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Modulation of transforming growth factor beta signalling pathway genes by transforming growth factor beta in human osteoarthritic chondrocytes: involvement of Sp1 in both early and late response cells to transforming growth factor beta

Transforming growth factor beta (TGF$\beta$) plays a central role in morphogenesis, growth, and cell differentiation. This cytokine is particularly important in cartilage where it regulates cell proliferation and extracellular matrix synthesis. While the action of TGF$\beta$ on chondrocyte metabolism has been extensively catalogued, the modulation of specific genes that function as mediators of TGF$\beta$ signalling is poorly defined. In the current study, elements of the Smad component of the TGF$\beta$ intracellular signalling system and TGF$\beta$ receptors were characterised in human chondrocytes upon TGF$\beta$1 treatment. Human articular chondrocytes were incubated with TGF$\beta$1. Then, mRNA and protein levels of TGF$\beta$ receptors and Smads were analysed by RT-PCR and western blot analysis. The role of specific protein 1 (Sp1) was investigated by gain and loss of function (inhibitor, siRNA, expression vector). We showed that TGF$\beta$1 regulates mRNA levels of its own receptors, and of Smad3 and Smad7. It modulates TGF$\beta$ receptors post-transcriptionally by affecting their mRNA stability, but does not change the Smad-3 and Smad-7 mRNA half-life span, suggesting a potential transcriptional effect on these genes. Moreover, the transcriptional factor Sp1, which is downregulated by TGF$\beta$1, is involved in the repression of both TGF$\beta$ receptors but not in the modulation of Smad3 and Smad7. Interestingly, Sp1 ectopic expression permitted also to maintain a similar expression pattern to early response to TGF$\beta$ at 24 hours of treatment. It restored the induction of Sox9 and COL2A1 and blocked the late response (repression of aggrecan, induction of COL1A1 and COL10A1). These data help to better understand the negative feedback loop in the TGF$\beta$ signalling system, and enlighten an interesting role of Sp1 to regulate TGF$\beta$ response.

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