Blockade of 11β-hydroxysteroid dehydrogenase type 1 enzyme inhibits experimental collagenase-induced osteoarthritis

Abstract

Abstract. Osteoarthritis (OA) is a common cause of functional deterioration in the joints of elderly adults and is a significant burden on the health of the aging population. 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1), which converts cortisone to cortisol, is known to contribute to a number of inflammatory diseases. However, the role of 11β-HSD1 in human OA remains unclear. The aim of this study was to identify the effects of the selective 11β-HSD1 inhibitor, BVT-2733, in murine collagenase-induced osteoarthritis (CIOA). CIOA mice were treated with BVT-2733 (100 mg/kg, orally) or control vehicle twice daily for five weeks. Cartilage and bone destruction were subsequently examined. The expression of bone markers and STAT3 phosphorylation in joint tissues were detected using western blot analysis. The concentrations of proinflammatory cytokines were determined by an enzyme-linked immunosorbent assay. Treatment with BVT-2733 attenuated cartilage and bone destruction, and reduced the expression of bone markers and p-STAT3 in the joints of CIOA mice. BVT-2733 also decreased the serum levels of interleukin (IL)-1β, IL-6, IL-17 and vascular endothelial growth factor. In conclusion, the present study showed that BVT-2733 inhibits multiple inflammatory signaling pathways in the joints of CIOA mice, suggesting that 11β-HSD1 inhibition may have therapeutic potential in human OA. IntroductionOsteoarthritis (OA) is a common cause of functional deterioration in the joints of older adults and confers a significant burden on the health of the elderly population (1). OA is characterized by the progressive destruction of cartilage. The current understanding of the molecular events during joint destruction suggests that activated synoviocytes are important in the pathogenesis of OA (2-3). Inflammatory mediators, including interleukin (IL)-1β, infiltrate the synovial membrane, resulting in further inflammation. (4). These mediators amplify and sustain the disease process in OA by inducing inflammatory mediators involved in cartilage degradation, such as matrix metalloproteinases (MMPs) (5). Thus, inflammatory mediator-activated pathways have received increasing attention as potential targets for the treatment of human OA in recent years.Endogenous glucocorticoid concentrations are determined by the activity of the hypothalamic-pituitary-adrenal axis, and tissue and intracellular exposure are further augmented through the activity of the 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1), which converts inactive cortisone to the active glucocorticoid, cortisol (6). The ability of 11β-HSD1 to elevate cellular glucocorticoid levels has been postulated to be involved in the modulation of a number of metabolic and inflammatory diseases (7,8). Therefore, the identification of mechanisms underlying 11β-HSD1 activity may improve the understanding of the pathogenesis of certain diseases. Tumor necrosis factor-α (TNF-α) and IL-1β are associated with 11β-HSD1 activity, which are also key mediators in OA pathogenesis (9)....