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

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.

The guanine nucleotide exchange factor Vav3 intervenes in the migration pathway of oligodendrocyte precursor cells on tenascin-C

“…Previous studies have illustrated an opposing connection between RhoA and Rac1, whereupon RhoA is able to directly inhibit Rac1 and in contrast Rac1 can block RhoA via its effector WAVE2 ( Parri and Chiarugi, 2010 ). However, Rac1 seems to be an important player concerning OPC migration, which could also be confirmed in a model of Ankylosing spondylitis (AS) ( Xiao et al, 2013 ; Cui et al, 2022 ) and so we conclude that inhibition of RhoA released Rac1 from blockage by RhoA and therefore intensified the motility of OPCs. Furthermore, blockage of Rac1 caused significantly decreased migration parameters (speed, halos, number of migrating cells) and therefore supports the idea of a Rac1-mediated migration behavior of OPCs on the different ECM substrates.…”

The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention

“…Moreover, activation of mechanistic target of rapamycin complex 1 (mTORC1) in subchondral bone pre-osteoblasts promoted secretion of CXCL12, which induced subchondral bone remodeling and cartilage degeneration [ 258 ]. Finally, a recent in vivo study demonstrated that CXCL12-CXCR4 stimulation induced migration of osteogenic precursor cells contributing to pathological formation of new bone in ankylosing spondylitis, a form of chronic arthritis characterized by chronic inflammation of the joints of the spine [ 259 ].…”

Differentially expressed protein‐coding genes in ankylosing spondylitis: Emerging insights into pathogenesis and therapeutic approaches

“…For some of the hub genes identified from the GSE41038 data set, their association with AS has been investigated in detail such as CD19, 120,121 CD38, 122 CXCR4, 123 and IL21R 124 . Whereas other hub genes have not yet been fully researched, but should be targeted by future studies.…”