Identification of Genes Regulating TRAIL-Induced Apoptosis in Rheumatoid Arthritis Fibroblasts-like Synoviocytes (RA FLS)

Rachel Audo^1,2, Bernard Combe^3,4, Michael Hahne⁵ and Jacques Morel⁶, ¹Rheumatology, Teaching Hospital of Lapeyronie, Montpellier, France, ²IGMM, CNRS UMR5535, Montpellier, Montpellier, France, ³Department of Rheumatology, Lapeyronie Hospital, Montpellier, France, ⁴Montpellier University, Montpellier, France, ⁵IGMM-CNRS UMR5535, Montpellier, France, ⁶Department of rheumatology, Lapeyronie Hospital and Montpellier University, Montpellier, France

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Apoptosis, cytokines, Fibroblasts, rheumatoid arthritis, synovial fluid, synovium and synovial cells

Session Information

Date: Monday, November 9, 2015

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

We previously described that sensitivity to TRAIL-induced apoptosis varied in rheumatoid arthritis (RA) fibroblasts-like-synoviocytes (FLS) from one patient to another, and was inversly correlated with disease severity. Therefore, we screened for genes differentially expressed in RA FLS sensitive and resistant to TRAIL induced apoptosis.

Methods:

The sensitivity of RAFLS was defined based on the percentage of TRAIL-induced apoptosis: 0-10% for resistant RAFLS (RAFLS-R) and above 25% for sensitive RAFLS (RAFLS-S). We performed transcriptomic comparison using microarray to compare sensitive (n=6) and resistant RAFLS (n=6). Differential expression was validated using quantitative PCR (q-RTPCR ) and we examined the implication of identified candidates in the regulation of apoptosis using siRNA .

Results:

Microarray analysis revealed 10 functional genes differentially expressed according to TRAIL sensitivity. These factors are implicated in different functions, such as the respiratory chain (ND3), the transport of lipids (OSBP2, PLTP), the regulation of signalling linked to extracellular factors (SULF2, GALNT1, SIAE) or the regulation of gene expression (TET2 and LARP6). We confirmed differential expression for GALNT1 (p<0.05) and LARP6 (p<0.05) by q-RTPCR, with an overexpression of LARP6 in RAFLS-R and of GALNT1 in RAFLS-S, while SULF2 also tended to be overexpressed in RAFLS-S (p=0.1). LARP6 protein was also significantly overexpressed in RAFLS-R (n=6) compared to RAFLS-S (n=7) (p<0.05). Using siRNA extinction, we demonstrated the implication of GALNT1, SULF2 and LARP6 in the control of TRAIL induced responses since the siRNA which target GALNT-1, SULF-2 significantly decreased (p<0.05, n=7) while siRNA targeting LARP6 significantly increased TRAIL-induced apoptosis of RAFLS (p<0.01, n=10).

DISCUSSION: Concurring with the demonstration of the importance of glycosylation in the regulation of TRAIL sensitivity in cancer cells line , we demonstrated that GALNT1 and SULF2 are factors participating in TRAIL-induced apoptosis in FLS. We also did the first demonstration that LARP6 participate to the resistance against TRAIL-induced apoptosis.

Conclusion: To conclude, we described several new potential targets controlling TRAIL induced cell death in RAFLS. These results are of particular interest since GALNT1 and LARP6 have been implicated in the regulation of cell death or in cancer and may represent interesting targets to induce apoptosis of RAFLS.

Disclosure: R. Audo, None; B. Combe, None; M. Hahne, None; J. Morel, None.

To cite this abstract in AMA style:

Audo R, Combe B, Hahne M, Morel J. Identification of Genes Regulating TRAIL-Induced Apoptosis in Rheumatoid Arthritis Fibroblasts-like Synoviocytes (RA FLS) [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/identification-of-genes-regulating-trail-induced-apoptosis-in-rheumatoid-arthritis-fibroblasts-like-synoviocytes-ra-fls/. Accessed .

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