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 1

Monocytes are pathogenic while neutrophils are protective in septic arthritis–induced bone destruction.

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Monocytes are pathogenic while neutrophils are protective in septic arth...
(A) The protective effect of neutrophils was examined by depleting mice of neutrophils (n = 10/group) using the anti-Ly6G antibody (Neutrophil depletion) or an isotype control (Controls). Knee swelling was measured in millimeters over a period of 7 days after intra-articular (i.a.) injection of 20 μL of PBS containing S. aureus LS-1 strain (4 × 103 CFU/knee) into the knee joints of NMRI mice. (B) Bacterial counts in the mouse knee joints (n = 5/group) were assessed. (C) Bone erosion scores of the knee joints (n = 5/group) were determined after micro-CT (μCT) scan. (E) Cumulative survival was monitored daily. (F) The pathogenic role of monocytes was investigated by depleting mice of monocytes (n = 22/group) using clodronate liposomes (Monocyte depletion) or PBS control liposomes (Controls), and knee swelling was followed for 10 days after infection using the same strategy. (G) Bacterial counts in mouse knee joints in the monocyte depletion group (n = 5) and controls (n = 6). (H) Bone erosion scores for the monocyte depletion group (n = 7) and controls (n = 16) and (I) cumulative survival. (D) Representative μCT images of knee joints from the control, neutrophil depletion, and monocyte depletion groups. Arrows indicate bone erosion. The data were pooled from 2 independent experiments. Statistical evaluations were performed using the Mann-Whitney test (A–C and F–H) or log-rank (Mantel-Cox) test (E and I). Data are presented as mean with SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.