AD-HIES Fracture Healing Impaired by STAT3 Dysfunction Affecting Stem Cell Mobilization

Recurrent fractures and delayed fracture healing are key clinical manifestations of autosomal dominant hyper-IgE syndrome (AD-HIES), caused by heterozygous mutations and loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene. However, the precise mechanisms underlying these defects remain unclear, and effective therapies are limited. In this study, we observed significantly delayed healing in pre-osteoblast-specific STAT3 haploinsufficient mice, mirroring the delayed healing seen in patients with AD-HIES. Inducible Col1a2-CreERT2 labels periosteal progenitors and contributes to the majority of chondrocytes and osteoblasts during fracture healing. Conditional STAT3 deficiency in Col1+ cells blocked fracture healing by disrupting endochondral ossification and stem cell mobilization. Single-cell RNA sequencing revealed that STAT3 deficiency reduced the abundance of C-X-C motif ligand 12 (CXCL12) mesenchymal cells, essential for fracture healing. CXCL12 directly enhanced chondrogenic and osteogenic differentiation of STAT3-deficient periosteal cells (PCs) and indirectly promoted vascularization through crosstalk between PCs and human umbilical vein endothelial cells (HUVECs) in vitro. STAT3 directly regulates CXCL12 transcription by promoting promoter activity. Notably, CXCL12 improved fracture healing blocked by complete osteoblast STAT3 deficiency and alleviated delayed healing associated with pre-osteoblast STAT3 haploinsufficiency. Pharmacological STAT3 activation effectively also improved delayed healing and promoted CXCL12 expression. These findings demonstrate that STAT3 dysregulation disrupts endochondral ossification and stem cell mobilization via CXCL12, a promising therapeutic target for improving fracture healing in patients with AD-HIES and other conditions with skeletal fragility.