PTPN14 phosphatase and YAP promote TGFβ signalling in rheumatoid synoviocytes

Abstract

ObjectiveWe aimed to understand the role of the tyrosine phosphatase PTPN14—which in cancer cells modulates the Hippo pathway by retaining YAP in the cytosol—in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).MethodsGene/protein expression levels were measured by quantitative PCR and/or Western blotting. Gene knockdown in RA FLS was achieved using antisense oligonucleotides. The interaction between PTPN14 and YAP was assessed by immunoprecipitation. The cellular localisation of YAP and SMAD3 was examined via immunofluorescence. SMAD reporter studies were carried out in HEK293T cells. The RA FLS/cartilage coimplantation and passive K/BxN models were used to examine the role of YAP in arthritis.ResultsRA FLS displayed overexpression of PTPN14 when compared with FLS from patients with osteoarthritis (OA). PTPN14 knockdown in RA FLS impaired TGFβ-dependent expression of MMP13 and potentiation of TNF signalling. In RA FLS, PTPN14 formed a complex with YAP. Expression of PTPN14 or nuclear YAP—but not of a non-YAP-interacting PTPN14 mutant—enhanced SMAD reporter activity. YAP promoted TGFβ-dependent SMAD3 nuclear localisation in RA FLS. Differences in epigenetic marks within Hippo pathway genes, including YAP, were found between RA FLS and OA FLS. Inhibition of YAP reduced RA FLS pathogenic behaviour and ameliorated arthritis severity.ConclusionIn RA FLS, PTPN14 and YAP promote nuclear localisation of SMAD3. YAP enhances a range of RA FLS pathogenic behaviours which, together with epigenetic evidence, points to the Hippo pathway as an important regulator of RA FLS behaviour.

MicroRNA-21 from bone marrow mesenchymal stem cell-derived extracellular vesicles targets TET1 to suppress KLF4 and alleviate rheumatoid arthritis

“…A previous report likewise revealed that TET1 was highly expressed in RA and that silencing TET1 relieved RA. 17 Consistent with these results, our microarray data revealed that TET1 was indeed upregulated in RA patients ( Figure 4c ). Moreover, TET1 was also found to be highly expressed in RA mouse joint tissues when examined by qPCR and western blot analysis ( Figure 4d ).…”

<p>YAP Triggers Bladder Cancer Proliferation by Affecting the MAPK Pathway</p>

“…[17][18][19] YAP is the major protein in the Hippo pathway, and its overexpression is involved in many diseases, especially cancer. 10,[19][20][21][22] The reciprocal antagonism between Hippo-YAP/TAZ and NF-κB signaling is important in osteoarthritis pathogenesis and regulates matrix-degrading enzymes and cartilage degradation. 23 In breast cancer, YAP activity is maintained in a certain level by TRPS1 to regulate tumor-infiltrating submit your manuscript | www.dovepress.com…”

Identification and validation of hub genes of synovial tissue for patients with osteoarthritis and rheumatoid arthritis

“…Tetsuji Kobata found that TGF-beta reduced OPG production by RA synovial fibroblasts, but dose-dependently increased OPG secretion in OA synovial fibroblasts [ 49 ]. Another study reported that compared with fibroblast-like synoviocytes (FLS) derived from OA patients, RA FLS displayed TGF-beta-dependent overexpression of non-receptor protein tyrosine phosphatase 14 (PTPN14), which promoted TGF-beta canonical signaling in turn [ 50 ]. Xu Cao et.…”