Analysis of the influence of Heparan sulfate proteoglycan Syndecan-1 on osteoclastogenesis and neoangiogenesis in chondro-osseous remodeling during fracture healing and potential therapeutic strategies

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The development of delayed fracture healing and pseudarthroses is not well understood to date, although it is of high clinical relevance due to long lasting and cost intensive treatment of these patients. New insights in bone metabolism and regeneration could help to use specific signaling pathways and processes of fracture healing to develop new therapeutic approaches in diagnostic and treatment of fracture healing complications. This project focusses on the process of enchondral ossification and neoangiogenesis at the chondro-osseous border in the callus. In preliminary investigations, we showed that the heparan sulfate proteoglycan Syndecan-1 influences osteoclastogenesis in vitro and deficiency of Syndecan-1 leads to a delay in the remodeling process of the cartilaginous callus due to a decreased osteoclast number. Single cell mRNA sequencing data pointed to further cell-cell interactions that might be influenced by Syndecan-1. Furthermore, we showed that Syndecan-1 was important for the development of blood vessels that drive the remodeling of cartilage to bone. The aim of this project is to characterize the function of Syndecan-1 during osteoclastogenesis and neoangiogenesis during fracture callus remodeling and to investigate differences in the healing process after application of recombinant Syndecan-1 or Synstatin peptides with regard as a new therapeutic strategy.Using a well-established femur shaft fracture model in mice we will investigate the application of recombinant (=shedded) Syndecan-1 to increase osteoclastogenesis during callus remodeling in wild type and Sydnecan-1 deficient mice. Additionally, we will explore further cell-cell interaction influenced by Syndecan-1 via in vitro co-culture and 3D organoid culture like chondrocytes and osteoblasts or endothelial cells. The role of Syndecan-1 for neoangiogenesis during fracture healing will be analyzed in vitro using primary endothelial cells as well as in vivo in our fracture model. The application of Synstatin peptides will allow us to modulate Syndecan-1 dependent VEGFR2/VEGF activation of angiogenesis in vitro and in vivo. In an translational approach we will determine the serum concentration of Syndecan-1 in patients after fracture, that develop disturbed healing to evaluate a possible function of Syndecan-1 as a prognostic marker to identify healing complications.