ObjectiveThe role of YAP/TAZ, two transcriptional co-activators involved in several cancers, was investigated in rheumatoid arthritis (RA).MethodsFibroblast like synoviocytes (FLS) from patients with RA or osteoarthritis were cultured in 2D or into 3D synovial organoids. Arthritis rat model (n=28) and colitis mouse model (n=21) were used. YAP/TAZ transcriptional activity was inhibited by verteporfin (VP). Multiple techniques were used to assess gene and/or protein expression and/or localization, cell phenotype (invasion, proliferation, apoptosis), bone erosion, and synovial stiffness.ResultsYAP/TAZ were transcriptionally active in arthritis (19-fold increase for CTGF expression, a YAP target gene, in RA vs. OA organoids; p<0.05). Stiff support of culture or pro-inflammatory cytokines further enhanced YAP/TAZ transcriptional activity in RA FLS. Inhibiting YAP/TAZ transcriptional activity with VP restored a common phenotype in RA FLS with a decrease in apoptosis resistance, proliferation, invasion, and inflammatory response. Consequently, VP blunted hyperplasic lining layer formation in RA synovial organoids. In vivo, VP treatment strongly reduced arthritis severity (mean arthritic index at 3.1 in arthritic group vs. 2.0 in VP treated group; p<0.01) by restoring synovial homeostasis and decreasing systemic inflammation. YAP/TAZ transcriptional activity also enhanced synovial membrane stiffening in vivo, thus creating a vicious loop with the maintenance of YAP/TAZ activation over time in FLS. YAP/TAZ inhibition was also effective in another inflammatory model of mouse colitis.ConclusionOur work reveals that YAP/TAZ were critical factors during arthritis. Thus, their transcriptional inhibition could be relevant to treat inflammatory related diseases.
Ultrashort pulse lasers have significant advantages over conventional continuous wave and long pulse lasers for the texturing of metallic surfaces, especially for nanoscale surface structure patterning. Furthermore, ultrafast laser beam polarization allows for the precise control of the spatial alignment of nanotextures imprinted on titanium-based implant surfaces. In this article, we report the biological effect of beam polarization on human mesenchymal stem cell differentiation. We created, on polished titanium-6aluminum-4vanadium (Ti-6Al-4V) plates, a laser-induced periodic surface structure (LIPSS) using linear or azimuthal polarization of infrared beams to generate linear or radial LIPSS, respectively. The main difference between the two surfaces was the microstructural anisotropy of the linear LIPSS and the isotropy of the radial LIPSS. At 7 d post seeding, cells on the radial LIPSS surface showed the highest extracellular fibronectin production. At 14 days, qRT-PCR showed on the same surface an increase in osteogenesis-related genes, such as alkaline phosphatase and osterix. At 21 d, mineralization clusters indicative of final osteoinduction were more abundant on the radial LIPSS. Taken together, we identified that creating more isotropic than linear surfaces enhances cell differentiation, resulting in an improved osseointegration. Thus, the fine tuning of ultrashort pulse lasers may be a promising new route for the functionalization of medical implants.
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