Constitutive PDGFRβ activation drives connective tissue overgrowth through STAT5-IGF1 signaling

Autosomal dominant gain-of-function mutations in platelet-derived growth factor receptor beta (PDGFRβ) cause overgrowth of the skeleton and other connective tissue in Kosaki overgrowth syndrome. However, the target cell type and signaling pathways underlying PDGFRβ-driven overgrowth are unknown. Normal postnatal growth is controlled by pituitary-secreted growth hormone (GH), which activates the STAT5 transcriptional factor to upregulate insulin-like growth factor 1 (IGF1). To investigate the role of the GH-STAT5-IGF1 pathway in PDGFRβ-related overgrowth, we generated mice with a PDGFRβ gain-of-function mutation in skeletal and fibroblast lineages, which resulted in STAT5 activation and gigantism. Conditional deletion of Stat5ab in connective tissue lineages rescued skeletal overgrowth and keloid-like fibrosis in the skin. Conditional deletion of GH receptor ( Ghr ) did not rescue overgrowth, indicating the physiological activator of STAT5 is not required for overgrowth. However, deletion of Igf1 , the STAT5 target gene, and its receptor, Igf1r , in connective tissue, rescued the overgrowth phenotype. These findings demonstrate a GHR-independent STAT5-IGF1 signaling pathway in mutant connective tissue cells, which mediates PDGFRβ-driven overgrowth in mice and potentially in humans with similar PDGFRB mutations.