Prostaglandin E2 Inhibits BMP Signaling and Delays Chondrocyte Maturation

Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Journal of Orthopaedic Research (Impact Factor: 2.99). 06/2009; 27(6):785-92. DOI: 10.1002/jor.20805
Source: PubMed


While cyclooxygenases are important in endochondral bone formation during fracture healing, mechanisms involved in prostaglandin E2 (PGE2) regulation of chondrocyte maturation are incompletely understood. The present study was undertaken to determine if PGE2 effects on chondrocyte differentiation are related to modulation of the bone morphogenetic protein (BMP) signaling pathway. In primary murine sternal chondrocytes, PGE2 differentially regulated genes involved in differentiation. PGE2 induced type II collagen and MMP-13, had minimal effects on alkaline phosphatase, and inhibited the expression of the maturational marker, type X collagen. In BMP-2-treated cultures, PGE2 blocked the induction of type X collagen. All four EP receptors were expressed in chondrocytes and tended to be inhibited by BMP-2 treatment. RCJ3.1C5.18 chondrocytes transfected with the protein kinase A (PKA) responsive reporter, CRE-luciferase, showed luciferase induction following exposure to PGE2, consistent with activation of PKA signaling and the presence of the EP2 and EP4 receptors. Both PGE2 and the PKA agonist, dibutyryl cAMP, blocked the induction of the BMP-responsive reporter, 12XSBE, by BMP-2 in RCJ3.1C5.18 chondrocytes. In contrast, PGE2 increased the ability of TGF-beta to activate the TGF-beta-responsive reporter, 4XSBE. Finally, PGE2 down-regulated BMP-mediated phosphorylation of Smads 1, 5, and 8 in RCJ3.1C5.18 cells and in primary murine sternal chondrocytes. Altogether, the findings show that PGE2 regulates chondrocyte maturation in part by targeting BMP/Smad signaling and suggest an important role for PGE2 in endochondral bone formation.

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Available from: Tian-Fang Li
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    • "Because of the diverse cell types that participate in cartilage formation during fracture healing, it is likely that these different types of cells use different signaling mechanisms when undergoing chondrogenic differentiation. It is known that TGFß, BMP, PTH, as well as Wnt signaling are all activated during fracture healing, and downstream molecules such as Smad, prostaglandin, Cox-2 and ß-catenin regulate this process [58], [59], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84]. Our work demonstrates that transcription factors Pax3, Nkx3.2 and Sox9 regulate chondrogenic differentiation of muscle progenitor cells. "
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    • "In agreement, we showed that production of MMP-13 in articular chondrocytes was reduced when treated with an EP2 agonist in vivo (Figure 7) and in vitro (Figure 8). Controversially others studies show that PGE2 plays a crucial role in the induction of MMP-13 and MMP-3 in chondrocytes in response to IL-1β in microsomal prostaglandin E synthase-deficient mice [35] or that of PGE2 inhibits chondrocyte maturation [36]. In the current study model, EP2 signaling was shown to inhibit the expression of MMP-13 mRNA, suggesting that EP2 signaling protects the articular cartilage from degeneration. "
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