Rescue of Impaired Fracture Healing in COX-2-/- Mice Via Activation of Prostaglandin E2 Receptor Subtype 4

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2009 Jul 25

PMID 19628768

Citations 54

Authors

Chao Xie

Bojian Liang

Ming Xue

Angela S P Lin

Alayna Loiselle

Edward M Schwarz

Robert E Guldberg

Regis J OKeefe

Xinping Zhang

Affiliations

Soon will be listed here.

Abstract

Although the essential role of cyclooxygenase (COX)-2 in fracture healing is known, the targeted genes and molecular pathways remain unclear. Using prostaglandin E2 receptor (EP)2 and EP4 agonists, we examined the effects of EP receptor activation in compensation for the lack of COX-2 during fracture healing. In a fracture-healing model, COX-2(-/-) mice showed delayed initiation and impaired endochondral bone repair, accompanied by a severe angiogenesis deficiency. The EP4 agonist markedly improved the impaired healing in COX-2(-/-) mice, as evidenced by restoration of bony callus formation on day 14, a near complete reversal of bone formation, and an approximately 70% improvement of angiogenesis in the COX-2(-/-) callus. In comparison, the EP2 agonist only marginally enhanced bone formation in COX-2(-/-) mice. To determine the differential roles of EP2 and EP4 receptors on COX-2-mediated fracture repair, the effects of selective EP agonists on chondrogenesis were examined in E11.5 long-term limb bud micromass cultures. Only the EP4 agonist significantly increased cartilage nodule formation similar to that observed during prostaglandin E2 treatment. The prostaglandin E2/EP4 agonist also stimulated MMP-9 expression in bone marrow stromal cell cultures. The EP4 agonist further restored the reduction of MMP-9 expression in the COX-2(-/-) fracture callus. Taken together, our studies demonstrate that EP2 and EP4 have differential functions during endochondral bone repair. Activation of EP4, but not EP2 rescued impaired bone fracture healing in COX-2(-/-) mice.

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