Mesenchymal Cells-Derived Igf2 Supports Bone Development And Remodeling

Silver-Russell Syndrome (SRS) skeletal deformities are commonly linked to IGF2 mutations and how mesenchymal cell-derived IGF2 regulates bone development/remodeling and its mechanism was investigated. ScRNA-seq data were reanalyzed to discover the expression pattern of Igf2. Then, mice models of specific deletion of Igf2 in three different cell types by crossing Igf2 flox with Osxcre, Prx1cre and Ocncre mice respectively were established. The skeletal systems of these mice and their bone formation and resorption abilities were analyzed by micro-CT, histological analyses, serum Elisa, immunofluorescence staining and calcein labeling. Moreover, the in vitro osteogenic capacity of their BMSCs were evaluated by ALP and alizarin red staining. Lastly, RNA-sequencing of mesenchymal cells isolated by flow cytometry sorting was carried out to elucidate the underlying mechanisms and administration of an agonist targeting STAT3 was also undertaken. Igf2 was enriched in skeletal stem/progenitor cells (SSPCs) rather than osteoblasts. Deformities were observed in the femur and other skeletons in OsxCre; Igf2fl/-, Prx1Cre; Igf2fl/- but not OcnCre; Igf2fl/- mice and induced by a reduction in osteogenesis with minimal changes in osteoclastogenesis. It is further revealed that Igf2 deletion impaired the osteogenesis via STAT3 and pharmacological activation of STAT3 could partially reverse the skeletal deformities. In summary, these finding reveals that IGF2 derived from SSPCs, rather than osteoblasts, supports the development and homeostasis of skeletal system via STAT3 signaling and targeting STAT3 might be a promising therapeutic strategy for SRS-related skeletal deformities.