Inhibition of caspase-9 reduces chondrocyte apoptosis and proteoglycan loss following mechanical trauma.
Abstract: Chondrocyte death, a notable feature of osteoarthritis, may play a role in the initiation of cartilage degeneration. The present study was aimed at uncovering the nature and involvement of cell death in the initiation of cartilage degeneration induced by mechanical trauma. Methods: Articular cartilage discs obtained from healthy skeletally mature horses were subjected to a single-impact load (500 g from 50 mm) using a simple drop-tower device and cultured in vitro for 48 h. Chondrocyte death was examined using two independent methods: transmission electron microscopy and caspase-3 activity assay. To elucidate the signalling mechanisms involved in impact-induced cell death measured by terminal deoxynucleotidyl transferase-deoxyuridine triphosphate (dUTP) nick-end labelling (TUNEL), cartilage discs were incubated with specific caspase-3, -8 and -9 inhibitors prior to impact. Additionally, weight gain and glycosaminoglycan (GAG) release, markers of cartilage degeneration were monitored. Results: After 48 h, ultrastructural evidence of apoptosis was observed. Caspase-3 was activated after 12h of culture post-impact. When quantified by TUNEL, impact trauma induced death in 52.6% of superficial chondrocytes after 48 h in culture, compared to 4.2% in unimpacted controls. Specific caspases-3 and -9 inhibitors significantly reduced impact-induced apoptosis to 24.3% and 14.7%, respectively. Caspase-8 inhibition had no effect on chondrocyte death (60.3%). Impact-induced GAG release into the medium was significantly reduced by inhibition of cell death, but weight gain remained unaffected by caspase inhibition. Conclusions: These results suggest that impact trauma-induced chondrocyte death is predominantly due to caspase-9-dependent apoptosis and is linked to cartilage degeneration.
Publication Date: 2006-05-12 PubMed ID: 16698290DOI: 10.1016/j.joca.2006.03.012Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research study examined osteoarthritis, whereby chondrocyte cell death may trigger cartilage degeneration. The findings suggest that impact trauma-induced chondrocyte death predominantly occurs due to caspase-9-dependent apoptosis and this is associated with cartilage degeneration.
Objectives and Methodology of the Study
- The study aimed at understanding the relationship between cell death and the onset of cartilage degeneration, specifically as caused by mechanical trauma.
- The researchers utilized articular cartilage discs from healthy, skeletally mature horses and subjected them to a single impact load using a drop-tower device, followed by in vitro culture for 48 hours.
- Chondrocyte death was studied using transmission electron microscopy and a caspase-3 activity assay.
- In order to decipher the signaling mechanisms involved in impact-induced cell death, specific caspase-3, -8 and -9 inhibitors were applied prior to impact.
- The signs of cartilage degeneration, such as weight gain and glycosaminoglycan (GAG) release, were monitored throughout the study.
Key Findings of the Study
- After 48 hours, signs of apoptosis were noted at the cell’s ultrastructural level and caspase-3 was found to be activated 12 hours after the post-impact culture.
- When quantified by TUNEL, a method for detecting DNA fragmentation resulting from apoptotic signaling cascades, it was found that impact trauma led to the death of 52.6% of superficial chondrocytes after 48 hours in culture.
- Specific inhibition of caspases-3 and -9 significantly brought down the rate of impact-induced apoptosis to 24.3% and 14.7%, respectively, while inhibition of caspase-8 did not have a significant effect on cell death.
- Impact-induced GAG release into the medium was significantly decreased by inhibiting cell death, although weight gain was not affected by caspase inhibition.
Conclusions Drawn from the Study
- The study’s results suggest that chondrocyte death induced by impact trauma is predominantly caspase-9-dependent and this apoptosis is associated with degeneration of cartilage.
- Thus, the observed involvement of caspase-9 in chondrocyte apoptosis and consequent cartilage degeneration offers new insights for understanding and potentially treating diseases like osteoarthritis.
Cite This Article
APA
Huser CA, Peacock M, Davies ME.
(2006).
Inhibition of caspase-9 reduces chondrocyte apoptosis and proteoglycan loss following mechanical trauma.
Osteoarthritis Cartilage, 14(10), 1002-1010.
https://doi.org/10.1016/j.joca.2006.03.012 Publication
Researcher Affiliations
- Comparative Orthopaedics Research Group, University of Cambridge, UK. ch353@cam.ac.uk
MeSH Terms
- Animals
- Apoptosis
- Cartilage, Articular / injuries
- Cartilage, Articular / pathology
- Caspase 3 / metabolism
- Caspase 8 / metabolism
- Caspase 9 / metabolism
- Caspases / metabolism
- Chondrocytes / metabolism
- Chondrocytes / pathology
- Glycosaminoglycans / metabolism
- Horses
- In Situ Nick-End Labeling
- Microscopy, Electron, Transmission
- Proteoglycans / metabolism
- Weight Gain
Citations
This article has been cited 18 times.- Jones RC, Lawrence KM, Higgins SM, Richardson SM, Townsend PA. Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1. Int J Mol Sci 2022 May 4;23(9).
- Ramesova A, Vesela B, Svandova E, Lesot H, Matalova E. Caspase-1 Inhibition Impacts the Formation of Chondrogenic Nodules, and the Expression of Markers Related to Osteogenic Differentiation and Lipid Metabolism. Int J Mol Sci 2021 Sep 3;22(17).
- Huang HT, Cheng TL, Ho CJ, Huang HH, Lu CC, Chuang SC, Li JY, Lee TC, Chen ST, Lin YS, Lee CY, Kang L, Lin SY, Chen CH. Intra-Articular Injection of (-)-Epigallocatechin 3-Gallate to Attenuate Articular Cartilage Degeneration by Enhancing Autophagy in a Post-Traumatic Osteoarthritis Rat Model. Antioxidants (Basel) 2020 Dec 23;10(1).
- Delco ML, Bonnevie ED, Szeto HS, Bonassar LJ, Fortier LA. Mitoprotective therapy preserves chondrocyte viability and prevents cartilage degeneration in an ex vivo model of posttraumatic osteoarthritis. J Orthop Res 2018 Feb 22;.
- Huang Y, Zhou J, Hakamivala A, Wu J, Hong Y, Borrelli J, Tang L. An optical probe for detecting chondrocyte apoptosis in response to mechanical injury. Sci Rep 2017 Sep 7;7(1):10906.
- Delco ML, Bonnevie ED, Bonassar LJ, Fortier LA. Mitochondrial dysfunction is an acute response of articular chondrocytes to mechanical injury. J Orthop Res 2018 Feb;36(2):739-750.
- Izawa T, Mori H, Shinohara T, Mino-Oka A, Hutami IR, Iwasa A, Tanaka E. Rebamipide Attenuates Mandibular Condylar Degeneration in a Murine Model of TMJ-OA by Mediating a Chondroprotective Effect and by Downregulating RANKL-Mediated Osteoclastogenesis. PLoS One 2016;11(4):e0154107.
- Davis CG, Eisner E, McGlynn M, Shelton JM, Richardson J, Borrelli J Jr, Chen CC. Posttraumatic Chondrocyte Apoptosis in the Murine Xiphoid. Cartilage 2013 Oct;4(4):345-53.
- Chubinskaya S, Wimmer MA. Key Pathways to Prevent Posttraumatic Arthritis for Future Molecule-Based Therapy. Cartilage 2013 Jul;4(3 Suppl):13S-21S.
- Singh JA. Stem cells and other innovative intra-articular therapies for osteoarthritis: what does the future hold?. BMC Med 2012 May 2;10:44.
- Kramer WC, Hendricks KJ, Wang J. Pathogenetic mechanisms of posttraumatic osteoarthritis: opportunities for early intervention. Int J Clin Exp Med 2011;4(4):285-98.
- Drewniak EI, Jay GD, Fleming BC, Zhang L, Warman ML, Crisco JJ. Cyclic loading increases friction and changes cartilage surface integrity in lubricin-mutant mouse knees. Arthritis Rheum 2012 Feb;64(2):465-73.
- Blanco FJ, Rego I, Ruiz-Romero C. The role of mitochondria in osteoarthritis. Nat Rev Rheumatol 2011 Mar;7(3):161-9.
- Lotz MK, Kraus VB. New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res Ther 2010;12(3):211.
- Nakachi N, Asoh S, Watanabe N, Mori T, Matsushita T, Takai S, Ohta S. Transduction of anti-cell death protein FNK suppresses graft degeneration after autologous cylindrical osteochondral transplantation. J Histochem Cytochem 2009 Mar;57(3):197-206.
- Henson FM, Vincent TA. Alterations in the vimentin cytoskeleton in response to single impact load in an in vitro model of cartilage damage in the rat. BMC Musculoskelet Disord 2008 Jun 24;9:94.
- Del Carlo M Jr, Loeser RF. Cell death in osteoarthritis. Curr Rheumatol Rep 2008 Jan;10(1):37-42.
- Haschtmann D, Stoyanov JV, Gédet P, Ferguson SJ. Vertebral endplate trauma induces disc cell apoptosis and promotes organ degeneration in vitro. Eur Spine J 2008 Feb;17(2):289-99.
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