The Journal of Bone and Joint Surgery (American). 2006;88:771-779.
doi:10.2106/JBJS.E.00762
© 2006 The Journal of Bone and Joint Surgery, Inc.
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Anti-Apoptotic Effects of Caspase Inhibitors on Rat Intervertebral Disc Cells

Jong-Beom Park, MD, PhD1, In-Chul Park, PhD2, Sung-Jin Park, MD1, Hyeon-Ok Jin, BS2, Jin-Kyung Lee, MD, PhD2 and K. Daniel Riew, MD3

1 Department of Orthopaedic Surgery, Uijongbu St. Mary's Hospital, The Catholic University of Korea School of Medicine, 65-1 Kumho-dong, Uijongbu-si, Kyunggi-do, 480-717, Republic of Korea. E-mail address for J.-B. Park: spinepjb{at}catholic.ac.kr
2 Department of Laboratory Medicine, Korea Institute of Radiological and Medical Science, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Republic of Korea
3 Department of Orthopaedic Surgery, Barnes-Jewish Hospital at Washington University School of Medicine, Suite 11300 West Pavilion, St. Louis, MO 63110

Investigation performed at The Catholic University of Korea School of Medicine, Seoul, Republic of Korea

In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from the Catholic Medical Center Research Foundation. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Background: Apoptosis is thought to be a critical component of disc degeneration. Two main pathways of Fas-mediated apoptosis have been identified: Type I, which is the death-inducing signaling complex pathway, and Type II, which is the mitochondrial pathway. The apoptotic pathway for anulus fibrosus cells, which is phenotypically different from that of nucleus pulposus cells, has not been elucidated to our knowledge. The ultimate initiators or executioners of apoptosis are caspases. There are also inhibitors of caspases, which have the potential of being used as anti-apoptotic therapeutic agents. We therefore undertook this study to determine (1) the apoptotic pathway of anulus fibrosus cells and (2) the anti-apoptotic potential of caspase inhibitors.

Methods: Rat anulus fibrosus cells were isolated, cultured, and placed in either 0% (apoptosis-promoting condition) or 10% (normal control) fetal bovine serum. We identified and quantified the presence of apoptotic cell death, caspase activities, and loss of mitochondrial membrane potential. In addition, we examined the cells for the expression of Fas, procaspases, and cytochrome-c. Finally, we analyzed the degree of anti-apoptotic effects of caspase inhibitors on the cells in 1% fetal bovine serum.

Results: The percentage of apoptosis and Fas expression in the cells incubated in 0% fetal bovine serum were increased compared with those in the cells incubated in 10% fetal bovine serum (both p < 0.001). Caspase-8, 9, and 3 activities were increased and expression of procaspases was decreased in the 0% fetal bovine serum compared with those in the 10% fetal bovine serum (all p < 0.001). In contrast, the loss of mitochondrial membrane potential and cytochrome-c release into the cytosol were unchanged in the 0% fetal bovine serum. Pancaspase and caspase-8 inhibitors reduced apoptotic cell death (p < 0.001 and p < 0.05, respectively), but caspase-9 inhibitor did not reduce apoptotic cell death.

Conclusions: Our results suggest that, unlike nucleus pulposus cells, anulus fibrosus cells are Fas Type-I cells, which undergo apoptosis through the death-inducing signaling complex. We also found that apoptosis of intervertebral disc cells can be attenuated by caspase inhibitors.

Clinical Relevance: Caspase inhibitors may play a therapeutic role in slowing disc degeneration that is due to inappropriate or excessive apoptosis of intervertebral disc cells.


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