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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
Authors
Wixted, John J.Fanning, Paul J.
Gaur, Tripti
O'Connell, Shannon L.
Silva, Jason
Mason-Savas, April
Ayers, David C.
Stein, Gary S.
Lian, Jane B.
UMass Chan Affiliations
Department of Orthopedic Surgery and Physical RehabilitationDepartment of Cell Biology
Department of Orthopedics
Document Type
Journal ArticlePublication Date
2009-10-23Keywords
AcetatesAnimals
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
Cell Biology
Metadata
Show full item recordAbstract
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.Source
J Cell Physiol. 2009 Oct;221(1):31-9. Link to article on publisher's siteDOI
10.1002/jcp.21809Permanent Link to this Item
http://hdl.handle.net/20.500.14038/49604PubMed ID
19544365Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1002/jcp.21809