Skeletal stem/progenitor cell-derived rather than osteoblast-derived IGF2 supports the development and homeostasis of skeletal system via STAT3

Rationale: Skeletal deformities are characteristic manifestations of Silver-Russell Syndrome with mutations in insulin-like growth factor 2 (IGF2) gene serving as the most prevalent genetic abnormality. However, the mechanism by which IGF2 influence bone development and homeostasis remains unclear. Besides, the expression pattern of Igf2 and the local cells-derived Igf2 at cellular level within bone microenvironment also lacked research. Methods: ScRNA-seq analysis was obtained from Gene Expression Omnibus (GEO) and analyzed 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 Osx(cre) , Prx1(cre) and Ocn(cre) mice respectively were established. The skeletal systems of these mice were analyzed, along with the in vitro osteogenic capacity of their bone marrow-derived mesenchymal stem cells (BMSCs). Lastly, RNA-sequencing (RNA-seq) was carried out to elucidate the underlying mechanisms, and administration of an agonist targeting the key molecule was also undertaken. Results: Igf2 was enriched in skeletal stem/progenitor cells (SSPCs) rather than osteoblasts and we have observed deformities in the femur and other skeletons in Osx(Cre); Igf2(fl/-), Prx1(Cre); Igf2(fl/-) but not Ocn(Cre); Igf2(fl/-) mice and the deformities were 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 reverse the skeletal deformities. Conclusions: 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.