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Biochemical and Molecular Actions of Nutrients

Punica granatum L. Extract Inhibits IL-1ß–Induced Expression of Matrix Metalloproteinases by Inhibiting the Activation of MAP Kinases and NF-B in Human Chondrocytes In Vitro¹

Division of Rheumatic Diseases, Department of Medicine and ^* Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106

²To whom correspondence should be addressed. E-mail: txh5{at}case.edu.

Interleukin (IL)-1ß induces the expression of matrix metalloproteinases (MMPs) implicated in cartilage resorption and joint degradation in osteoarthritis (OA). Pomegranate fruit extract (PFE) was recently shown to exert anti-inflammatory effects in different disease models. However, no studies have been undertaken to investigate whether PFE constituents protect articular cartilage. In the present studies, OA chondrocytes or cartilage explants were pretreated with PFE and then stimulated with IL-1ß at different time points in vitro. The amounts of proteoglycan released were measured by a colorimetric assay. The expression of MMPs, phosphorylation of the inhibitor of B (IB) and mitogen-activated protein kinases (MAPKs) was determined by Western immunoblotting. Expression of mRNA was quantified by real-time PCR. MAPK enzyme activity was assayed by in vitro kinase assay. Activation of nuclear factor-B (NF-B) was determined by electrophoretic mobility shift assay. PFE inhibited the IL-1ß–induced proteoglycan breakdown in cartilage explants in vitro. At the cellular level, PFE (6.25–25 mg/L) inhibited the IL-1ß–induced expression of MMP-1, -3, and -13 protein in the medium (P < 0.05) and this was associated with the inhibition of mRNA expression. IL-1ß–induced phosphorylation of p38-MAPK, but not that of c-Jun-N-terminal kinase or extracellular regulated kinase, was most susceptible to inhibition by low doses of PFE, and the addition of PFE blocked the activity of p38-MAPK in a kinase activity assay. PFE also inhibited the IL-1ß–induced phosphorylation of IB and the DNA binding activity of the transcription factor NF-B in OA chondrocytes. Taken together, these novel results indicate that PFE or compounds derived from it may inhibit cartilage degradation in OA and may also be a useful nutritive supplement for maintaining joint integrity and function.

KEY WORDS: • osteoarthritis • pomegranate • signal transduction • cartilage

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