Aims Periprosthetic joint infection (PJI) is known to disrupt bone metabolism. Unlike lipopolysaccharide (LPS) from Gram-negative bacteria (GNB), lipoteichoic acid (LTA) from Gram-positive cocci (GPC) induces minimal osteoclast activation and bone resorption. Clinically, patients with Gram-positive bacterial component-associated PJI (GPC-PJI) exhibit less osteolytic activity than those with Gram-negative bacterial PJI (GNB-PJI), suggesting a milder disruption of bone homeostasis. In this study, we identified elevated levels of chemokine (C-X-C motif) ligand 5 (CXCL5) in the synovial fluid (SF) of GPC-PJI patients and investigated its regulatory role in osteoclast signalling and bone remodelling. A murine bone loss model was employed to assess its in vivo function. Methods SF samples from patients with PJI and aseptic loosening (AL) were analyzed using cytokine protein arrays and enzyme-linked immunosorbent assay (ELISA) to compare CXCL5 expression in the AL, GPC-PJI, and GNB-PJI groups. In vitro, MC3T3-E1 osteoblasts were used to examine CXCL5 induction following LTA stimulation, while RAW264.7 macrophages were used to evaluate the effects of CXCL5 on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation. In vivo, a mouse model received intra-articular LTA and intraperitoneal CXCL5 neutralizing antibody to investigate the role of CXCL5 in maintaining bone integrity under infectious conditions. Results CXCL5 was significantly upregulated in PJI patients, particularly in GPC-PJI cases. LTA stimulation increased CXCL5 secretion from osteoblasts in a dose-dependent manner. Functionally, CXCL5 inhibited osteoclast formation and reduced nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) expression. Kinase profiling revealed that CXCL5 suppressed osteoclastogenesis via PLCγ2 phosphorylation and c-Fos downregulation. In vivo, CXCL5 neutralization exacerbated LTA-induced bone loss. Conclusion CXCL5 is highly expressed in GPC-PJI and protects bone by inhibiting osteoclast differentiation through PLCγ2 and c-Fos signalling. In vivo evidence confirms its key role in preserving bone homeostasis during Gram-positive bacterial infection. Cite this article: Bone Joint Res 2026;15(3):215–226.
Chang et al. (Wed,) studied this question.