Open AccessPerturbation of nuclear lamin A causes cell death in chondrocytes
Author(s) -
Attur Mukundan,
BenArtzi Ami,
Yang Qing,
AlMussawir Hayf E.,
Worman Howard J.,
Palmer Glyn,
Abramson Steven B.
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.34360
Subject(s) - lamin , chondrocyte , apoptosis , biology , microbiology and biotechnology , western blot , nuclear lamina , blot , lmna , cartilage , chemistry , gene , nuclear protein , genetics , transcription factor , anatomy , nucleus
Objective Mutations in LMNA encoding the A‐type lamins cause several diseases, including those with features of premature aging and skeletal abnormalities. The aim of this study was to examine the expression of lamin A in cartilage from patients with osteoarthritis (OA) and the effects of its overexpression on chondrocyte senescence and apoptosis. Methods Human chondrocyte‐like cells (SW‐1353) were used. RNA isolated from human OA and non‐OA cartilage was used for profiling messenger RNA expression, using Affymetrix microarray analysis. The effects of lamin A overexpression on mitochondrial function and apoptosis were examined by assessing mitochondrial membrane potential, ATP levels, and cytochrome c release, and with a TUNEL assay. Western blotting was performed to determine protein expression. Results Lamin A expression was markedly elevated in OA cartilage samples compared with non‐OA control samples. Western blot analysis confirmed increased expression of lamin A in OA compared with non‐OA cartilage. Interleukin‐1β treatment inhibited lamin A accumulation, whereas treatment with prostaglandin E 2 (PGE 2 ) caused a marked increase in lamin A accumulation. These effects of exogenous PGE 2 on lamin A expression were mediated via the EP 2 /EP 4 receptors. Transfected chondrocytes that expressed lamin A displayed markers of early senescence/apoptosis. Conclusion The results of this study suggest that lamin A is up‐regulated in OA chondrocytes, and that increased nuclear accumulation of lamin A in response to catabolic stress may account for the premature aging phenotype and apoptosis of OA chondrocytes.