除盲肠的Col 1a 1-Dkk-1-Tg小鼠的OA评分较低（5.1 +/- 0.6 vs 8.4 +/- 0.6; P = 0.002）。软骨下骨分数和骨赘体积减少。然而，来自Col 1a 1-Dkk-1-Tg小鼠的软骨外植体显示蛋白聚糖损失和增加的NITEGE表达。结论：Col 1a 1-Dkk-1-Tg小鼠成骨细胞中血管内皮生长因子（VEGF）的表达降低，从而降低软骨细胞中基质金属蛋白酶信使RNA的表达。OA中的Wnt激活影响整个关节，特别是骨。通过Dkk-1选择性抑制骨中的这一通路通过VEGF抑制降低OA严重程度。
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/beta-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/beta-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.