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. 2007;9(4):R75.
doi: 10.1186/ar2273.

Prostaglandin PGE2 at very low concentrations suppresses collagen cleavage in cultured human osteoarthritic articular cartilage: this involves a decrease in expression of proinflammatory genes, collagenases and COL10A1, a gene linked to chondrocyte hypertrophy

Elena V Tchetina  1 , John A Di Battista, David J Zukor, John Antoniou, A Robin Poole
Affiliations

Prostaglandin PGE2 at very low concentrations suppresses collagen cleavage in cultured human osteoarthritic articular cartilage: this involves a decrease in expression of proinflammatory genes, collagenases and COL10A1, a gene linked to chondrocyte hypertrophy

Elena V Tchetina et al. Arthritis Res Ther. 2007.

Abstract

Suppression of type II collagen (COL2A1) cleavage by transforming growth factor (TGF)-beta2 in cultured human osteoarthritic cartilage has been shown to be associated with decreased expression of collagenases, cytokines, genes associated with chondrocyte hypertrophy, and upregulation of prostaglandin (PG)E2 production. This results in a normalization of chondrocyte phenotypic expression. Here we tested the hypothesis that PGE2 is associated with the suppressive effects of TGF-beta2 in osteoarthritic (OA) cartilage and is itself capable of downregulating collagen cleavage and hypertrophy in human OA articular cartilage. Full-depth explants of human OA knee articular cartilage from arthroplasty were cultured with a wide range of concentrations of exogenous PGE2 (1 pg/ml to 10 ng/ml). COL2A1 cleavage was measured by ELISA. Proteoglycan content was determined by a colorimetric assay. Gene expression studies were performed with real-time PCR. In explants from patients with OA, collagenase-mediated COL2A1 cleavage was frequently downregulated at 10 pg/ml (in the range 1 pg/ml to 10 ng/ml) by PGE2 as well as by 5 ng/ml TGF-beta2. In control OA cultures (no additions) there was an inverse relationship between PGE2 concentration (range 0 to 70 pg/ml) and collagen cleavage. None of these concentrations of added PGE2 inhibited the degradation of proteoglycan (aggrecan). Real-time PCR analysis of articular cartilage from five patients with OA revealed that PGE2 at 10 pg/ml suppressed the expression of matrix metalloproteinase (MMP)-13 and to a smaller extent MMP-1, as well as the proinflammatory cytokines IL-1beta and TNF-alpha and type X collagen (COL10A1), the last of these being a marker of chondrocyte hypertrophy. These studies show that PGE2 at concentrations much lower than those generated in inflammation is often chondroprotective in that it is frequently capable of selectively suppressing the excessive collagenase-mediated COL2A1 cleavage found in OA cartilage. The results also show that chondrocyte hypertrophy in OA articular cartilage is functionally linked to this increased cleavage and is often suppressed by these low concentrations of added PGE2. Together these initial observations reveal the importance of very low concentrations of PGE2 in maintaining a more normal chondrocyte phenotype.

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Figures

Figure 1
Figure 1
Inhibition of collagen cleavage by prostaglandin E2 (PGE2) and transforming growth factor (TGF)-β2. (a–d) The effect of 5 ng/ml TGF-β2 and PGE2 at various concentrations (1 pg to 10 ng/ml) on collagen cleavage in human osteoarthritic (OA) explants from patients of indicated age and gender; (e) means ± SDs for all four patients; (f) inhibition of type II collagen cleavage by collagenase in human OA articular explants by 10 pg/ml PGE2; (g) concentration relationship between PGE2 in control cultures and collagen cleavage. The average medium levels of PGE2 in the dose-dependent studies were as follows: 6.3 ± 1.2 pg/ml for the 77-year-old female (a); 13.9 ± 4.1 pg/ml for the 50-year-old female (b); 7.8 ± 2.1 pg/ml for the 66-year-old male (c); and 61.6 ± 7.6 pg/ml for the 82-year-old female (d). (f) Thirteen OA articular cartilage explants were cultured with (10 pg/ml PGE2) or without (control) for 16 days and collagen cleavage was evaluated by the accumulation of C1,2C neoepitope in the medium and chymotrypsin-derived cartilage extracts. (g) The relationship between PGE2 concentration and collagen cleavage in 16 OA explants that served as controls. Significant differences from the control (P < 0.05) are indicated by asterisks.
Figure 2
Figure 2
Prostaglandin E2 (PGE2) does not affect total proteoglycan release. (a–d) Percentage release of total proteoglycan (glycosaminoglycan (GAG) release) was measured in conditioned media of human osteoarthritic cartilage explants cultured with 5 ng/ml transforming growth factor-β2 or PGE2 at concentrations from 1 pg/ml to 10 ng/ml. The age and sex of each patient are indicated. Significant differences from controls (P < 0.05) are indicated by asterisks.
Figure 3
Figure 3
PGE2 downregulates the expression of genes responsible for collagen cleavage, chondrocyte hypertrophy and inflammation. Relative expression with reference to glyceraldehyde-3-phosphate dehydrogenase is shown compared with controls for genes in osteoarthritic cartilages determined by real-time PCR analyses in explant cultures at 24 hours cultured in the presence or absence (control) of 10 pg/ml prostaglandin E2 (PGE2). Control bars are shown as 1.0 as required for relative quantification with the real-time PCR protocol. Means ± SD for all five patients (a–e) are shown in (f). Asterisks indicate significant differences from the control (P < 0.05). The age and sex of each patient are indicated. The average levels of PGE2 in the medium in the gene expression studies were as follows: 62.3 ± 6.1 pg/ml for the 66-year-old female (a); 7.2 ± 1.9 pg/ml for the 53-year-old female (b); 0 pg/ml for the 67-year-old female (c); 65.7 ± 7.3 pg/ml for the 90-year-old female (d); and 30.4 ± 7.6 pg/ml for the 82-year-old female (e).
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