This study sought to examine the expression of genes implicated in phosphate transport and pathological calcification in osteoarthritis (OA) and rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and investigate the biological effects of phosphate. Results revealed that several genes, which were implicated in phosphate transport and pathological calcification, were differentially expressed in OA FLS and RA FLS. Phosphate stimulated the expression of matrix metalloproteinse-1, matrix metalloproteinse-3, cyclooxygenase-2, and interleukin-1β in a dose-dependent manner. Phosphate also induced OA FLS cell death but not RA FLS cell death at higher concentration. Calcification inhibitors, phosphocitrate (PC), and ethane-1-hydroxy-1,1-diphosphonate (EHDP), effectively inhibited these detrimental biological effects of phosphate. These findings suggest that abnormal expression of genes implicated in phosphate transport and pathological calcification may contribute to the progression of OA through the induction of extracellular matrix-degrading enzymes, proinflammatory cytokines, cell death, and calcium deposits. Calcification inhibitors such as PC and EHDP are potent inhibitors of these detrimental biological effects of phosphate. 1. Introduction Osteoarthritis (OA) is characterized by the degeneration of articular cartilage. Although the precise biochemical events that initiates OA are not well understood, many risk or contributory factors have been identified including aging, obesity, and pathological calcification. Basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPPD) crystals are the two most common forms of articular calcium phosphate crystals. These crystals are found in the synovial fluid of the patients with OA, and their presence in the synovial fluid correlates with the radiographic evidence of cartilaginous degeneration [1–3]. Calcium phosphate crystals were also found in the synovial fluid of up to 26% of the patients with rheumatoid arthritis (RA), and a worse clinical outcome was associated with the presence of these crystals [4]. BCP and CPPD crystals stimulate the expression of matrix metalloproteinases (MMPs), mitogenesis, and endocytotic activity of cells in monolayer culture [5, 6]. These crystals may also alter the biomechanical properties of menisci and articular cartilage [7]. Recently, Cheung et al. demonstrated that calcium phosphocitrate (CaPC), a potent calcification inhibitor, reduced the degeneration of articular cartilage in Hartley guinea pig [8]. Their study has provided support for the hypothesis that
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