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
View: Text | PDF
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

×

Figure 4

Anti-RANKL treatment provides robust protection against bone destruction in locally induced septic arthritis in mice.

Options: View larger image (or click on image) Download as PowerPoint
Anti-RANKL treatment provides robust protection against bone destruction...
(A) Measurement of knee swelling (in mm, n = 10/group) of NMRI mice treated with anti-mouse CSF1R antibodies (anti-MCSFR) or an isotype control (Controls), administered 3 hours prior to intra-articular (i.a.) infection of 20 μL of PBS containing S. aureus LS-1 strain (4 × 103 CFU/knee). (B) Bacterial counts of S. aureus in mouse knee joints (n = 5/group) and (C) bone erosion scores of mouse knee joints (n = 5/group) were determined after μCT scan on day 10 after the mice were sacrificed. (D) Knee swelling measurements (in mm, n = 10/group) of NMRI mice treated with anti-mouse RANKL antibodies (anti-RANKL) or an isotype control (Controls), administered 1 day prior to i.a. infection of 20 μL of PBS containing S. aureus LS-1 strain (4 × 103 CFU/knee). (E) Bacterial counts (n = 5/group) and (F) bone erosion scores (n = 5/group) were determined after μCT scan on day 10 after the mice were sacrificed. To mimic more accurately the clinical progress, additional assessments were conducted with varied administration timing, 2 days after infection (G–I), and (J) representative μCT images are shown. Arrows indicate bone erosion. (K) Representative TRAP staining images of mouse knee joints that received injections of PBS, isotype control antibody, or anti-RANKL antibody. The insets (lower panels) represent higher magnification images of the boxed areas, with the arrows indicating TRAP-positive cells. Scale bar: 100 μm. Statistical evaluations were performed using the Mann-Whitney test, and the data are presented as mean with SEM. *P < 0.05; **P < 0.01.