Background: TAR DNA-binding protein-43 (TDP-43, transactive response DNA binding protein 43 kDa) accumulates in the cytoplasm of affected neurons and glia, as large inclusions of stress granules (SGs). However, the mechanism of TDP-43 interaction with the target genes and its specific role in osteoarthritis (OA) progression is still unknown. The goal of this study was to identify the role of TDP-43 in OA progression by modulating its target genes. Methods: MSCs were transfected with TDP-43 gene lentivirus. The role of elevated TDP-43 expression in the differentiation of MSCs to chondrocytes was investigated. Cell function assay was used to evaluate the proliferation and apoptosis of Human chondrocytes (HCs) co-cultured with MSC. Truncated TDP-43/p35 expression and SGs formation in HCs were identified using cyto-immunofluorescence assay. Critical genes mediating apoptotic and proliferative signaling in HCs were measured using co-culturing MSC assays. The phosphorylation of key kinases was analyzed using the HTRF phosphokinase assay, and the expression of key genes in proliferative and apoptotic signaling transduction pathways was detected using qRT-PCR. Results: The MSCs differentiated into HCs after transfection of TDP-43 genes. The TDP-43 can degrade truncated TDP-43/p35, and promote SGs formation and HCs proliferation, and inhibit HCs apoptosis after co-culturing with MSCs. TDP-43 overexpression in MSCs promoted high expression of RACK1 and promoted phosphorylation of key kinases in HCs. Critical genes were highly expressed in P38 MAPK/MKK3 proliferative signaling, but not in P38 MAPK/JNK MAPK signaling. Conclusions: The chondrogenically differentiation of MSCs was not influenced by transfection of TDP-43 genes, and promoted HCs growth after co-culturing with HCs. The data indicated that TDP-43/p35 contributed to SGs formation by promoting RACK1 expression. The study sheds new light on post-transcriptional regulation and apoptosis in OA by RACK1, which is a potential treatment strategy for OA. (C) 2016 Elsevier Masson SAS. All rights reserved.