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[摘要]：Cartilage oligomeric matrix protein (COMP), a secreted glycoprotein synthesized by chondrocytes, regulates proliferation and type II collagen assembly. Mutations in the COMP gene cause pseudoachondroplasia and multiple epiphyseal dysplasia. Previously, we have shown that expression of D469de1-COMP in transgenic mice causes intracellular retention of D469de1-COMP, thereby recapitulating pseudoachondroplasia chondrocyte pathology. This inducible transgenic D469de1-COMP mouse is the only in vivo model to replicate the critical cellular and clinical features of pseudoachondroplasia. Here, we report developmental studies of D469de1-COMP-induced chondrocyte pathology from the prenatal period to adolescence. D469de1-COMP retention was limited prenatally and did not negatively affect the growth plate until 3 weeks after birth. Results of immunostaining, transcriptome analysis, and ciRT-PCR suggest a molecular model in which D469de1-COMP triggers apoptosis during the first postnatal week. By 3 weeks (when most chondrocytes are retaining D469de1-COMP), inflammation, oxidative stress, and DNA damage contribute to chondrocyte cell death by necroptosis. Importantly, by crossing the D469de1COMP mouse onto a Chop null background (Ddit3 null), thereby eliminating Chop, the unfolded protein response was disrupted, thus alleviating both D469de1-COMP intracellular retention and premature chondrocyte cell death. Chop therefore plays a significant role in processes that mediate D469del-COMP retention. Taken together, these results suggest that there may be an optimal window before the induction of significant D469de1-COMP retention during which endoplasmic reticulum stress could be targeted. (Anz J Pathol 2012, 180:727-737 DOI: 10.1016/j,ajpatb.2011.10.035) |
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