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J. Biol. Chem., Vol. 280, Issue 35, 31156-31165, September 2, 2005

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Multiple Signals Induce Endoplasmic Reticulum Stress in Both Primary and Immortalized Chondrocytes Resulting in Loss of Differentiation, Impaired Cell Growth, and Apoptosis^*

Ling Yang, Sara G. Carlson, Denise McBurney, and Walter E. Horton, Jr.¶

From the Department of Anatomy, Northeastern Ohio University College of Medicine, Rootstown, Ohio 44272 and The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195

The endoplasmic reticulum is the site of synthesis and folding of secretory proteins and is sensitive to changes in the internal and external environment of the cell. Both physiological and pathological conditions may perturb the function of the endoplasmic reticulum, resulting in endoplasmic reticulum stress. The chondrocyte is the only resident cell found in cartilage and is responsible for synthesis and turnover of the abundant extracellular matrix and may be sensitive to endoplasmic reticulum stress. Here we report that glucose withdrawal, tunicamycin, and thapsigargin induce up-regulation of GADD153 and caspase-12, two markers of endoplasmic reticulum stress, in both primary chondrocytes and a chondrocyte cell line. Other agents such as interleukin-1 or tumor necrosis factor induced a minimal or no induction of GADD153, respectively. The endoplasmic reticulum stress resulted in decreased chondrocyte growth based on cell counts, up-regulation of p21, and decreased PCNA expression. In addition, perturbation of endoplasmic reticulum function resulted in decreased accumulation of an Alcian Blue positive matrix by chondrocytes and decreased expression of type II collagen at the protein level. Further, quantitative real-time PCR was used to demonstrate a down-regulation of steady state mRNA levels coding for aggrecan, collagen II, and link protein in chondrocytes exposed to endoplasmic reticulum stress-inducing conditions. Ultimately, endoplasmic reticulum stress resulted in chondrocyte apoptosis, as evidenced by DNA fragmentation and annexin V staining. These findings have potentially important implications regarding consequences of endoplasmic reticulum stress in cartilage biology.

Received for publication, January 28, 2005 , and in revised form, June 21, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Anatomy, Northeastern Ohio University College of Medicine, 4209 State Route 44, Rootstown, OH 44272. Tel.: 330-325-6290; Fax: 330-325-5910; E-mail: wehj{at}neoucom.edu.

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