Fluid shear stress-induced osteoarthritis: roles of cyclooxygenase-2 and its metabolic products in inducing the expression of proinflammatory cytokines and matrix metalloproteinases

Abstract

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)E2 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-Δ (12,14)-prostaglandin J2 (15d-PGJ2)-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.

Keywords: 15d-PGJ2; PGE2; apoptosis; chondrocytes; inflammation.

Figure 1.

Imbalance of PICs and MMPs in OA. Levels of PICs, including IL-1β, IL-6, IL-8, TNF-α, CXCL2, and CCL3, are elevated in OA cartilage; in contrast, IFN-γ is down-regulated in OA. Moreover, the expression levels of MMPs, such as MMP-1, MMP-2, MMP-3, MMP-7, MMP-12, MMP-13, MMP-14, MMP-16, MMP-23, and MMP-24, are increased in OA cartilage, whereas MMP-9 is down-regulated in the serum of patients with OA. These actions cause the imbalance of PICs and MMPs, potentially contributing to the physiopathology of OA.

Figure 2.

Similarities of fluid shear stress in vivo and in vitro. Fluid shear stress exists in normal joint cartilage and is induced by daily activities. A fluid shear stress experimental model was established in vitro to mimic in vivo fluid shear stress and the in vitro experimental model produces similar fluid shear stress as in vivo.

Figure 3.

Shear stress mediates the regulation of PICs and MMPs in different experimental models. Shear stress induces the expression of IL-1β, IL-6, IL-8, IL-10, TNF-α, CXCL1, CCL1, and MCP-1 in different cells. In addition, shear stress also increases the production of MMP-1, MMP-2, MMP-9, MMP-13, MMP-14, and TIMP-1 in different cell models. Induction of these PICs and MMPs mediates the shear stress-induced pathogenesis of OA.

Figure 4.

Shear stress reveals the mechanisms by which OA induces PICs and MMPs in human chondrocytes. At the early stage of OA, shear stress mediates the development and progression of OA by inducing the expression of IL-6 and MMP-9 in human chondrocytes. Involvement of COX-2 and its derived PGE₂ is implicated in the production of IL-6 and MMP-9, which is mediated by PI3-K-, ERK1/2-, PKA- and JNK-activated NF-κB pathways. In contrast, the apoptotic mechanism shows its effect on the physiopathology of OA at the late stage. Plk1 and Plk3 play pivotal roles in mediating chondrocytic apoptosis via a p53-dependent pathway.

Figure 5.

Networks of shear stress-induced OA progression. Mechanisms of PICs and MMPs in mediating high fluid shear stress in OA development are summarized. Indeed, the increased expression of PICs and MMPs in response to high fluid shear stress is believed to play a key role in the development of OA via a COX-2/PGE₂-dependent pathway at the early stage of the disease. At the late stage of OA, 15d-PGJ₂ exerts its effects on the pathogenesis of OA by inducing apoptosis but not an inflammatory mechanism. However, we could not distinctly segregate the inflammatory mechanism from apoptotic mechanism and thoroughly separate OA progression into 2 stages due to the roles of PICs in apoptosis.