Abstract
As a downstream product of cyclooxygenase 2 (COX-2), prostaglandin E2 (PGE2) plays a crucial role in the regulation of bone formation. It has four different receptor subtypes (EP1 through EP4), each of which exerts different effects in bone. EP2 and EP4 induce bone formation through the protein kinase A (PKA) pathway, whereas EP3 inhibits bone formation in vitro. However, the effect of EP1 receptor signaling during bone formation remains unclear. Closed, stabilized femoral fractures were created in mice with EP1 receptor loss of function at 10 weeks of age. Healing was evaluated by radiographic imaging, histology, gene expression studies, micro–computed tomographic (µCT), and biomechanical measures. EP1−/− mouse fractures have increased formation of cartilage, increased fracture callus, and more rapid completion of endochondral ossification. The fractures heal faster and with earlier fracture callus mineralization with an altered expression of genes involved in bone repair and remodeling. Fractures in EP1−/− mice also had an earlier appearance of tartrate-resistant acid phosphatase (TRAcP)–positive osteoclasts, accelerated bone remodeling, and an earlier return to normal bone morphometry. EP1−/− mesenchymal progenitor cells isolated from bone marrow have higher osteoblast differentiation capacity and accelerated bone nodule formation and mineralization in vitro. Loss of the EP1 receptor did not affect EP2 or EP4 signaling, suggesting that EP1 and its downstream signaling targets directly regulate fracture healing. We show that unlike the PGE2 receptors EP2 and EP4, the EP1 receptor is a negative regulator that acts at multiple stages of the fracture healing process. Inhibition of EP1 signaling is a potential means to enhance fracture healing. © 2011 American Society for Bone and Mineral Research.
Highlights
7.9 million skeletal fractures occur each year in the United States.[1]
While COX-1 is constitutively expressed and plays a largely homeostatic role in bone, COX-2 expression is induced by mitogens and inflammatory cytokines to upregulate PG synthesis during repair as well as in settings of inflammation and tumorigenesis.[5,6] Several experiments have confirmed that Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibition of cyclooxygenase 2 (COX-2) during the inflammatory stage of healing delays the rate of fracture repair.[7,8,9] Prior studies show significant delay in fracture healing in COX-2 null mice compared with wild-type littermates and COX-1 null mice.[10,11] COX-2À/À mice have reduced callus formation, delayed chondrogenesis and impaired endochondral bone formation, and reduced vascularization, primary bone formation, and remodeling.[10]
Despite the known importance of COX-2/prostaglandin E2 (PGE2) on fracture healing and bone repair, this study is the first to define the role of the EP1 receptor in this process
Summary
7.9 million skeletal fractures occur each year in the United States.[1]. Nonsteroidal anti-inflammatory drugs (NSAIDs) taken to reduce pain following fracture have been linked to decreased bone repair in several clinical studies.[3,4] NSAIDs inhibit the activity of cyclooxygenase (COX) enzymes COX-1 and COX-2. These enzymes play a critical role in the synthesis of prostaglandins (PGs) from arachidonic acid. While COX-1 is constitutively expressed and plays a largely homeostatic role in bone, COX-2 expression is induced by mitogens and inflammatory cytokines to upregulate PG synthesis during repair as well as in settings of inflammation and tumorigenesis.[5,6] Several experiments have confirmed that NSAID inhibition of cyclooxygenase 2 (COX-2) during the inflammatory stage of healing delays the rate of fracture repair.[7,8,9] Prior studies show significant delay in fracture healing in COX-2 null mice compared with wild-type littermates and COX-1 null mice.[10,11] COX-2À/À mice have reduced callus formation, delayed chondrogenesis and impaired endochondral bone formation, and reduced vascularization, primary bone formation, and remodeling.[10]
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