Radboud University Medical Center, Nijmegen, The Netherlands.
University Medical Center Utrecht, Utrecht, The Netherlands.
Arthritis Rheumatol. 2017 Oct;69(10):1978-1983. doi: 10.1002/art.40206. Epub 2017 Aug 29.
Increased Wnt signaling in chondrocytes is associated with development of osteoarthritis (OA). However, OA is considered a disease of the entire joint, where the synovium has been attributed an important role in disease pathogenesis and progression. This study was undertaken to determine whether Wnt signaling in synovial tissue could contribute to pathologic development of OA through the production of matrix metalloproteinases (MMPs), and to assess the relationship of synovial expression of Frizzled (FZD) receptors and the Wnt inhibitor FRZB to MMP expression and disease progression in patients with early OA in the Dutch Cohort Hip and Cohort Knee (CHECK) study cohort.
In mouse knee joints, human WNT8A and mouse Wnt16 were overexpressed using adenoviral vectors, and expression of messenger RNA (mRNA) for MMPs in the synovium was determined by reverse transcription-polymerase chain reaction or Luminex assay. In human synovial tissue from a subgroup of patients with early OA with knee pain enrolled in the CHECK cohort, levels of Wnt family members were assessed for linkage to MMP expression and disease progression. In addition, MMP production in human synovium from patients with end-stage OA was determined after stimulation of Wnt signaling with WNT3A or inhibition with FRZB or DKK1 in the synovium.
Overexpression of WNT8A and Wnt16 in mouse knee joints induced MMP expression in vivo. Expression of MMPs relevant to human OA in the synovium from CHECK study participants significantly correlated with expression of FZD1, FZD10, and FRZB mRNA. Moreover, increased FZD1 mRNA expression and decreased FRZB mRNA expression were observed in CHECK study patients who experienced disease progression compared to those who were nonprogressors. Stimulation of human OA synovium with WNT3A induced the production of various MMPs, whereas inhibition of Wnt signaling with FRZB or DKK1 reduced the production of MMPs.
Wnt signaling in the synovium may potently induce progression of OA via increased production of MMPs.
软骨细胞中 Wnt 信号的增加与骨关节炎（OA）的发展有关。然而，OA 被认为是整个关节的一种疾病，滑膜在疾病发病机制和进展中被认为具有重要作用。本研究旨在确定滑膜组织中的 Wnt 信号是否可以通过产生基质金属蛋白酶（MMPs）来促进 OA 的病理发展，并评估荷兰队列髋关节和膝关节研究队列（CHECK）研究中早期 OA 患者滑膜中Frizzled（FZD）受体和 Wnt 抑制剂 FRZB 的表达与 MMP 表达和疾病进展的关系。
在小鼠膝关节中，使用腺病毒载体过表达人 WNT8A 和小鼠 Wnt16，并通过逆转录聚合酶链反应或 Luminex 测定来确定滑膜中 MMPs 的信使 RNA（mRNA）表达。在 CHECK 队列中招募的患有膝关节疼痛的早期 OA 患者的滑膜组织的亚组中，评估了 Wnt 家族成员的水平与 MMP 表达和疾病进展的关系。此外，在 Wnt 信号通过 WNT3A 刺激或通过 FRZB 或 DKK1 在滑膜中抑制后，测定来自终末期 OA 患者的人滑膜中 MMP 的产生。
在小鼠膝关节中过表达 WNT8A 和 Wnt16 诱导体内 MMP 表达。CHECK 研究参与者滑膜中与人类 OA 相关的 MMPs 的表达与 FZD1、FZD10 和 FRZB mRNA 的表达显著相关。此外，与非进展者相比，经历疾病进展的 CHECK 研究患者的 FZD1 mRNA 表达增加和 FRZB mRNA 表达降低。WNT3A 刺激人 OA 滑膜诱导各种 MMP 的产生，而 FRZB 或 DKK1 抑制 Wnt 信号降低 MMP 的产生。
滑膜中的 Wnt 信号可能通过增加 MMP 的产生而有力地诱导 OA 的进展。
