Erythromycin inhibits wear debris-induced inflammatory osteolysis in a murine model.

Abstract

Up to 20% of patients with total joint arthroplasty will develop radiographic evidence of aseptic loosening (AL), which most likely results from an inflammatory response to billions of wear debris shed from the implant. Our previous work has demonstrated that erythromycin (EM), a macrolide antibiotic, inhibits wear debris-induced inflammatory osteoclastogenesis through the reduction of cytokine production and osteoclast differentiation, both of which involve the NF-kappaB pathway. The aim of the current study was to determine whether EM inhibits wear debris-induced inflammatory osteolysis in a murine osteolysis model. Ultrahigh molecular-weight polyethylene (UHMWPE) debris was introduced into established air pouches on BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. EM (2 mg/kg/day) was given to mice intraperitoneally 2 days before UHMWPE introduction and maintained until the sacrifice of the mice. Mice with and without EM treatment, as well as control mice injected with saline alone were included in this study. Pouch tissues were collected 14 days after UHMWPE inoculation for molecular and histology analysis. Our findings indicate that: (1) EM reduced UHMWPE-induced tissue inflammation, including the diminished pouch membrane thickness, reduced inflammatory cellular infiltration, and lowered IL-1beta and TNF-alpha expression (mRNA and protein); (2) EM inhibited UHMWPE-induced osteoclastogenesis, with reduced gene activation of RANK, RANKL, and CPK, and diminished RANKL expression in UHMWPE stimulated pouches, and (3) EM markedly reduced the number of TRAP(+) cells in pouch tissues, and protected against bone collagen depletion. In conclusion, this study provides the evidence that EM inhibits the UHMWPE particles-induced inflammatory osteolysis in a murine model, and represents a promising therapeutic candidate for the prevention and treatment of AL.

• Authors: Weiping Ren, Bin Wu, Xin Peng, Lois Mayton, Dongzi Yu, Juanjie Ren, Ben D Chen, Paul H Wooley
• Journal: Journal of orthopaedic research : official publication of the Orthopaedic Research Society (J Orthop Res) Vol. 24 Issue 2 Pg. 280-90 (Feb 2006) ISSN: 0736-0266 [Print] United States
• PMID: 16435361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2005 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Chemical References

• Anti-Inflammatory Agents
• Carrier Proteins
• Interleukin-1
• Membrane Glycoproteins
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Tnfrsf11a protein, mouse
• Tnfsf11 protein, mouse
• Tumor Necrosis Factor-alpha
• Erythromycin

Topics

• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Carrier Proteins (metabolism)
• Disease Models, Animal
• Erythromycin (therapeutic use)
• Female
• Inflammation (drug therapy, metabolism, pathology)
• Injections, Intraperitoneal
• Interleukin-1 (metabolism)
• Membrane Glycoproteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Osteolysis (metabolism, pathology, prevention & control)
• Prosthesis Failure
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Skull (drug effects, pathology)
• Tumor Necrosis Factor-alpha (metabolism)