**5. Conclusions**

To our knowledge, this is the first study that demonstrated a cytokine-dependent increase in the gene expression of TRPA1, TRPV2, and TRPV4 and a decrease in the gene expression of TRPC6 and TRPV1 in human IVD cells. Although TRPA1 and TRPV1 are commonly associated with inflammatory pain, their activation in inflamed IVD cells did not have profound pro-inflammatory and catabolic effects. Instead, TRPA1 expression and activation was associated with ECM metabolism. Future studies will use targeted gene editing techniques to elucidate the exact role of TRPA1/TRPV1 in DDD.

#### **Supplementary Materials:** Supplementary materials can be found at http://www.mdpi.com/1422-0067/20/7/ 1767/s1.

**Author Contributions:** T.K. performed cell culture experiments, calcium flux analysis and drafted part of the manuscript. J.Z. performed cell culture experiments. M.V. performed cell culture experiments. A.S. performed tissue analyses. W.K.T. and V.Y.L. performed and evaluated FAST staining. K.B. and Z.H. secured the mouse experiments. L.A.A. provided fetal IVD cell lysates. O.N.H. and J.K. provided human IVD samples and clinical expertise. O.K. performed cell culture experiments, supervised the study and drafted parts of the manuscript. K.W.-K. supervised the study and conceived funding. The authors declare no conflict of interest.

**Acknowledgments:** This study was funded by the Swiss National Science Foundation (SNF PP00P2\_163678/1), the Spine Society of Europe (Eurospine 2016\_4), and Hungarian grants GINOP-2.3.2.-15-2016-00048 "Stay Alive" and EFOP 3.6.2. "Live longer". We thank H. Greutert for technical assistance in the study.

**Conflicts of Interest:** The authors declare no conflict of interest.
