Reduced Osteoarthritis Severity in Aged Mice With Deletion of Macrophage Migration Inhibitory Factor

Abstract

Objective 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. Methods 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. Results 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. Conclusions 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.

Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway

“…Despite this, we found the protective effect of 4-IPP against bone loss was more potent in the calvarial osteolysis model when compared with the OVX model. This is likely because of the fact that MIF expression is elevated in inflammatory bone conditions such as wear particle-induced osteolysis, osteoarthritis, and rheumatoid arthritis (20,44,45), which may explain the better outcome observed in the calvarial osteolysis model.…”

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

“…An articular cartilage structure score was also generated as previously described (McNulty et al., 2011), which showed similar results to the Safranin‐O staining score but with less sensitivity to subtle changes in OA progression (data not shown). Slides stained with hematoxylin and eosin were used to assess osteophyte score, with each quadrant graded on a 0–3 scale for osteophyte size as previously described (Rowe et al., 2017). For immunohistochemistry with a primary antibody targeting tdTomato (cat # 600‐401‐379; Rockland Immunochemicals, Limerick, PA) or targeting Mmp‐13 (ab84594; Abcam, Cambridge, UK), antigen retrieval was performed with heated sodium citrate and sections were stained using the VECTASTAIN ® Elite ABC‐HRP kit (Vector Laboratories, Burlingame, CA).…”

Macrophage migration inhibitory factor knockout attenuates endotoxin-induced cardiac dysfunction in mice

“…Many studies have shown the prospects of using anti-MIF antibodies in basic research and clinical applications. The inhibition of MIF may cause the reduction of the severity of age-related osteoarthritis in mice [15]. Targeted deletion of MIF gene delays the development of chronic lymphocytic leukaemia and prolongs survival in mice [16].…”