The impairment of the pSmad1/5/8-HDAC1-Smad4 complex causes the induction of PUMA and the accumulation of Puma, activating the Puma downstream events, including the release of cytochrome c from the mitochondria and the activation of Apaf-1, Caspase-9, and Caspase-3, eventually leading to the pathogenesis of IDD (Figure 8). Here, CASP9 is linked to intervertebral disk degenerative disorder.