The prostaglandin E2 system: A toolbox for skeletal repair?

Abstract

Prostaglandins, a group of lipid mediators, govern a multitude of biologic processes, including inflammation, platelet aggregation, and cell growth. Because of the key role of prostaglandins in inflammation and pain, their metabolism represents the final target of nonsteroidal antiinflammatory drugs (NSAIDs). In the US, sales volumes for NSAIDs of far more than $1 billion per year highlight the enormous economic impact of these agents and the important role of prostaglandin inhibition in clinical practice (1). Prostaglandin E2 (PGE2), the most widely produced member of the prostaglandin group, originates from arachidonic acid that is released from the cell membrane by phospholipase A2, followed by enzymatic conversion by cyclooxygenase (COX) and PGE synthase 1 (PGES-1). PGE2 not only triggers pain and inflammation but also promotes matrix degradation and tissue damage by stimulating the expression of matrixdegrading enzymes (2). Inflammatory cytokines such as interleukin-1 or tumor necrosis factor strongly increase PGE2 levels, but PGE2 secretion may also increase in response to other stimuli including growth factors, hypoxia, and a number of hormones. Apart from the well-defined role of PGE2 in tissue inflammation, there is increasing evidence that it is involved in the maintenance and repair of the skeletal system. At first glance, the effects of PGE2 on tissue homeostasis of bone and cartilage seem confusing, because they conflict with the long-known destructive potential of the prostaglandins. Nevertheless, both catabolic and anabolic effects have already been described for PGE2 in these tissues. In terms of catabolism, PGE2 can promote osteoclastic bone resorption (3,4) and enhance breakdown of the extracellular matrix by increasing the expression of matrix metalloproteinase 3 (MMP-3) or MMP-13 (2,5). Regarding its anabolic aspects, PGE2 may stimulate chondrogenesis, chondrocyte proliferation (6), cartilage matrix synthesis (7), as well as osteoblast activity (8). To shed light on the apparent ambivalent role of PGE2, a multidimensional view is necessary that addresses the developmental stage, type of tissue, disease status, concentration of PGE2, and specific receptor status of the different cell types. So far, 4 different receptors of PGE2 have been identified, designated EP1, EP2, EP3, and EP4 (9). Specific signal transduction properties characterize each receptor, as follows: EP1 stimulates intracellular Ca2 mobilization, whereas EP2 and EP4 bind GS proteins to enhance cAMP levels and activate protein kinase A. In contrast to EP2 and EP4, binding to EP3 results in decreased cAMP concentrations through Gi, Gq, or GS, depending on the EP3 isoform. The 4 receptor subtypes are expressed differentially within various types of tissues. Within articular cartilage and growth plate cartilage, all 4 receptor subtypes are detectable. Their respective expression patterns, however, vary between the different types of cartilage tissues and depend on the stage of development. Early in the process of cartilage development, PGE2 promotes proliferation and DNA synthesis of chondrocytes via binding to EP1 within the growth plate (6), while PGE2 stabilizes the phenotype of chondrocytes within articular cartilage via binding to EP2 and EP4 in later stages (10). Concentration-dependent effects of PGE2 may also contribute to its pleiotropic and sometimes even contradictory effects, as particularly shown in cartilage metabolism. In experimental settings, administration of PGE2 at low doses (slightly above the physiologic level) can promote chondrocyte proliferation (6) and suppress the expression of the degradative enzymes MMP-3 and MMP-13 (11). PGE2 may also stimulate the expression of cartilage-specific genes, including type II collagen, SOX9, and aggrecan, and inhibit the expression of Supported by the DFG (GE 1975/2-1). Kolja Gelse, MD, Christian Beyer, MD: University of Erlangen–Nuremberg and University Hospital Erlangen, Erlangen, Germany. Address correspondence to Kolja Gelse, MD, Department of Orthopaedic Trauma Surgery, University Hospital Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany. E-mail: kolja. gelse@web.de. Submitted for publication November 1, 2010; accepted in revised form November 9, 2010.