Laboratory of Rheumatology, GIGA I3, CHU de Liege, University of Liege, Liege, Belgium.
Orthopedic Surgery Unit, CHU of Liege, Belgium.
Cell Death Dis. 2019 Feb 4;10(2):103. doi: 10.1038/s41419-019-1377-8.
CEMIP (for "Cell migration-inducing protein" also called KIAA1199 and Hybid for "Hyaluronan-binding protein") expression is increased in cancers and described as a regulator of cell survival, growth and invasion. In rheumatoid arthritis, CEMIP is referred to as an angiogenic marker and participates in hyaluronic acid degradation. In this study, CEMIP expression is investigated in healthy and osteoarthritis (OA) cartilage from human and mouse. Its role in OA physiopathology is deciphered, specifically in chondrocytes proliferation and dedifferentiation and in the extracellular matrix remodeling. To this end, CEMIP, αSMA and types I and III collagen expressions were assessed in human OA and non-OA cartilage. CEMIP expression was also investigated in a mouse OA model. CEMIP expression was studied in vitro using a chondrocyte dedifferentiation model. High-throughput RNA sequencing was performed on chondrocytes after CEMIP silencing. Results showed that CEMIP was overexpressed in human and murine OA cartilage and along chondrocytes dedifferentiation. Most of genes deregulated in CEMIP-depleted cells were involved in cartilage turnover (e.g., collagens), mesenchymal transition and fibrosis. CEMIP regulated β-catenin protein level. Moreover, CEMIP was essential for chondrocytes proliferation and promoted αSMA expression, a fibrosis marker, and TGFβ signaling towards the p-Smad2/3 (Alk5/PAI-1) pathway. Interestingly, CEMIP was induced by the pSmad1/5 (Alk1) pathway. αSMA and type III collagen expressions were overexpressed in human OA cartilage and along chondrocytes dedifferentiation. Finally, CEMIP was co-expressed in situ with αSMA in all OA cartilage layers. In conclusion, CEMIP was sharply overexpressed in human and mouse OA cartilage and along chondrocytes dedifferentiation. CEMIP-regulated transdifferentiation of chondrocytes into "chondro-myo-fibroblasts" expressing α-SMA and type III collagen, two fibrosis markers. Moreover, these "chondro-myo-fibroblasts" were found in OA cartilage but not in healthy cartilage.
CEMIP（细胞迁移诱导蛋白的缩写，也称为 KIAA1199）的表达在癌症中增加，并被描述为细胞存活、生长和侵袭的调节剂。在类风湿关节炎中，CEMIP 被称为血管生成标志物，并参与透明质酸的降解。在这项研究中，研究了健康和骨关节炎（OA）软骨中的 CEMIP 表达。解析了其在 OA 病理生理学中的作用，特别是在软骨细胞增殖和去分化以及细胞外基质重塑中的作用。为此，评估了人 OA 和非 OA 软骨中的 CEMIP、αSMA 和 I 型和 III 型胶原的表达。还在小鼠 OA 模型中研究了 CEMIP 的表达。使用软骨细胞去分化模型在体外研究了 CEMIP 的表达。在 CEMIP 沉默后，对软骨细胞进行了高通量 RNA 测序。结果表明，CEMIP 在人及鼠 OA 软骨中过度表达，并与软骨细胞去分化相关。在 CEMIP 耗尽的细胞中，大多数下调的基因参与软骨代谢（例如胶原）、间充质转化和纤维化。CEMIP 调节β-catenin 蛋白水平。此外，CEMIP 对于软骨细胞增殖是必需的，并促进了αSMA 的表达，αSMA 是纤维化标志物，以及 TGFβ 信号向 p-Smad2/3（Alk5/PAI-1）途径。有趣的是，CEMIP 是由 pSmad1/5（Alk1）途径诱导的。在人 OA 软骨中，αSMA 和 III 型胶原的表达随着软骨细胞去分化而过度表达。最后，CEMIP 在所有 OA 软骨层中与 αSMA 原位共表达。总之，CEMIP 在人及鼠 OA 软骨中过度表达，并与软骨细胞去分化相关。CEMIP 调节软骨细胞向表达α-SMA 和 III 型胶原的“软骨肌成纤维细胞”的转分化，α-SMA 和 III 型胶原是两种纤维化标志物。此外，这些“软骨肌成纤维细胞”在 OA 软骨中发现，但在健康软骨中未发现。
