Perturbation of nuclear lamin A causes cell death in chondrocytes.

Abstract

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.

• Authors: Mukundan Attur, Ami Ben-Artzi, Qing Yang, Hayf E Al-Mussawir, Howard J Worman, Glyn Palmer, Steven B Abramson
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 64 Issue 6 Pg. 1940-9 (Jun 2012) ISSN: 1529-0131 [Electronic] United States
• PMID: 22231515 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 by the American College of Rheumatology.

Chemical References

• Interleukin-1beta
• Lamin Type A
• Dinoprostone

Topics

• Aged
• Aged, 80 and over
• Apoptosis (drug effects, physiology)
• Cartilage, Articular (drug effects, metabolism)
• Chondrocytes (drug effects, metabolism)
• Dinoprostone (pharmacology)
• Female
• Humans
• Interleukin-1beta (pharmacology)
• Lamin Type A (genetics, metabolism)
• Male
• Middle Aged
• Osteoarthritis, Knee (genetics, metabolism)