Olexandr Korchynskyi
Rzeszow University, Poland
Title: Proinflamatory control of skeletogenic signaling pathways
Biography
Biography: Olexandr Korchynskyi
Abstract
Impaired bone homeostasis contributes to development of osteopenia, osteolysis and joint erosions during the rheumatoid arthritis (RA). On the other hand, bone morphogenetic proteins (BMP) and their intracellular mediators Smad proteins, are crucially important regulators of bone formation and regeneration. Using in-vitro tissue culture approaches we showed that activation of NF-κB pathway with proinflammatory cytokines IL-1β and TNFα inhibits osteogenic differentiation of pluripotent mesenchymal precursor cells through Smad7-independent inhibition of Smad1/5 transcriptional activity. Neither Smad1/5 phosphorylation by BMPR-Is, nor direct Smad1/5 binding to DNA into BMP target genes promoters are affected by the activation of NF-κB pathway with TNFα, or by the overexpression of NF-κB signaling components. Nevertheless, Smad1/5 transactivation and, consequently, transcription of BMP target genes is greatly reduced upon activation of NF-κB signaling with a requirement new protein synthesis. Furthermore, we found two distinct TNFα target genes that are novel potent inhibitors of BMP signaling. One of them, twist family BHLH transcription factor 1 (TWIST1) is a transcriptional target of NF-κB and has been implicated into repression of RUNX2 driven osteogenesis. Another one, KLF10/TIEG is induced by TNFα in NF-κB-independent manner. shRNA mediated knockdown of the expression of each of these BMP signaling repressors results in partial rescue of BMP-Smad-driven transcription from inhibition by TNFα. We generated crosses of BMP reporter mice with p65/RelA knockout mice and found that NF-κB (most likely, via TWIST1) controls the intensity and the duration of BMP signals in vivo already during the embryogenesis. Thus, our data demonstrate TIEG1 and TWIST1 as transcriptional repressors of BMP-Smad signaling and as the central candidates responsible for proinflammatory control of osteogenic program possibly also involved in the development of osteolysis and joint erosions during the RA.