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.
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.
Wixted
John J
JJ
Department of Orthopedic Surgery and Physical Rehabilitation, University of Massachusetts Medical School, Worcester, Massachusetts, USA. wixtedj@ummhc.org
Fanning
Paul J
PJ
Gaur
Tripti
T
O'Connell
Shannon L
SL
Silva
Jason
J
Mason-Savas
April
A
Ayers
David C
DC
Stein
Gary S
GS
Lian
Jane B
JB
D000085:Acetates / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D003521:Cyclopropanes; D017102:Fracture Healing / Q000187:drug effects*; D050723:Fractures, Bone / Q000000981:diagnostic imaging / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D006984:Hypertrophy; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010012:Osteogenesis / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology; D011859:Radiography; D018077:Receptors, Leukotriene / Q000378:metabolism*; D013440:Sulfides
D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; C083169:leukotriene D4 receptor; C093875:montelukast; C063449:zileuton; D006918:Hydroxyurea