The Chondroprotective Role of Erythromycin in a Murine Joint Destruction Model.
OBJECTIVE
Inflammation is a major player in the joint destruction process. Macrolide antibiotics have recently been found to have a novel anti-inflammatory function, but their effects on the joint are unknown. Our objective was to investigate the effect of macrolide antibiotic erythromycin on cartilage gene expression under inflammatory conditions as well as on joint pathology in an in vivo inflammatory joint destruction model.


METHODS
In our in vivo studies, mouse knee joints were injected with monosodium iodoacetate (MIA), a chemical that inhibits glycolysis and causes joint inflammation and matrix loss. Erythromycin was administered by daily intraperitoneal injection. Changes in joint cartilage and synovium were evaluated by histological analysis. In our in vitro studies, primary bovine articular chondrocytes were treated with erythromycin in the presence of pro-inflammatory cytokine IL-1β or lipopolysaccharide (LPS), and cartilage gene expression analysis was performed.


RESULTS
Regional differences in cartilage matrix destruction along the medial-lateral axis were observed in joints of MIA-injected mice. Erythromycin treatment inhibited cartilage matrix loss and synovitis in these joints. In addition, erythromycin inhibited IL-1β and LPS-induced expression of MMPs and iNOS, as well as the positive regulatory loop between IL-1β and Toll-like receptor 4 (TLR4) in articular chondrocytes. Furthermore, erythromycin prevented LPS-induced NF-κB activation, a key mediator of TLR4-mediated cartilage destruction process.


CONCLUSIONS
Erythromycin has the ability to inhibit catabolic gene expression mediated by IL-1β and TLR4 in chondrocytes in vitro and maintains cartilage matrix levels in experimental inflammatory joint destruction in vivo, suggesting that it possesses a chondroprotective activity.
Program in Cellular, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA.
Tomoya
T
Uchimura
Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.
Andrea T
AT
Foote
Department of Orthopaedic Surgery, Providence Hospital, Southfield, MI, USA.
David C
DC
Markel
Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA.
Weiping
W
Ren
Program in Cellular, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA; Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA; Department of Orthopedics, Tufts Medical Center, Boston, MA, USA.
Li
L
Zeng
IL-1β; TLR4; antibiotics; chondrocytes; erythromycin; osteoarthritis
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