RANKL-targeted therapy inhibits bone resorption in experimental Staphylococcus aureus-induced arthritis.
BACKGROUND
Bacterial arthritis causes rapidly progressing joint destruction in humans. We have shown that addition of bisphosphonates or corticosteroids to conventional antimicrobial agents decreases the activity of osteoclasts, thereby reducing bone destruction. Here we assess the effect of RANKL-targeted treatments using soluble receptor decoy and osteprotegerin (OPG) on the course and outcome of staphylococcal arthritis.


METHODS
Treatment was initiated 3 days after Staphylococcus aureus inoculation and included RANK-Fc, OPG-Fc, and OPG-Fc in combination with antibiotics. Control groups were treated with antibiotics, huFc, and PBS. Joints were evaluated for clinical signs of arthritis and histologically for bone and cartilage destruction. Bone mineral density (BMD) was evaluated using a peripheral quantitative computed tomography. Circulating markers of bone metabolism, inflammatory cytokines, and chemokines were analyzed in each group.


RESULTS
Mice treated with RANK-Fc or OPG-Fc in combination with antibiotics preserved total BMD and trabecular bone as compared to huFc or antibiotics. Treatment with RANK-Fc or OPG-Fc diminished the levels of bone resorption markers (osteocalcin, CTX-I, and TRACP5b). Neither RANK-Fc nor OPG-Fc influenced significantly the frequency and severity of arthritis.


CONCLUSIONS
Inhibition of RANKL signalling efficiently prevents bone loss in the mouse model of bacterial arthritis even when started in the overt phase of infection.
Verdrengh
Margareta
M
Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, Guldhedsgatan 10A, S-41346 Göteborg, Sweden.
Bokarewa
Maria
M
Ohlsson
Claes
C
Stolina
Marina
M
Tarkowski
Andrej
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000382:microbiology; D001862:Bone Resorption / Q000382:microbiology / Q000517:prevention & control*; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D051379:Mice; D008814:Mice, Inbred NZB; D053244:Osteoprotegerin / Q000627:therapeutic use; D053245:RANK Ligand / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects
D000900:Anti-Bacterial Agents; D053244:Osteoprotegerin; D053245:RANK Ligand