Perturbation of nuclear lamin A causes cell death in chondrocytes.
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.


CONCLUSIONS
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.
New York University School of Medicine, New York, NY, USA.
Mukundan
M
Attur
Ami
A
Ben-Artzi
Qing
Q
Yang
Hayf E
HE
Al-Mussawir
Howard J
HJ
Worman
Glyn
G
Palmer
Steven B
SB
Abramson
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000378:metabolism*
D053583:Interleukin-1beta; D034904:Lamin Type A; D015232:Dinoprostone