Combination treatment with anti-RANKL and antibiotics for preventing joint destruction in septic arthritis
Zhicheng Hu, Meghshree Deshmukh, Anders Jarneborn, Miriam Bollmann, Carmen Corciulo, Pradeep Kumar Kopparapu, Abukar Ali, Mattias N. D. Svensson, Cecilia Engdahl, Rille Pullerits, Majd Mohammad, Tao Jin
Zhicheng Hu, Meghshree Deshmukh, Anders Jarneborn, Miriam Bollmann, Carmen Corciulo, Pradeep Kumar Kopparapu, Abukar Ali, Mattias N. D. Svensson, Cecilia Engdahl, Rille Pullerits, Majd Mohammad, Tao Jin
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Research Article Bone biology Infectious disease

Combination treatment with anti-RANKL and antibiotics for preventing joint destruction in septic arthritis

Abstract

Septic arthritis, the most severe joint disease, is frequently caused by Staphylococcus aureus (S. aureus). A substantial proportion of patients with septic arthritis experience poor joint outcomes, often necessitating joint replacement surgery. Here, we show that monocyte depletion confers full protection against bone erosion in a septic arthritis mouse model. In the infected synovium, Ly6Chi monocytes exhibited increased expression of osteoclastogenesis-related molecules, including CCR2, c-Fms, and RANK. S. aureus lipoproteins induced elevated levels of RANKL, MCSF, and CCL2 in joints, with synovial fibroblasts identified as the major RANKL producer. Anti-RANKL treatment prevented bone destruction in both local and hematogenous septic arthritis murine models. Importantly, combining anti-RANKL treatment with antibiotics provided robust protection against joint damage. Our results indicate that the infiltration and transformation of monocytes into bone-destructive, osteoclast-like cells are key mechanisms in septic arthritis. Combining anti-RANKL and antibiotic therapy represents a promising therapy against this devastating disease.

Authors

Zhicheng Hu, Meghshree Deshmukh, Anders Jarneborn, Miriam Bollmann, Carmen Corciulo, Pradeep Kumar Kopparapu, Abukar Ali, Mattias N. D. Svensson, Cecilia Engdahl, Rille Pullerits, Majd Mohammad, Tao Jin

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Figure 3

S. aureus Lpps induce the expression of osteoclastogenesis-related cytokines in injected joints.

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S. aureus Lpps induce the expression of osteoclastogenesis-related cyto...
Supernatants from knee homogenates of NMRI mice on day 3 after intra-articular (i.a.) injection of 20 μL of PBS (healthy; n = 4) or Lpl1(+sp) or Lpl1(-sp) (4 μg/knee; n = 5/group) were assessed for the levels of CCL2 (MCP-1, A), MCSF (B), and RANKL (C) by ELISA. Levels of CCL2 (MCP-1, D), MCSF (E), and RANKL (F) in the supernatants from knee homogenates of NMRI mice on day 3 after i.a. injection of 20 μL of PBS (healthy; n = 4) or the synthetic lipopeptides, P2C or P3C (4 μg/knee; n = 4 to 6/group). Levels of CCL2 (MCP-1, G), MCSF (H), and RANKL (I) in the supernatants from knee homogenates of NMRI mice depleted of monocytes/macrophages using clodronate liposomes (Monocyte depletion) or PBS control liposomes (Control) on day 3 after i.a. injection of 20 μL of P2C (4 μg/knee; n = 6/group). Data were pooled from 2 independent experiments. Mouse knee synovial fibroblasts were stimulated with P2C or P3C (20 ng/mL; n = 5/group), or Lpl1(+sp) or Lpl1(-sp) (0.2 μg/mL; n = 5/group) for 48 hours. The expression levels of RANKL were analyzed with the TaqMan assay, and the relative gene expression was calculated using the ΔCt method (J). The fold-changes in gene expression levels were normalized against medium-only samples (K). Statistical evaluations were performed using 1-way ANOVA with Tukey’s multiple-comparison test (A–I), repeated measures 1-way ANOVA with Dunnett’s multiple-comparison test (J), and the Mann-Whitney test (K), with the data presented as mean with SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.