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As transforming growth factor-beta-1 (TGF-\u03b21) 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 <jats:italic>Ank<\/jats:italic> expression by TGF-\u03b21. Chondrocytes were exposed to 10 ng\/mL of TGF-\u03b21, and <jats:italic>Ank<\/jats:italic> 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 <jats:italic>Ank<\/jats:italic> and <jats:italic>PC-1<\/jats:italic> in TGF-\u03b21-induced ePPi generation. Finally, selective kinase inhibitors and dominant-negative\/overexpression plasmid strategies were used to explore the contribution of several signaling pathways to <jats:italic>Ank<\/jats:italic> induction by TGF-\u03b21. TGF-\u03b21 strongly increased <jats:italic>Ank<\/jats:italic> expression at the mRNA and protein levels, as well as ePPi production. Using small interfering RNA technology, we showed that <jats:italic>Ank<\/jats:italic> contributed approximately 60% and <jats:italic>PC-1<\/jats:italic> nearly 20% to TGF-\u03b21-induced ePPi generation. Induction of <jats:italic>Ank<\/jats:italic> by TGF-\u03b21 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, G\u00f66976 (a Ca<jats:sup>2+<\/jats:sup>-dependent PKC inhibitor) diminished TGF-\u03b21-induced <jats:italic>Ank<\/jats:italic> expression by 60%, whereas a 10% inhibition was observed with rottlerin (a PKC\u03b4 inhibitor). These data suggest a regulatory role for calcium in TGF-\u03b21-induced <jats:italic>Ank<\/jats:italic> expression. Finally, we demonstrated that the stimulatory effect of TGF-\u03b21 on <jats:italic>Ank<\/jats:italic> 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-\u03b21 on Ank mRNA level. These data show that TGF-\u03b21 increases ePPi levels, mainly by the induction of the <jats:italic>Ank<\/jats:italic> gene, which requires activation of Ras, Raf-1, ERK, and Ca<jats:sup>2+<\/jats:sup>-dependent PKC pathways in chondrocytes.<\/jats:p>","DOI":"10.1186\/ar2330","type":"journal-article","created":{"date-parts":[[2007,11,22]],"date-time":"2007-11-22T19:13:30Z","timestamp":1195758810000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["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"],"prefix":"10.1186","volume":"9","author":[{"given":"Frederic","family":"Cailotto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Bianchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Sebillaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narayanan","family":"Venkatesan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Moulin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Yves","family":"Jouzeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Netter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2007,11,22]]},"reference":[{"key":"2181_CR1","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.jbspin.2004.12.010","volume":"72","author":"R Liu-Bryan","year":"2005","unstructured":"Liu-Bryan R, Liote F: Monosodium urate and calcium pyrophosphate dihydrate (CPPD) crystals, inflammation, and cellular signaling. 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