ROR2 preserves alveolar bone homeostasis by orchestrating IRAK4-dependent suppression of CXCL8-driven osteolysis.

Alveolar bone resorption, driven by imbalanced osteogenesis and osteolysis, is a hallmark of periodontitis and orthodontic complications, yet molecular mechanisms coordinating stromal-immune crosstalk remain elusive. Here, we identify receptor tyrosine kinase-like orphan receptor 2 (ROR2) in alveolar bone-derived mesenchymal stem cells (ABMSCs) as a critical suppressor of inflammatory osteolysis. Using conditional knockout mice, we demonstrate that ROR2 deficiency in ABMSCs exacerbates alveolar bone loss by amplifying CXCL8 secretion, which enhances osteoclastogenesis while impairing osteogenic differentiation. Mechanistically, ROR2 sequesters interleukin-1 receptor-associated kinase 4 (IRAK4) via its Ig-like C2 domain, disrupting Myddosome assembly and downstream IRF7-driven CXCL8 transcription. Genetic ablation of IRAK4 in ROR2-deficient ABMSCs rescues pathological bone remodeling, restoring osteoblast-osteoclast equilibrium. Building on these findings, we engineer a thermosensitive chitosan/β-glycerophosphate hydrogel loaded with CXCL8-neutralizing antibodies, which effectively attenuates periodontitis-induced bone loss in vivo by suppressing osteoclast coverage and preserving osteogenic capacity. Our work unveils a ROR2/IRAK4/CXCL8 regulatory axis in ABMSCs that governs stromal-immune crosstalk during inflammatory osteolysis, offering a translatable strategy to recalibrate bone homeostasis in periodontal and orthodontic disorders.