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An Autocrine or Paracrine Fas-Mediated Counterattack: A Potential Mechanism for Apoptosis of Notochordal Cells in Intact Rat Nucleus Pulposus

Study Design. Immunohistochemistry and in situ nick end-labeling (TUNEL) were performed in rat lumbar intervertebral discs. Objectives. To demonstrate the mechanism of notochordal cell death in the nucleus pulposus (NP). Summary of Background Data. With age, notochordal cells gradually disappear in the NP. We hypothesized that this phenomenon might be related to Fas-mediated apoptosis. Materials and Methods. Expressions of Fas; Fas ligand (FasL); caspase 3, 8, 9, 10; Ki-67 protein; and TUNEL were examined in 4-week-, 6-month- and 12-month-old rat NPs. Apoptosis (TUNEL-positive) and proliferation potential (Ki-67-positive) indexes of notochordal cells were calculated and compared among age groups. Results. Notochordal cells constitutively expressed both Fas and FasL. Among their downstream initiator (caspase 8, 9, and 10) and executioner (caspase 3) caspases tested, caspase 9 and 3 were expressed. Proliferation potential of the notochordal cells was the highest at 4 weeks (1.96 ± 1.3%) and decreased to a significantly lower level at 6 (0.81 ± 0.68%) and 12 months (0.8 ± 0.37%; P = 0.03 and 0.01, respectively). In contrast, apoptosis of the notochordal cells was the lowest at 4 weeks (3.52 ± 1.07%) and increased to a significantly higher level at 6 (19.38 ± 10.99%) and 12 months (21.51 ± 16.99%; P < 0.001 in both comparisons). Conclusions. Fas-mediated mitochondrial caspase 9 pathway is constitutively present in the rat notochordal cells. The constitutive expression of Fas, FasL and its downstream caspases, as well as the homogeneity ofnotochordal cell population suggests an autocrine or paracrine Fas-mediated counterattack to be a potential mechanism for apoptosis of rat notochordal cells. A regulated negative balance of notochordal cell proliferation against apoptosis is likely to involve the disappearance of notochordal cells in the rat NP. This information on the mechanism for apoptosis of notochordal cells could be important in the investigation of intervertebral disc development as well as aging and perhaps degeneration.