Dysfunction of Collagen Synthesis and Secretion in Chondrocytes Induced byWisp3Mutation

Abstract

Wisp3gene mutation was shown to cause spondyloepiphyseal dysplasia tarda with progressive arthropathy (SRDT-PA), but the underlying mechanism is not clear. To clarify this mechanism, we constructed the wild and mutatedWisp3expression vectors and transfected into human chondrocytes lines C-20/A4;Wisp3proteins subcellular localization, cell proliferation, cell apoptosis, andWisp3-mediated gene expression were determined, and dynamic secretion of collagen in transfected chondrocytes was analyzed by14C-proline incorporation experiment. MutatedWisp3protein increased proliferation activity, decreased apoptosis of C-20/A4 cells, and aggregated abnormally in cytoplasm. Expression of collagen II was also downregulated in C-20/A4 cells transfected with mutatedWisp3. Wild typeWisp3transfection increased intracellular collagen content and extracellular collagen secretion, but the mutatedWisp3lost this function, and the peak phase of collagen secretion was delayed in mutatedWisp3transfected cells. Thus abnormal protein distribution, cell proliferation, collagen synthesis, and secretion inWisp3mutated chondrocytes might contribute to the pathogenesis of SEDT-PA.