Weng Lin-Hsiu, Wang Ching-Jen, Ko Jih-Yang, Sun Yi-Chih, Wang Feng-Sheng
Chang Gung Memorial Hospital-Kaohsiung Medical Center and Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Arthritis Rheum. 2010 May;62(5):1393-402. doi: 10.1002/art.27357.
OBJECTIVE: Perturbation of Wnt signaling components reportedly regulates chondrocyte fate and joint disorders. The Wnt inhibitor Dkk-1 mediates remodeling of various tissue types. We undertook this study to examine whether control of Dkk-1 expression prevents joint deterioration in osteoarthritic (OA) knees. METHODS: Anterior cruciate ligament transection-and collagenase-induced OA in rat knees was treated with end-capped phosphorothioate Dkk-1 antisense oligonucleotide (Dkk-1-AS). Articular cartilage destruction, cartilage degradation markers, bone mineral density (BMD), and subchondral trabecular bone volume of injured knee joints were measured using Mankin scoring, enzyme-linked immunosorbent assay, dual x-ray absorptiometry, and histomorphometry. Dkk-1-responsive molecule expression and apoptotic cells in knee tissue were detected by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and TUNEL staining. RESULTS: Up-regulated Dkk-1 expression was associated with increased Mankin score and with increased serum levels of cartilage oligomeric matrix protein and C-telopeptide of type II collagen (CTX-II) during OA development. Dkk-1-AS treatment alleviated OA-associated increases in Dkk-1 expression, Mankin score, cartilage fibrillation, and serum cartilage degradation markers. Dkk-1-AS also alleviated epiphyseal BMD loss and subchondral bone exposure associated with altered serum levels of osteocalcin and CTX-I. The treatment abrogated chondrocyte/osteoblast apoptosis and subchondral trabecular bone remodeling in OA. Dkk-1 knockdown increased levels of nuclear beta-catenin and phosphorylated Ser(473)-Akt but attenuated expression of inflammatory factors (Toll-like receptor 4 [TLR-4], TLR-9, interleukin-1beta, and tumor necrosis factor alpha), the apoptosis regulator Bax, matrix metalloproteinase 3, and RANKL in OA knee joints. CONCLUSION: Interference with the cartilage- and bone-deleterious actions of Dkk-1 provides therapeutic potential for alleviating cartilage destruction and subchondral bone damage in OA knee joints.
目的：据报道，Wnt信号通路成分的扰动可调节软骨细胞命运和关节疾病。Wnt抑制剂Dkk-1介导多种组织类型的重塑。我们进行这项研究以检查控制Dkk-1表达是否能预防骨关节炎（OA）膝关节的关节退变。 方法：用封端的硫代磷酸酯Dkk-1反义寡核苷酸（Dkk-1-AS）治疗大鼠膝关节前交叉韧带横断和胶原酶诱导的OA。使用Mankin评分、酶联免疫吸附测定、双能X线吸收法和组织形态计量学测量受伤膝关节的关节软骨破坏、软骨降解标志物、骨矿物质密度（BMD）和软骨下小梁骨体积。通过定量逆转录聚合酶链反应、免疫印迹和TUNEL染色检测膝关节组织中Dkk-1反应性分子表达和凋亡细胞。 结果：在OA发展过程中，Dkk-1表达上调与Mankin评分增加以及软骨寡聚基质蛋白和II型胶原C末端肽（CTX-II）血清水平升高相关。Dkk-1-AS治疗减轻了OA相关的Dkk-1表达增加、Mankin评分、软骨纤维化和血清软骨降解标志物。Dkk-1-AS还减轻了与血清骨钙素和CTX-I水平改变相关的骨骺BMD损失和软骨下骨暴露。该治疗消除了OA中软骨细胞/成骨细胞凋亡和软骨下小梁骨重塑。Dkk-1敲低增加了核β-连环蛋白和磷酸化Ser(473)-Akt的水平，但减弱了OA膝关节中炎症因子（Toll样受体4 [TLR-4]、TLR-9、白细胞介素-1β和肿瘤坏死因子α）、凋亡调节因子Bax、基质金属蛋白酶3和RANKL的表达。 结论：干扰Dkk-1对软骨和骨的有害作用为减轻OA膝关节的软骨破坏和软骨下骨损伤提供了治疗潜力。
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