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[摘要]：Mutations in the cartilage oligomeric matrix protein gene (COMP) cause pseudoachondroplasia (PSACH). This dysplasia results from the intracellular retention of mutant COMP protein and premature death of growth-plate chondrocytes. Toward better understanding of these underlying mechanisms, we examined D469de1-COMP activation of the unfolded protein response and cell death pathways in rat chondrosarcoma cells. Using an inducible expression system, we examined the effects of D469de1-COMP retention after 4 days of mRNA expression and then 5 days without inducing agent. Retention of D469de1-COMP stimulated Chop (Ddit3) and Gadd34 (Ppp1rl5a) and triggered reactivation of protein translation that exacerbated intracellular retention. High levels of Nox4 and endoplasmic reticulum receptor stress-inducible Ero1 beta generated reactive oxygen species, causing oxidative stress. Increased expression of Gadd genes and presence of gamma H2AX indicated that DNA damage was occurring. The presence of cleaved apoptosis inducing factor (tAIF) and the absence of activated caspases indicated that retention of D469de1-COMP triggers cell death in chondrocytes by necroptosis, a caspase-independent programmed necrosis. Loss of growth-plate chondrocytes by necroptosis was also found in our pseudoachondroplasia mouse model. These results suggest a model in which D469de1-COMP expression induces persistent endoplasmic reticulum stress, oxidative stress, and DNA damage, thus priming chondrocytes for necroptosis. We define for the first time the precise mechanisms underlying D469de1-COMP pathology in pseudoachondroplasia and suggest that oxidative stress and ALF may be promising therapeutic targets. (Am J Pathol 2012, 180:738-748; DOI: 10.1016/j.ajpath.2011.10.033) |
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