If this type of therapy is effective in larger animals then it could be used for extended periods due to the non-invasive patient-friendly characteristics of topical applications. In this study, recombinant lentiviruses encoding the elements necessary for expression of a COMP-specific shRNA were used to provide a continuous supply of shRNA for COMP-specific siRNA duplexes. Three cell types, COS-7, primary human chondrocytes and rat chondrosarcoma cells, were used to assay the effectiveness of various COMP-directed shRNAs. COS-7 cells were used to screen and assess the ability of individual shRNAs to reduce COMP expression. Primary human chondrocytes were used to demonstrate the effectiveness of shRNA against endogenously expressed COMP. RCS cells were used to assess the effect of shRNA targeted against human COMP in the presence of other ECM proteins. The results presented here indicate that shRNA directed at COMP reduces expression levels and the Paeonolide cellular phenotypes of rER retention, indicating potential therapeutic utility. PSACH is a severe dwarfing condition caused by mutations in COMP that specifically affects growth plate chondrocytes. These mutations Alibiflorin interfere with protein folding which initiates the ER stress response causing retention of COMP and other ECM proteins that assemble prematurely into ordered intracellular matrix. The massive intracellular retention of this matrix network causes chondrocyte death and results in diminished limb growth and joint abnormalities. The objective of this study was to determine whether suppression/reduction of COMP expression could resolve the cellular chondrocyte pathology. We show that COMP mRNA and protein levels can be significantly decreased by shRNAs directed against the COMP type 3 repeat domain. Specifically, shRNA 3B was effective at reducing endogenous and recombinant COMP expression and maintaining this reduction for up to ten weeks. The shRNAmediated reduction of MT-COMP expression prevented the development of the PSACH cellular phenotype as demonstrated by the absence of retained COMP and other ECM proteins.