Induction of bovine articular chondrocyte senescence with oxidized low-density lipoprotein through lectin-like oxidized low-density lipoprotein receptor 1

✍ Scribed by Satoshi Zushi; Masao Akagi; Hideki Kishimoto; Takeshi Teramura; Tatsuya Sawamura; Chiaki Hamanishi

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 254 KB
• Volume: 60
• Category: Article
• ISSN: 0004-3591
• DOI: 10.1002/art.24816

✦ Synopsis

Abstract

Objective

Findings of recent in vivo and in vitro studies suggest that oxidized low‐density lipoprotein (ox‐LDL) plays a role in the degeneration of cartilage. The purpose of this study was to determine whether ox‐LDL induces chondrocyte senescence through binding to lectin‐like ox‐LDL receptor 1 (LOX‐1).

Methods

The effects of ox‐LDL on senescence of cultured bovine articular chondrocytes (BACs) were investigated by observing senescence‐associated (SA) β‐galactosidase (β‐gal) activity, cell proliferation activity, and telomerase activity. Telomerase activity was measured after adding LY294002 (a specific inhibitor of phosphatidylinositol 3‐kinase [PI3K]) or after adding insulin‐like growth factor 1 (IGF‐1; an activator of PI3K) plus ox‐LDL to the culture medium to elucidate the involvement of the PI3K/Akt pathway. Immunoblot analysis was used to investigate whether ox‐LDL affects the phosphorylation of Akt. To ascertain whether these effects were attributable to ox‐LDL binding to LOX‐1, BACs were preincubated with TS‐20, an anti‐bovine LOX‐1 blocking antibody.

Results

The activity of SA β‐gal was increased and the incorporation of bromodeoxyuridine into BACs was decreased by ox‐LDL in a dose‐dependent manner. The telomerase activity of BACs was suppressed by the addition of ox‐LDL in a time‐ and dose‐dependent manner. LY294002 suppressed the telomerase activity of BACs, and IGF‐1 reversed the ox‐LDL–induced suppression of telomerase activity. In addition, ox‐LDL rapidly decreased the amount of phosphorylated Akt in BACs. Pretreatment of cultured BACs with TS‐20 recovered these effects.

Conclusion

These data show that ox‐LDL binding to LOX‐1 induces stress‐induced premature senescence of chondrocytes and results in suppression of telomerase activity by inactivating the PI3K/Akt pathway. Oxidized LDL may play an important role in the pathogenesis of osteoarthritis by inducing chondrocyte senescence.