通过比较多个微阵列数据集鉴定与小鼠骨关节炎和软骨细胞肥大相关的 TGFβ 调控基因。

Identification of TGFβ-related genes regulated in murine osteoarthritis and chondrocyte hypertrophy by comparison of multiple microarray datasets.

机构信息

Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Orthopedics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.

出版信息

Bone. 2018 Nov;116:67-77. doi: 10.1016/j.bone.2018.07.008. Epub 2018 Jul 21.

DOI:10.1016/j.bone.2018.07.008

PMID:30010080

Abstract

OBJECTIVE

Osteoarthritis (OA) is a joint disease characterized by progressive degeneration of articular cartilage. Some features of OA, including chondrocyte hypertrophy and focal calcification of articular cartilage, resemble the endochondral ossification processes. Alterations in transforming growth factor β (TGFβ) signaling have been associated with OA as well as with chondrocyte hypertrophy. Our aim was to identify novel candidate genes implicated in chondrocyte hypertrophy during OA pathogenesis by determining which TGFβ-related genes are regulated during murine OA and endochondral ossification.

METHODS

A list of 580 TGFβ-related genes, including TGFβ signaling pathway components and TGFβ-target genes, was generated. Regulation of these TGFβ-related genes was assessed in a microarray of murine OA cartilage: 1, 2 and 6 weeks after destabilization of the medial meniscus (DMM). Subsequently, genes regulated in the DMM model were studied in two independent murine microarray datasets on endochondral ossification: the growth plate and transient embryonic cartilage (joint development).

RESULTS

A total of 106 TGFβ-related genes were differentially expressed in articular cartilage of DMM-operated mice compared to sham-control. From these genes, 43 were similarly regulated during chondrocyte hypertrophy in the growth plate or embryonic joint development. Among these 43 genes, 18 genes have already been associated with OA. The remaining 25 genes were considered as novel candidate genes involved in OA pathogenesis and endochondral ossification. In supplementary data of published human OA microarrays we found indications that 15 of the 25 novel genes are indeed regulated in articular cartilage of human OA patients.

CONCLUSION

By focusing on TGFβ-related genes during OA and chondrocyte hypertrophy in mice, we identified 18 known and 25 new candidate genes potentially implicated in phenotypical changes in chondrocytes leading to OA. We propose that 15 of these candidates warrant further investigation as therapeutic target for OA as they are also regulated in articular cartilage of OA patients.

摘要

目的

骨关节炎（OA）是一种以关节软骨进行性退变为特征的关节疾病。OA 的一些特征，包括软骨细胞肥大和关节软骨的局灶性钙化，类似于软骨内骨化过程。转化生长因子β（TGFβ）信号的改变与 OA 以及软骨细胞肥大有关。我们的目的是通过确定哪些 TGFβ相关基因在 OA 发病机制中以及软骨细胞肥大过程中受到调节，来鉴定参与 OA 发病过程中软骨细胞肥大的新候选基因。

方法

生成了一个包含 580 个 TGFβ相关基因的列表，包括 TGFβ信号通路成分和 TGFβ靶基因。在内侧半月板不稳定（DMM）后 1、2 和 6 周的鼠 OA 软骨的微阵列中评估这些 TGFβ相关基因的调节。随后，在两个独立的关于软骨内骨化的鼠微阵列数据集（生长板和短暂胚胎软骨（关节发育））中研究 DMM 模型中调节的基因。

结果

与 sham-control 相比，DMM 操作小鼠的关节软骨中共有 106 个 TGFβ相关基因表达差异。在这些基因中，有 43 个在生长板或胚胎关节发育中的软骨细胞肥大过程中受到类似的调节。在这 43 个基因中，已有 18 个与 OA 有关。其余 25 个基因被认为是参与 OA 发病机制和软骨内骨化的新候选基因。在已发表的人类 OA 微阵列的补充数据中，我们发现有迹象表明，25 个新基因中的 15 个确实在人类 OA 患者的关节软骨中受到调节。