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Mitochondrial Involvement in Fas-Mediated Apoptosis of Human Lumbar Disc Cells
Jong-Beom Park, MD, PhD1; Jin-Kyung Lee, MD, PhD2; Sung-Jin Park, MD1; Ki-Won Kim, MD1; 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, Seoul 480-130, Korea. E-mail address for J.-B. Park: spinepjb@catholic.ac.kr
2 Department of Laboratory Medicine, Korea Institute of Radiological and Medical Science, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Korea
3 Cervical Spine Service, Department of Orthopaedic Surgery, Barnes-Jewish Hospital at Washington University School of Medicine, Suite 11300 West Pavilion, St. Louis, MO 63110
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Investigation performed at The Catholic University of Korea School of Medicine, Seoul, Korea

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2005 Jun 01;87(6):1338-1342. doi: 10.2106/JBJS.D.02527
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Abstract

Background: Two main pathways of Fas-mediated apoptosis have been identified: the Type-I (death-inducing signaling complex) pathway and the Type-II (mitochondrial) pathway. While apoptotic cell death has been implicated in lumbar degenerative disc disease, we are not aware of any studies in which surgically removed discs from live humans have been examined to determine which of the two pathways is involved in the apoptosis of disc cells. As an initial step in the development of therapies to inhibit inappropriate or premature apoptosis of disc cells, our objective was to determine which pathway is involved.

Methods: We examined thirty-two samples of herniated lumbar disc tissue with use of immunohistochemical staining and Western blot analysis to determine the presence of several proteins, including caspase-8 (associated with the Type-I pathway); BID (BH3 interacting domain death agonist), cytochrome-c, and caspase-9 (associated with the Type-II pathway); and caspase-3 (an executioner of apoptosis). The TUNEL (terminal deoxynucleotidyl transferase [TDT]-mediated dUTP nick end labeling) assay was performed to confirm the occurrence of apoptosis of the disc cells.

Results: The proteins associated with the Type-II pathway (BID, cytochrome-c, and caspase-9) stained positively in all samples. Although the protein associated with the Type-I pathway (caspase-8) was not detected on immunohistochemical analysis, a small amount of caspase-8 was detected on Western blot analysis. However, the expression of Type-II proteins was still higher than the expression of caspase-8 on Western blot analysis. The expression of caspase-3 was identified in all samples with immunohistochemical and Western blot analysis. TUNEL-positive disc cells were identified in all samples.

Conclusions: The results of the present study suggest that human disc cells are Type-II cells, which undergo apoptotic cell death through mitochondrial involvement.

Clinical Relevance: Future therapeutic modalities to inhibit inappropriate or premature apoptotic cell death in degenerating discs should be directed to the mitochondrial pathway.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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