细胞因子诱导的富含半胱氨酸的丝氨酸核蛋白1（CSRNP1）选择性地促进了人类软骨细胞中MMP1的表达。,PLOS ONE

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细胞因子诱导的富含半胱氨酸的丝氨酸核蛋白1（CSRNP1）选择性地促进了人类软骨细胞中MMP1的表达。
PLOS ONE ( IF 2.9 ) Pub Date : 2018-11-15 , DOI: 10.1371/journal.pone.0207240
Christopher D Macdonald ₁ , Adrian M D Falconer ₁ , Chun Ming Chan ₁ , David J Wilkinson ₁ , Andrew Skelton ₁ , Louise Reynard ₁ , Gary J Litherland ₁ , G Nicholas Europe-Finner ₁ , Andrew D Rowan ₁

Affiliation

胶原蛋白分解基质金属蛋白酶（MMPs）-1和MMP-13导致的不可逆软骨胶原蛋白分解是与组织破坏（如关节炎）相关的病理学中的关键事件。炎症与此类病理密切相关，并在类风湿和骨关节炎中均发生，这使其与表征这些疾病的主要组织损伤高度相关。炎症诱导的活化蛋白1（AP-1）转录因子是MMP1和MMP13基因的重要调节剂，它们的表达途径之间也相互作用。在这里，我们检查了MMP1表达的调节，并使用体内染色质免疫沉淀分析方法，我们证明了cFos仅在该基因转录沉默时才结合近端MMP1启动子内的AP-1顺式元件，如先前对MMP13观察到的那样。然而，随后的小干扰RNA介导的沉默证实，cFos显着促进MMP1表达。相反，沉默ATF3（主要的MMP13调节剂）不会影响MMP1的表达，而沉默与Wnt相关的富含半胱氨酸-丝氨酸的核蛋白-1（CSRNP1）则导致MMP1的显着抑制，而不是MMP13的抑制。此外，在类似于cFOS的mRNA和蛋白水平上，CSRNP1的表达出现了一个短暂的峰值，随后与cFOS不同，CSRNP1的表达持续存在。最后，DNA结合分析表明，CSRNP1与MMP1和MMP13的近端启动子区域内的AP-1共有样序列的结合对MMP1具有优先选择性，而激活转录因子3（ATF3）的结合则是MMP13所独有的。这些数据进一步扩展了我们对先前报道的这些MMP基因差异调节的理解，并强烈表明，尽管cFos调节MMP1 / 13的表达，但下游因子（如CSRNP1和ATF3）最终在炎症刺激下充当转录调节因子这些有效的胶原蛋白分解酶。

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Cytokine-induced cysteine- serine-rich nuclear protein-1 (CSRNP1) selectively contributes to MMP1 expression in human chondrocytes.

Irreversible cartilage collagen breakdown by the collagenolytic matrix metalloproteinases (MMPs)-1 and MMP-13 represents a key event in pathologies associated with tissue destruction such as arthritis. Inflammation is closely associated with such pathology and occurs in both rheumatoid and osteoarthritis making it highly relevant to the prevailing tissue damage that characterises these diseases. The inflammation-induced activating protein-1 (AP-1) transcription factor is an important regulator of both MMP1 and MMP13 genes with interplay between signalling pathways contributing to their expression. Here, we have examined the regulation of MMP1 expression, and using in vivo chromatin immunoprecipitation analyses we have demonstrated that cFos bound to the AP-1 cis element within the proximal MMP1 promoter only when the gene was transcriptionally silent as previously observed for MMP13. Subsequent small interfering RNA-mediated silencing confirmed however, that cFos significantly contributes to MMP1 expression. In contrast, silencing of ATF3 (a prime MMP13 modulator) did not affect MMP1 expression whilst silencing of the Wnt-associated regulator cysteine- serine-rich nuclear protein-1 (CSRNP1) resulted in substantial repression of MMP1 but not MMP13. Furthermore, following an early transient peak in expression of CSRNP1 at the mRNA and protein levels similar to that seen for cFOS, CSRNP1 expression subsequently persisted unlike cFOS. Finally, DNA binding assays indicated that the binding of CSRNP1 to the AP-1 consensus-like sequences within the proximal promoter regions of MMP1 and MMP13 was preferentially selective for MMP1 whilst activating transcription factor 3 (ATF3) binding was exclusive to MMP13. These data further extend our understanding of the previously reported differential regulation of these MMP genes, and strongly indicate that although cFos modulates the expression of MMP1/13, downstream factors such as CSRNP1 and ATF3 ultimately serve as transcriptional regulators in the context of an inflammatory stimulus for these potent collagenolytic MMPs.

更新日期：2019-11-01

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