Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: a novel role of the cysteinyl LT-1 receptor
Department of Orthopedics; Department of Cell Biology; Department of Orthopedic Surgery and Physical Rehabilitation
Medical Subject Headings
Acetates; Animals; Arachidonate 5-Lipoxygenase; Cell Proliferation; Chondrocytes; Fracture Healing; Fractures, Bone; Gene Expression Regulation; Hydroxyurea; Hypertrophy; Leukotriene Antagonists; Leukotriene B4; Mice; Models, Biological; Osteogenesis; Quinolines; Receptors, Leukotriene
Inflammatory mediators and drugs which affect inflammation can influence the healing of injured tissues. Leukotrienes are potent inflammatory mediators, and similar to prostaglandins, are metabolites of arachidonic acid which can have positive or negative effects on bone and cartilage tissues. Here we tested the hypothesis that blocking the negative regulation of leukotrienes, would lead to enhanced endochondral bone formation during fracture repair. A closed femoral fracture was created in mice. Animals were divided into three groups for treatment with either montelukast sodium, a cysteinyl leukotriene type 1 receptor antagonist (trade name Singulair), zileuton, a 5-lipoxygenase enzyme inhibitor (trade name Zyflo), or carrier alone. The fractures were analyzed using radiographs, quantitative gene expression, histology and histomorphometry, and immunohistochemistry. Both the montelukast sodium group and the zileuton group exhibited enhanced fracture repair when compared with controls. Both treatment groups exhibited increased callous size and earlier bone formation when compared to controls as early as day 7. Gene expression analysis of treatment groups showed increased markers of chondrocyte proliferation and differentiation, and increased early bone formation markers when compared with controls. Treatment with montelukast sodium directly targeted the cysteinyl leukotriene type 1 receptor, leading to increased chondrocyte proliferation at early time points. These novel findings suggests a potential mechanism by which the cysteinyl leukotriene type 1 receptor acts as a negative regulator of chondrocyte proliferation, with important and previously unrecognized implications for both fracture repair, and in a broader context, systemic chondrocyte growth and differentiation.
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Citation: J Cell Physiol. 2009 Oct;221(1):31-9. Link to article on publisher's site
Wixted, John J.; Fanning, Paul J.; Gaur, Tripti; O'Connell, Shannon L.; Silva, Jason; Mason-Savas, April; Ayers, David C.; Stein, Gary S.; and Lian, Jane B., "Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: a novel role of the cysteinyl LT-1 receptor" (2009). Stein, Stein, Lian, vanWijnen Lab Publications. 33.