Apoptotic pathways in degenerative disk lesions in the wrist.
ABSTRACT Degenerative articular disk perforations of the triangular fibrocartilage (TFC) of the wrist could result from chronic loading of the ulnocarpal joint. Apoptosis played a crucial role in fibrocartilage cell loss, and the purpose of this study was to clarify which apoptotic pathway was involved in the development of degenerative disk lesions. We also investigated whether ulna length played an etiologic role in the occurrence of fibrocartilage cell loss.
Included in the study were 17 patients with degenerative articular disk tears of the TFC (Palmer type 2C). After arthroscopic debridement of the TFC, histologic sections were examined to assess the presence of apoptosis. Apoptosis was determined by use of caspase 3, caspase 8, and caspase 9 immunohistochemistry. Furthermore, Fas ligand and BID (BH3 interacting domain death) agonist were applied for immunohistochemical analysis.
Cells positive for caspase 3, caspase 8, caspase 9, Fas ligand, and BID were found in all specimens. The number of cells positive for caspase 3 and BID was significantly increased in specimens from patients with an ulna-positive variance. In contrast, for cells positive for caspase 8, caspase 9, and Fas ligand, no significant difference was found between specimens from patients with an ulna-positive variance and those from patients with an ulna-neutral/ulna-negative variance.
The extrinsic and intrinsic apoptotic pathways are involved in the development of degenerative disk lesions. Fibrocartilage cell loss occurs mainly through the intrinsic apoptotic pathway. The accumulation of apoptotic cells is not significantly different between the 3 zones of the TFC. It could be verified that ulna length is correlated with fibrocartilage cell loss.
Ulnar shortening is a valuable treatment option for degenerative TFC lesions. Knowledge of the specific apoptotic pathway that is causing degenerative disk lesions is critical in selecting the appropriate and most beneficial therapeutic treatment to halt further cell loss and the degeneration of the TFC.
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ABSTRACT: 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. 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. 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. The results of the present study suggest that human disc cells are Type-II cells, which undergo apoptotic cell death through mitochondrial involvement.The Journal of Bone and Joint Surgery 07/2005; 87(6):1338-42. · 3.23 Impact Factor
Article: Caspases and neuroprotection.[show abstract] [hide abstract]
ABSTRACT: Apoptotic cell death has been implicated in the pathogenesis of both acute and chronic neurodegenerative disorders. The caspase family of cysteine proteases are involved both in the initiation and final execution of apoptosis. Inhibition of the caspase family prevents cell death in a number of models of neurodegenerative cell death in vivo and in vitro. This sparing of neurons does not always correlate with long-term functional recovery, possibly due to the limitations of the available inhibitors. In this review, the evidence for a neuroprotective role of caspase inhibition in models of Parkinson's disease and cerebral ischemia is critically evaluated.Current opinion in investigational drugs (London, England: 2000) 01/2003; 3(12):1745-52. · 3.55 Impact Factor
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ABSTRACT: Eliciting tenderness in the region of the ulnar fovea is a possibly useful clinical test for defining the source of ulnar-sided wrist pain. Until now, no reports of the clinical sensitivity and specificity of this test have been available. Based on anecdotal observations, a hypothesis was developed stating that ulnar fovea tenderness (positive "ulnar fovea sign") is sensitive and specific in detecting two ulnar-sided wrist conditions: foveal disruption of the distal radioulnar ligaments and ulnotriquetral (UT) ligament injuries. The clinical records of 272 consecutive patients with wrist arthroscopy performed by the senior author from 1998 through to 2005 were reviewed. Relevant clinical and surgical data were abstracted. The ulnar fovea sign test is executed by pressing the examiner's thumb distally into the interval between the ulnar styloid process and flexor carpi ulnaris tendon, between the volar surface of the ulnar head and the pisiform. A positive ulnar fovea sign is designated when there is exquisite tenderness that the patient claims replicates their pain, with comparisons made with the contralateral side. There were a total of 90 foveal disruptions and 68 UT ligament injuries diagnosed during wrist arthroscopy. The ulnar fovea sign was positive in 156 patients. The sensitivity of the fovea sign in detecting foveal disruptions and/or UT ligament injuries was 95.2%. Its specificity was 86.5%. The hypothesis stating that the ulnar fovea sign is a useful clinical maneuver to detect foveal disruptions and UT ligament tears is supported. The conditions represent 2 common sources of ulnar-sided wrist pain. The differentiation between the 2 conditions may be made clinically, where UT ligament tears are typically associated with a stable distal radioulnar joint and foveal disruptions are typically associated with an unstable distal radioulnar joint. Diagnostic II.The Journal Of Hand Surgery 04/2007; 32(4):438-44. · 1.57 Impact Factor