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The Effect of Prostaglandin E₂ on Costochondral Chondrocyte Differentiation Is Mediated by Cyclic Adenosine 3',5'-Monophosphate and Protein Kinase C¹

Departments of Periodontics (Z.S., R.M.G., B.D.B.), Orthopedics (Z.S., V.L.S., D.D.D., B.D.B.), and Biochemistry (B.D.B.), University of Texas Health Science Center, San Antonio, Texas 78284; Hebrew University (Z.S.), 91010 Jerusalem, Israel; and Lackland Air Force Base (R.M.G.), San Antonio, Texas 78246

Address all correspondence and requests for reprints to: Barbara D. Boyan, Ph.D., Department of Orthopedics, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7774. E-mail: messier{at}uthscsa.edu

Recent studies indicate that vitamin D metabolites exert rapid effects on growth plate chondrocytes via changes in PG production and protein kinase C (PKC) activity. This suggests that these two products of vitamin D action may be interrelated. To test this hypothesis, we examined the effect of PGE₂ on rat costochondral resting zone and growth zone cartilage cells and determined whether the effects of PGE₂ are mediated by changes in the level of cAMP and/or PKC activity, whether there is a relationship between cAMP production and PKC activity, and whether cell maturation-specific effects are involved. Confluent, fourth passage resting zone and growth zone cartilage cell cultures were incubated in DMEM containing 10% FBS, 50 µg/ml vitamin C, and 1% antibiotics. The PGE₂ concentration was varied from 0.007–15 ng/ml. Low concentrations of PGE₂ caused a dose-dependent increase in cell number and [³H]thymidine incorporation and stimulated alkaline phosphatase specific activity. These effects were comparable in resting zone and growth zone cartilage cells at the same PGE₂ concentrations. At higher concentrations, PGE₂ caused a general increase in the synthesis of collagenase-digestible protein and noncollagenase-digestible protein in resting zone cartilage cells and of collagenase-digestible protein in growth zone cartilage cells, resulting in a net increase in the percent collagen synthesis for both cell types. cAMP production was increased over the entire range of chondrocyte response. Prevention of cAMP metabolism with the protein kinase A inhibitors H-8 and H-89 blocked the PGE₂-dependent inhibition of PKC in resting zone cartilage cells in a dose-dependent manner. H-8 alone had no effect on PKC in resting zone cartilage cells, but stimulated PKC activity in growth zone cartilage cells; H-89 alone stimulated PKC activity in resting zone cartilage cells. These results suggest that low levels of PGE₂ promote differentiation, whereas high doses promote an anabolic response; PGE₂ increases cAMP production and PKC activity in a cell maturation-dependent manner; PGE₂ exerts its effects via cAMP production and PKC activity; and regulation of PGE₂-dependent PKC is via cAMP.

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