Prostaglandin E2 and its cognate EP receptors control human adult articular cartilage homeostasis and are linked to the pathophysiology of osteoarthritis.
OBJECTIVE
To elucidate the pathophysiologic links between prostaglandin E(2) (PGE(2)) and osteoarthritis (OA) by characterizing the catabolic effects of PGE(2) and its unique receptors in human adult articular chondrocytes.


METHODS
Human adult articular chondrocytes were cultured in monolayer or alginate beads with and without PGE(2) and/or agonists of EP receptors, antagonists of EP receptors, and cytokines. Cell survival, proliferation, and total proteoglycan synthesis and accumulation were measured in alginate beads. Chondrocyte-related gene expression and phosphatidylinositol 3-kinase/Akt signaling were assessed by real-time reverse transcription-polymerase chain reaction and Western blotting, respectively, using a monolayer cell culture model.


RESULTS
Stimulation of human articular chondrocytes with PGE(2) through the EP2 receptor suppressed proteoglycan accumulation and synthesis, suppressed aggrecan gene expression, did not appreciably affect expression of matrix-degrading enzymes, and decreased the type II collagen:type I collagen ratio. EP2 and EP4 receptors were expressed at higher levels in knee cartilage than in ankle cartilage and in a grade-dependent manner. PGE(2) titration combined with interleukin-1 (IL-1) synergistically accelerated expression of pain-associated molecules such as inducible nitric oxide synthase and IL-6. Finally, stimulation with exogenous PGE(2) or an EP2 receptor-specific agonist inhibited activation of Akt that was induced by insulin-like growth factor 1.


CONCLUSIONS
PGE(2) exerts an antianabolic effect on human adult articular cartilage in vitro, and EP2 and EP4 receptor antagonists may represent effective therapeutic agents for the treatment of OA.
Li
Xin
X
Rush University Medical Center, Chicago, Illinois.
Ellman
Michael
M
Muddasani
Prasuna
P
Wang
James H-C
JH
Cs-Szabo
Gabriella
G
van Wijnen
Andre J
AJ
Im
Hee-Jeong
HJ
D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D000843:Ankle Joint / Q000378:metabolism* / Q000473:pathology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002358:Cartilage, Articular / Q000187:drug effects* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000473:pathology; D024042:Collagen Type I / Q000378:metabolism; D024043:Collagen Type II / Q000378:metabolism; D015232:Dinoprostone / Q000819:agonists / Q000494:pharmacology*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011509:Proteoglycans / Q000096:biosynthesis; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013582:Synovial Fluid / Q000737:chemistry / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology
D053674:Aggrecans; D001713:Biphenyl Compounds; D024042:Collagen Type I; D024043:Collagen Type II; D007375:Interleukin-1; D011509:Proteoglycans; D018078:Receptors, Prostaglandin E; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; C046926:AH 23848; D019869:Phosphatidylinositol 3-Kinases; D015232:Dinoprostone