CXCL12/CXCR4-Rac1-mediated migration of osteogenic precursor cells contributes to pathological new bone formation in ankylosing spondylitis

Haowen Cui; Zihao Li; Siwen Chen; Xiang Li; Dongying Chen; Jianru Wang; Zemin Li; Wenjun Hao; Fangling Zhong; Kuibo Zhang; Zhaomin Zheng; Zhongping Zhan; Hui Liu

doi:10.1126/sciadv.abl8054

CXCL12/CXCR4-Rac1-mediated migration of osteogenic precursor cells contributes to pathological new bone formation in ankylosing spondylitis

Sci Adv. 2022 Apr 8;8(14):eabl8054. doi: 10.1126/sciadv.abl8054. Epub 2022 Apr 6.

Authors

Haowen Cui^{1

2}, Zihao Li^{1

2}, Siwen Chen^{1

2}, Xiang Li^{1

2}, Dongying Chen³, Jianru Wang^{1

2}, Zemin Li^{1

2}, Wenjun Hao^{1

2}, Fangling Zhong^{1

2}, Kuibo Zhang⁴, Zhaomin Zheng^{1

2}, Zhongping Zhan³, Hui Liu^{1

2}

Affiliations

¹ Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China.
² Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080 Guangdong, China.
³ Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China.
⁴ Department of Spine Surgery, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China.

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by inflammatory back pain and spinal ankylosis due to pathological new bone formation. Here, we identified CXCL12 as a critical contributor to pathological new bone formation through recruitment of osteogenic precursor cells (OPCs). CXCL12 was found highly expressed in the regions that would potentially develop pathological new bone. OPCs were recruited to the regions where CXCL12 was up-regulated. Inhibition of CXCL12/CXCR4 axis with AMD3100 or conditional knockout of CXCR4 attenuated OPCs migration and subsequent pathological new bone formation in animal models of AS. By contrast, a genetically engineered animal model with CXCL12 overexpression developed a joint ankylosis phenotype. Furthermore, Rac1 was found essential for OPCs migration and pathological new bone formation. These findings ravel the novel role of CXCL12 in AS and indicate a potential strategy for targeting the CXCL12/CXCR4-Rac1 axis to prevent progression of axial skeleton ankylosis.