Journal
FASEB JOURNAL
Volume 27, Issue 12, Pages 4664-4677Publisher
WILEY
DOI: 10.1096/fj.13-234542
Keywords
PGE(2); 15d-PGJ(2); inflammation; apoptosis; chondrocytes
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Funding
- U.S. National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [RO1 (AR053358)]
- Fundamental Research Funds of China [N120520001, N120320001]
- Liaoning Province High School Talent Support Program of China [LJQ2013029]
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The mechanical overloading of cartilage is involved in the pathophysiology of osteoarthritis (OA) by both biochemical and mechanical pathways. The application of fluid shear stress to chondrocytes recapitulates the earmarks of OA, as evidenced by the release of proinflammatory cytokines (PICs), matrix metalloproteinases (MMPs), and apoptotic factors. Dysregulations or mutations in these genes might directly cause OA in addition to determining the stage at which OA becomes apparent, the joint sites involved, and the severity of the disease and how rapidly it progresses. However, the underlying mechanisms remain unknown. In this review, we propose that the dysregulation of cyclooxygenase-2 (COX-2) is associated with fluid shear stress-induced OA via its metabolic products at different stages of the disease. Indeed, high fluid shear stress rapidly induces the production of PICs and MMPs via COX-2-derived prostaglandin (PG)E-2 at the early stage of OA. In contrast, prolonged shear exposure (>12 h) aggravates the condition by concurrently up-regulating the expression of proapoptotic genes and down-regulating the expression of antiapoptotic genes in a 15-deoxy-Delta (12,14)-prostaglandin J(2) (15d-PGJ(2))-dependent manner at the late stage of disease. These observations may help to resolve long-standing questions in OA progression and provide insight for development of strategies to treat and combat OA.
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