Laboratorio de Reumatología Experimental y Observacional, y Servicio de Reumatología, Instituto de Investigacion Sanitaria de Santiago (IDIS), Hospital Clínico Universitario de Santiago de Compostela (CHUS), SERGAS. Travesía da Choupana s/n, Santiago de Compostela, 15706, Spain.
Servicio de Reumatología, Instituto de Investigacion Sanitaria de Santiago (IDIS), Hospital Clínico Universitario de Santiago de Compostela (CHUS), SERGAS. Travesía da Choupana s/n, Santiago de Compostela, 15706, Spain.
Sci Rep. 2018 Jun 7;8(1):8731. doi: 10.1038/s41598-018-26027-x.
Rheumatoid arthritis (RA) is a systemic autoimmune disease including synovitis and synovial hyperplasia that contribute to joint destruction. Pivotal pathogenic mechanisms in this process are the dysregulated proliferation and apoptosis of fibroblast-like synoviocytes (FLS). Unfortunately, the mechanisms of FLS dysregulation are not completely elucidated. Here, we explored a new hypothesis based in the potent anti-proliferative and pro-apoptotic activity of retinoids in some types of cancer. Specifically, we investigated the role of retinoids and of the retinoic acid binding proteins, CRABP2 and FABP5, on the proliferation and apoptosis of FLS from RA by adding all-trans retinoic acid (ATRA) or silencing CRABP2 and FABP5. We showed an unconventional behaviour of RA FLS, which were relatively insensitive to ATRA. In effect, ATRA increased the resistance to apoptosis despite the high CRABP2/FABP5 ratio of RA FLS; and CRABP2 suppression sensitized RA FLS to Fas-induced apoptosis. This latter effect was associated with changes in expression of kinases, ASK1 up-regulation and ERK down-regulation, and increased phosphorylation of JNK. In addition, the potentiation of FLS apoptosis by CRABP2 silencing persisted in the presence of pro-inflammatory mediators, TNF e IL1β. Therefore, the results point to CRABP2 as a potential target to decrease synovial hyperplasia in RA.
类风湿关节炎（RA）是一种系统性自身免疫性疾病，包括滑膜炎和滑膜增生，导致关节破坏。该过程中的关键致病机制是成纤维样滑膜细胞（FLS）的失调增殖和凋亡。不幸的是，FLS 失调的机制尚未完全阐明。在这里，我们基于维甲酸在某些类型的癌症中具有强大的抗增殖和促凋亡活性提出了一个新的假设。具体而言，我们通过添加全反式维甲酸（ATRA）或沉默 CRABP2 和 FABP5 来研究维甲酸和维甲酸结合蛋白 CRABP2 和 FABP5 对 RA FLS 增殖和凋亡的作用。我们展示了 RA FLS 的一种非传统行为，其对 ATRA 的相对不敏感。实际上，尽管 RA FLS 的 CRABP2/FABP5 比值较高，但 ATRA 增加了对凋亡的抵抗力；CRABP2 抑制使 RA FLS 对 Fas 诱导的凋亡敏感。后一种作用与激酶表达的变化、ASK1 的上调和 ERK 的下调以及 JNK 的磷酸化增加有关。此外，CRABP2 沉默增强 FLS 凋亡的作用在存在促炎介质 TNF 和 IL1β 的情况下仍然存在。因此，这些结果表明 CRABP2 可能是减少 RA 滑膜增生的潜在靶点。
