Perturbation of nuclear lamin A causes cell death in chondrocytes

New York University School of Medicine, New York, NY, USA.
Arthritis & Rheumatology (Impact Factor: 7.76). 06/2012; 64(6):1940-9. DOI: 10.1002/art.34360
Source: PubMed


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.
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.
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.
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.

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    • "Recently, increased accumulation of lamin A in osteoarthritis (OA) chondrocytes and cartilage (Ruiz-Romero et al., 2008; Attur et al., 2012) has been reported. OA is one of the most common skeletal disorders clinically manifested by joint pain, swelling and progressive loss of function. "
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    • "This phenotype is characterized by increased production of cytokines including IL-6 and IL-1, matrix metalloproteinases, and growth factors such as EGF with some features in common with the OA chondrocyte phenotype. Studies have shown increased expression of MMP-3 and MMP-13 in aged cartilage [118, 119] as well as age-related accumulation of collagen neoepitopes representing denatured or cleaved collagen [120, 121]. It was shown that increased MMPs mediate cartilage matrix damage during aging, and collagenases and cathepsin K were also implicated in this process recently [122]. "
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