Thursday, January 14, 2010


The modulation of the oxidative stress response in chondrocytes by Wip1 and its effect on senescence and dedifferentiation during in vitro expansion.

"Rapid senescence or dedifferentiation during in vitro expansion results in loss of chondrocyte phenotype and the formation of fibrous cartilage replacement tissue, rather than hyaluronic cartilage, after transplantation. Wild-type p53-inducible phosphatase (Wip1), a well-established stress modulator, was highly expressed in early-passage chondrocytes, but declined rapidly during in vitro expansion. Stable Wip1-expressing chondrocytes generated by microporation were less susceptible to the onset of senescence and dedifferentiation, and were more resistant to oxidative stress. The increased resistance of Wip1 chondrocytes to oxidative stress was due to modulation of p38 mitogen-activated protein kinase (MAPK) activity. Importantly, chondrocytes expressing Wip1 maintained their innate chondrogenic properties for a longer period of time, resulting in improvements in cartilage regeneration after transplantation. Chondrocytes from Wip1 knockout (Wip1(-/-)) mice were defective in cartilage regeneration compared with those from wild-type mice."

Could upregulating Wip1 in GP chondrocytes be a way to grow taller?

"Antioxidants such as N-acetyl cysteine (NAC) and ascorbic acid delay chondrocyte senescence and degeneration by attenuating ROS insult"

"Low oxygen tension protects cells from the onset of senescence. Oxidative stress in chondrocytes induces telomere genomic instability, expression of matrix metalloproteinases (MMPs), and downregulation of Sirt1, a mammalian Sir2 ortholog, through p38 MAPK activation"

"Wip1 is encoded by PPM1D (for protein phosphatase 1D Mg2+-dependent, delta isoform) and is a type 2C protein phosphatase (PP2C). A number of stress mediators such as p53, p38, Chk1/2, ATM, and γ-H2AX are dephosphorylated and inactivated by Wip1. "

"late-passage chondrocytes, defined as passage five chondrocytes (P5-Chon), showed morphological changes typical of cells undergoing senescence, including an enlarged nucleus and a flat, spread-out morphology"

"The expression of collagen II (Col II) and aggrecan (AGG) was markedly suppressed in P5-Chon compared with that in control cells, while the expression of collagen X (Col X) was highly increased"

"Levels of mitochondrial ROS were higher in P5-Chon. Telomere length in P5-Chon was unaltered"

"To mimic this stressful environment, chondrocytes were exposed to hydrogen peroxide (H2O2) to induce acute oxidative stress in the presence or absence of β-mercaptoethanol (BME), a strong reducing agent that is used to assess the specific effects of H2O2-induced oxidative injury. Exposure to H2O2 markedly increased SA-β-gal activity in chondrocytes, and this effect was highly attenuated by supplementation with BME"

" In both early- and late-passage chondrocytes (P2- and P8-Chon), supplementation with BME significantly reduced the number of SA-β-gal positive cells. Furthermore, Col X expression decreased whereas Col II expression increased"

"The area of cartilage tissue in Wip1−/− mice was approximately 1.68-fold lower (0.16 ± 0.0034 mm2) than that in wild-type mice (0.27 ± 0.0032 mm2). The cartilage tissue from Wip1−/− mice was also much thinner than that from wild-type mice (86.75 ± 9.3913 μm vs 119.49 ± 3.8486 μm)."

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