Deletion of Macrophage Migration Inhibitory Factor Reduces Severity of Osteoarthritis in Aged Mice.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is elevated in the serum and synovial fluid of osteoarthritic (OA) patients. In this study, the potential role of MIF in OA was studied using human joint tissues and in vivo in mice with age-related and surgically induced OA.,MIF in conditioned media from human chondrocytes and meniscal cells and from cartilage explants was measured by ELISA. Severity of OA was analyzed histologically in male wild-type and Mif-/- mice at 12- and 22-months of age and following destabilization of the medial meniscus (DMM) surgery in 12-week old Mif-/- mice as well as in wild-type mice treated with a neutralizing MIF antibody. Synovial hyperplasia was graded in S100A8 immunostained histologic sections. Bone morphometric parameters were measured by microCT analysis.,Human OA chondrocytes secreted 3-fold higher levels of MIF than normal chondrocytes, while normal and OA meniscal cells produced equivalent amounts. Compared to age- and strain-matched controls, the cartilage, bone, and synovium in older adult mice with Mif deletion were protected from changes of naturally occurring age-related OA. No protection from DMM-induced OA was seen in young adult Mif-/- mice or in wild-type mice treated with anti-MIF. Increased bone density in 8 week-old mice with Mif deletion was not maintained at 12-months.,These results demonstrate a differential mechanism in the pathogenesis of naturally occurring age-related OA compared to injury-induced OA. The inhibition of MIF may represent a novel therapeutic target in the reduction of age-related OA. This article is protected by copyright. All rights reserved.