Prostaglandin E2 Exerts Catabolic Effects in Osteoarthritis Cartilage: Evidence for Signaling via the EP4 Receptor

Abstract

Elevated levels of PGE2 have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions of PGE2 in cartilage metabolism have not previously been studied in detail. To do so, we cultured cartilage explants, obtained from patients undergoing knee replacement surgery for advanced OA, with PGE2 (0.1–10 μM). PGE2 inhibited proteoglycan synthesis in a dose-dependent manner (maximum 25% inhibition (p < 0.01)). PGE2 also induced collagen degradation, in a manner inhibitable by the matrix metalloproteinase (MMP) inhibitor ilomastat. PGE2 inhibited spontaneous MMP-1, but augmented MMP-13 secretion by OA cartilage explant cultures. PCR analysis of OA chondrocytes treated with PGE2 with or without IL-1 revealed that IL-1-induced MMP-13 expression was augmented by PGE2 and significantly inhibited by the cycolooygenase 2 selective inhibitor celecoxib. Conversely, MMP-1 expression was inhibited by PGE2, while celecoxib enhanced both spontaneous and IL-1-induced expression. IL-1 induction of aggrecanase 5 (ADAMTS-5), but not ADAMTS-4, was also enhanced by PGE2 (10 μM) and reversed by celecoxib (2 μM). Quantitative PCR screening of nondiseased and end-stage human knee OA articular cartilage specimens revealed that the PGE2 receptor EP4 was up-regulated in OA cartilage. Moreover, blocking the EP4 receptor (EP4 antagonist, AH23848) mimicked celecoxib by inhibiting MMP-13, ADAMST-5 expression, and proteoglycan degradation. These results suggest that PGE2 inhibits proteoglycan synthesis and stimulates matrix degradation in OA chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for OA disease modification.

Curcumin inhibits pro-inflammatory mediators and metalloproteinase-3 production by chondrocytes

“…Indeed, PGE 2 is an important inflammatory mediator, largely involved in inflammatory pain. In addition to exacerbating joint inflammation, PGE 2 can also affect cartilage remodeling by inhibiting proteoglycan synthesis and by stimulating matrix degradation [23,24]. NO has regulatory, proinflammatory, and destructive effects.…”

Shear-induced Interleukin-6 Synthesis in Chondrocytes

“…Attur et al (27) concluded that the PGE 2 -mediated proteoglycan degradation and up-regulation of cartilage-degrading enzymes, such as matrix metalloproteinase-13, in human OA chondrocytes occurs via an EP4-dependent/EP2-independent signaling pathway. In contrast, Li et al (14) reported that EP2 is the major mediator of PGE 2 -induced suppression of proteoglycan accumulation in articular chondrocytes, which is not accompanied by any significant modulation of MMP activity.…”

“…Numerous studies suggest that PGE 2 exerts catabolic effects in articular cartilage (14,27,32), as evidenced by the decreased aggrecan synthesis and total proteoglycan accumulation. Attur et al (27) concluded that the PGE 2 -mediated proteoglycan degradation and up-regulation of cartilage-degrading enzymes, such as matrix metalloproteinase-13, in human OA chondrocytes occurs via an EP4-dependent/EP2-independent signaling pathway.…”

“…1C). Thus, we next investigated the effects of an EP2 receptor antago- nist, AH6809 (9,27), and an EP3 receptor agonist, sulprostone (14), on shear-induced cAMP formation and IL-6 synthesis. Incubation of T/C-28a2 chondrocytes with AH6809 (3 M) does not alter the mRNA, and protein expression levels of EP2 receptor in shear-stimulated cells (Fig.…”

Molecular mechanisms of osteoarthritis using gene microarrays

“…Interleukin-1 (IL1) can induce the expression of two matrix metalloproteinase members MMP-13 and MMP-1via the p38/c-JUN N-terminal kinase (JNK) pathway and p38/MEK signaling pathway, respectively (Mengshol et al, 2000). Both MMP-13 and MMP-1 can cleave cartilage matrix collagen, especially MMP-13, which preferentially degrades type II collagen (Knäuper et al, 1996), and aberrant expression of these two genes has been reported previously in OA patients (Tetlow et al, 2001;Attur et al, 2009). Additionally, when the survival signals from extracellular matrix or growth factors are lost, programmed cell death or apoptosis occurs in chondrocytes (Del Carlo and Loeser, 2008).…”