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ANK is a multipass transmembrane protein transporter thought to play a role in the export of intracellular inorganic pyrophosphate and so to contribute to the pathophysiology of chondrocalcinosis. As transforming growth factor-beta-1 (TGF-β1) was shown to favor calcium pyrophosphate dihydrate deposition, we investigated the contribution of ANK to the production of extracellular inorganic pyrophosphate (ePPi) by chondrocytes and the signaling pathways involved in the regulation of  Ank  expression by TGF-β1. Chondrocytes were exposed to 10 ng/mL of TGF-β1, and  Ank  expression was measured by quantitative polymerase chain reaction and Western blot. ePPi was quantified in cell supernatants. RNA silencing was used to define the respective roles of  Ank  and  PC-1  in TGF-β1-induced ePPi generation. Finally, selective kinase inhibitors and dominant-negative/overexpression plasmid strategies were used to explore the contribution of several signaling pathways to  Ank  induction by TGF-β1. TGF-β1 strongly increased  Ank  expression at the mRNA and protein levels, as well as ePPi production. Using small interfering RNA technology, we showed that  Ank  contributed approximately 60% and  PC-1  nearly 20% to TGF-β1-induced ePPi generation. Induction of  Ank  by TGF-β1 required activation of the extracellular signal-regulated kinase (ERK) pathway but not of p38-mitogen-activated protein kinase or of protein kinase A. In line with the general protein kinase C (PKC) inhibitor calphostin C, Gö6976 (a Ca 2+ -dependent PKC inhibitor) diminished TGF-β1-induced  Ank  expression by 60%, whereas a 10% inhibition was observed with rottlerin (a PKCδ inhibitor). These data suggest a regulatory role for calcium in TGF-β1-induced  Ank  expression. Finally, we demonstrated that the stimulatory effect of TGF-β1 on  Ank  expression was inhibited by the suppression of the Ras/Raf-1 pathway, while being enhanced by their constitutive activation. Transient overexpression of Smad 7, an inhibitory Smad, failed to affect the inducing effect of TGF-β1 on Ank mRNA level. These data show that TGF-β1 increases ePPi levels, mainly by the induction of the  Ank  gene, which requires activation of Ras, Raf-1, ERK, and Ca 2+ -dependent PKC pathways in chondrocytes.

arthritis research and therapy

Inorganic pyrophosphate generation by transforming growth factor-beta-1 is mainly dependent on ANK induction by Ras/Raf-1/extracellular signal-regulated kinase pathways in chondrocytes