TGF-β Initiates β-Catenin-Mediated CTGF Secretory Pathway in Old Bovine Nucleus Pulposus Cells: A Potential Mechanism for Intervertebral Disc Degeneration.

We have recently demonstrated that overexpression of Smurf2 under the control of type II collagen alpha 1 () promoter induces an intervertebral disc degeneration phenotype in transgenic mice. The chondrocyte-like cells that express type II collagen and Smurf2 in the transgenic mouse discs are prone to degenerate. However, how the chondrocyte-like cells contribute to disc degeneration is not known. Here, we utilized primary old bovine nucleus pulposus (NP) cells as substitutes for the chondrocyte-like cells in transgenic mouse discs to identify mechanism. We found that 35% of the cells were senescent; TGF-β treatment of the cells induced a rapid moderate accumulation of β-catenin, which interacted with connective tissue growth factor (CTGF/CCN2) in the cytoplasm and recruited it to the membrane for secretion. The TGF-β-initiated β-catenin-mediated CTGF secretory cascade did not occur in primary young bovine NP cells; however, when Smurf2 was overexpressed in young bovine NP cells, the cells became senescent and allowed this cascade to occur. These results suggest that Smurf2-induced disc degeneration in transgenic mice occurs through activation of CTGF secretory pathway in senescent disc cells.