Date: Monday, October 22, 2018
Session Title: Rheumatoid Arthritis – Etiology and Pathogenesis Poster II
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Non-Receptor Protein Tyrosine Phosphatase 14 (PTPN14) was identified in a phosphatase expression profile survey to be highly expressed in synovial fibroblasts derived from patients with rheumatoid arthritis (RA FLS). PTPN14 is a negative regulator of transcriptional co-activator YAP -a key Hippo pathway player- in cancer cells. Here we aimed to investigate the role of PTPN14 in RA FLS.
Gene expression level in RA FLS and FLS from osteoarthritis patients (OA FLS) was measured by qPCR. Specific gene knockdown was achieved using antisense oligonucleotides. PTPN14, YAP and SMAD3 protein expression levels were visualized in Western blotting and immunofluorescence. Immunoprecipitation was used to detect protein-protein interaction. The passive K/BxN arthritis and RA FLS/cartilage co-implantation models were used to assess effects of chemical inhibition of YAP.
RA FLS displayed TGFbeta-dependent overexpression of PTPN14 compared to OA FLS (p < 0.01). PTPN14 knockdown in RA FLS impaired TGFbeta-dependent expression of matrix metalloproteinase 13 (p < 0.05) and potentiation of inflammatory cytokine signaling. In RA FLS, PTPN14 forms a complex with YAP, promoting TGFbeta-dependent YAP and SMAD3 nuclear localizations. Chemical inhibition of YAP inhibited RA FLS pathogenic behavior and ameliorated arthritis severity in vivo (p < 0.0001).
In RA FLS, TGFbeta-dependent PTPN14 overexpression acts as a positive feedback TGFbeta-signaling regulator. Surprisingly, in RA FLS PTPN14 enhances nuclear YAP-mediated promotion of SMAD signaling. YAP promotes a wide range of RA FLS pathogenic behaviors, pointing to the Hippo pathway as a potential important regulator of RA FLS and a player in RA pathogenesis.
To cite this abstract in AMA style:Bottini A, Wu DJ, Ai R, LeRoux M, Bartok B, Bombardieri M, Zhang V, Doody KM, Sacchetti C, Zoccheddu M, Lonic A, Boyle DL, Hammaker D, Meng TC, Corr M, Stanford SM, Lewis MJ, Wang W, Firestein GS, Khew-Goodall Y, Pitzalis C, Bottini N. Non-Receptor Protein Tyrosine Phosphatase 14 (PTPN14) Promotes YAP-Dependent Tgfbeta Signaling in RA FLS [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/non-receptor-protein-tyrosine-phosphatase-14-ptpn14-promotes-yap-dependent-tgfbeta-signaling-in-ra-fls/. Accessed July 2, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/non-receptor-protein-tyrosine-phosphatase-14-ptpn14-promotes-yap-dependent-tgfbeta-signaling-in-ra-fls/