GREM1, FRZB and DKK1 mRNA levels correlate with osteoarthritis and are regulated by osteoarthritis-associated factors.
GREM1, FRZB and DKK1 mRNA levels correlate with osteoarthritis and are regulated by osteoarthritis-associated factors.
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DOI：
10.1186/ar4306
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发表时间：
2013-09-19
影响因子：
4.9
通讯作者：
Karperien M
中科院分区：
文献类型：
--
作者：
Leijten JC;Bos SD;Landman EB;Georgi N;Jahr H;Meulenbelt I;Post JN;van Blitterswijk CA;Karperien M
至少在一部分患者中，骨关节炎与关节软骨细胞的肥大分化有关。最近，我们发现骨形态发生蛋白（BMP）和无翅型MMTV整合位点（WNT）信号拮抗剂Gremlin 1（GREM1）、卷曲相关蛋白（FRZB）和dickkopf 1同源物（非洲爪蟾）（DKK1）是关节软骨肥大分化的天然刹车。在这项研究中，我们研究了与骨关节炎或软骨细胞肥大调节有关的因素是否影响 GREM1、FRZB 和 DKK1 表达水平。通过定量 PCR 研究了健康青春期前儿童和健康成人的关节软骨以及同一骨关节炎关节的保存和降解骨关节炎软骨中的 GREM1、FRZB 和 DKK1 mRNA 水平。随后，我们将人关节软骨细胞暴露于 WNT、BMP、IL-1β、印度刺猬、甲状旁腺激素相关肽、机械负荷、不同的介质张力或不同的氧水平，并使用时程分析研究 GREM1、FRZB 和 DKK1 的表达水平。 GREM1、FRZB 和 DKK1 mRNA 表达在骨关节炎中显着降低。此外，与来自同一骨关节炎关节的宏观保存的软骨相比，这种下调在软骨降解方面更强。 WNT、BMP、IL-1β 信号传导和机械负荷调节 GREM1、FRZB 和 DKK1 mRNA 水平。印度刺猬、甲状旁腺激素相关肽和张力影响至少一种拮抗剂的 mRNA 水平，而氧水平没有表现出任何统计上显着的影响。有趣的是，BMP 和 WNT 信号传导上调了彼此拮抗剂的表达。总之，当前的研究证明了骨关节炎与软骨中 GREM1、FRZB 和 DKK1 基因表达之间存在负相关，并提供了对潜在转录调控的深入了解。此外，我们发现 BMP 和 WNT 信号传导在负反馈回路中相连，这可能通过平衡 BMP 和 WNT 活性对于关节软骨稳态至关重要。
Osteoarthritis is, at least in a subset of patients, associated with hypertrophic differentiation of articular chondrocytes. Recently, we identified the bone morphogenetic protein (BMP) and wingless-type MMTV integration site (WNT) signaling antagonists Gremlin 1 (GREM1), frizzled-related protein (FRZB) and dickkopf 1 homolog (Xenopus laevis) (DKK1) as articular cartilage’s natural brakes of hypertrophic differentiation. In this study, we investigated whether factors implicated in osteoarthritis or regulation of chondrocyte hypertrophy influence GREM1, FRZB and DKK1 expression levels. GREM1, FRZB and DKK1 mRNA levels were studied in articular cartilage from healthy preadolescents and healthy adults as well as in preserved and degrading osteoarthritic cartilage from the same osteoarthritic joint by quantitative PCR. Subsequently, we exposed human articular chondrocytes to WNT, BMP, IL-1β, Indian hedgehog, parathyroid hormone-related peptide, mechanical loading, different medium tonicities or distinct oxygen levels and investigated GREM1, FRZB and DKK1 expression levels using a time-course analysis. GREM1, FRZB and DKK1 mRNA expression were strongly decreased in osteoarthritis. Moreover, this downregulation is stronger in degrading cartilage compared with macroscopically preserved cartilage from the same osteoarthritic joint. WNT, BMP, IL-1β signaling and mechanical loading regulated GREM1, FRZB and DKK1 mRNA levels. Indian hedgehog, parathyroid hormone-related peptide and tonicity influenced the mRNA levels of at least one antagonist, while oxygen levels did not demonstrate any statistically significant effect. Interestingly, BMP and WNT signaling upregulated the expression of each other’s antagonists. Together, the current study demonstrates an inverse correlation between osteoarthritis and GREM1, FRZB and DKK1 gene expression in cartilage and provides insight into the underlying transcriptional regulation. Furthermore, we show that BMP and WNT signaling are linked in a negative feedback loop, which might prove essential in articular cartilage homeostasis by balancing BMP and WNT activity.
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影响因子：
8
作者：
Kaler, P.;Augenlicht, L.;Klampfer, L.
通讯作者：
Klampfer, L.
影响因子：
4.2
作者：
Jikko, A;Kato, Y;Fuchihata, H
通讯作者：
Fuchihata, H
影响因子：
4.9
作者：
Dreier R
通讯作者：
Dreier R
DOI：
10.2741/martel
发表时间：
1999-10-15
期刊：
Frontiers in Bioscience
影响因子：
--
作者：
Martel-Pelletier, Johanne;Alaaeddine, Nada;Pelletier, Jean-Pierre
通讯作者：
Pelletier, Jean-Pierre
影响因子：
27.4
作者：
Bos, Steffan D.;Bovee, Judith V. M. G.;Meulenbelt, Ingrid
通讯作者：
Meulenbelt, Ingrid