Pos1199 Cxcl12 as a Novel Regulator of Pathological Bone Formation in Ankylosing Spondylitis: Insights and Therapeutic Potential

Background: Ankylosing spondylitis (AS) is a debilitating condition characterized by severe spinal deformities, inflammation, and excessive bone formation, imposing significant socioeconomic burdens. Current treatments alleviate symptoms but fail to address bone structural damage. Pathological bone formation often occurs at entheses, where tendons and ligaments connect to bone. Osteogenic precursor cells (OPCs) play a crucial role, but their migration to new bone sites is poorly understood. C-X-C motif chemokine ligand 12 (CXCL12) is implicated in cell migration and bone-related processes, but its role in AS remains unclear. This study explores CXCL12/CXCR4 signaling in OPC recruitment and new bone formation, providing insights into AS pathogenesis and potential therapeutic targets. Objectives: Our study aims to elucidate the role of CXCL12 in AS-related pathological bone formation, focusing on its impact on OPC recruitment via CXCL12/CXCR4-Rac1 signaling. We aim to demonstrate that inhibiting this pathway suppresses OPC migration and bone formation. Additionally, we'll validate a genetically engineered animal model with CXCL12 overexpression, shedding light on CXCL12's previously undiscovered role in AS. Methods: We established mouse models, including the DBA/1 model, lipopolysaccharide-induced spondyloarthritis model, and Achilles tendon semi-transection model. Additionally, genetically edited mouse models were generated, including DBA1;CXCL12 col2 transgenic mice, CXCL12hi/hi;Col2a1-creERT mice, and CXCR4fl/fl;Prx1-creERT mice. Results: We utilized the aforementioned three mouse models to validate the phenomenon of CXCL12 promoting pathological new bone formation through the recruitment of osteoprogenitor cells. Furthermore, various genetically engineered mouse models were employed to investigate the pivotal role played by the CXCL12/CXCR4-Rac1 mechanism in this process. Overexpression of CXCL12 in genetically engineered animals with a DBA/1 background demonstrated a stable joint ankylosis phenotype, providing a valuable model for the study of AS. Conclusion: This study elucidates the novel role of CXCL12 in AS and offers potential strategies for targeting the CXCL12/CXCR4-Rac1 axis to prevent the progression of axial skeletal ankylosis. Acknowledgements: NIL. Disclosure of Interests: None declared.