Unraveling Smad2/4-dependent osteoclast differentiation through transcriptome analysis

• Applicants: Berno Dankbar, Ph.D., since 2/2020; Professor Dr. Uwe Kornak
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433083000

We have recently shown that Myostatin, a member of the TGFβ superfamily, strongly enhances osteoclast formation and that deficiency or inhibition of Myostatin highly ameliorates bone erosion in joints of arthritic mice. Interestingly, preliminary experiments revealed a high similarity between myostatin and Activin A: both enhance RANKL-induced osteoclast formation and act via Smad2/4 transcriptional regulators, indicating that both factors promote osteoclastogenesis in a similar way. Moreover, simultaneous inhibition of both factors led to a complete repression of osteoclast formation, pointing to Myostatin and Activin A being essential factors in the process of osteoclast differentiation. However, it remains to be established which transcripts are induced in response to these factors and which of those mediate the osteoclast promoting effects. In the current project, we aim to analyse which transcripts are induced by Myostatin and Activin A, in particular which isoforms and splice variants. For this purpose, we will perform paired-end deep sequencing of mRNA isolated from murine primary and human iPSC-derived osteoclasts and progenitor cells either stimulated with TGFβ1, Myostatin or Activin A, or in which these factors are deleted or inhibited. We trust this project will provide new insights into the mechanisms of osteoclast-mediated bone destruction and facilitate the development of novel treatment strategies.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: David de Gorter, Ph.D., until 2/2020