Pegsunercept

Chemokines are thought to play an important role in several aspects of bone metabolism including the recruitment of leukocytes and the formation of osteoclasts. We investigated the impact of diabetes on chemokine expression in normal and diabetic fracture healing. Fracture of the femur was performed in streptozotocin-induced diabetic and matched normoglycemic control mice. Microarray analysis was carried out and chemokine mRNA levels in vivo were assessed. CCL4 were examined in fracture calluses by immunohistochemistry and the role of TNF in diabetes-enhanced expression was investigated by treatment of animals with the TNF-specific inhibitor, pegsunercept. In vitro studies were conducted with ATDC5 chondrocytes. Diabetes significantly upregulated mRNA levels of several chemokines in vivo including CCL4, CCL8, CCL6, CCL11, CCL20, CCL24, CXCL2, CXCL5 and chemokine receptors CCR5 and CXCR4. Chondrocytes were identified as a significant source of CCL4 and its expression in diabetic fractures was dependent on TNF (P<0.05). TNF-α significantly increased mRNA levels of several chemokines in vitro which were knocked down with FOXO1 siRNA (P<0.05). CCL4 expression at the mRNA and proteins levels was induced by FOXO1 over-expression and reduced by FOXO1 knockdown. The current studies point to the importance of TNF-α as a mechanism for diabetes enhanced chemokine expression by chondrocytes, which may contribute to the accelerated loss of cartilage observed in diabetic fracture healing. Moreover, in vitro results point to FOXO1 as a potentially important transcription factor in mediating this effect.

Periodontitis is the most common lytic bone disease and one of the first clinical manifestations of diabetes. Diabetes increases the risk of periodontitis. The aim of the present study was to examine mechanisms by which diabetes aggravates periodontitis. Ligature‐induced periodontitis was examined in Goto‐Kakizaki rats with type 2 diabetes. A tumor necrosis factor (TNF)‐specific‐inhibitor, pegsunercept, was applied to diabetic rats after the onset of periodontal disease. Interferon‐γ (IFN‐γ), TNF‐α, interleukin‐1 β (IL‐1β), fibroblast growth factor‐2 (FGF‐2), transforming growth factor beta‐1 (TGFβ‐1), bone morphogenetic protein‐2 (BMP‐2), and BMP‐6 were measured by real‐time RT‐PCR, and histological sections were examined for leukocyte infiltration and several parameters related to bone resorption and formation. Inflammation was prolonged in diabetic rats and was reversed by the TNF inhibitor, which reduced cytokine mRNA levels, leukocyte infiltration, and osteoclasts. In contrast, new bone and osteoid formation and osteoblast numbers were increased significantly vs. untreated diabetic animals. TNF inhibition in diabetic animals also reduced apoptosis, increased proliferation of bone‐lining cells, and increased mRNA levels of FGF‐2, TGFβ‐1, BMP‐2, and BMP‐6. Thus, diabetes prolongs inflammation and osteoclastogenesis in periodontitis and through TNF limits the normal reparative process by negatively modulating factors that regulate bone.—Pacios, S., Kang, J., Galicia, J., Gluck, K., Patel, H., Ovaydi‐Mandel, A., Petrov, S., Alawi, F., Graves, D. T. Diabetes aggravates periodontitis by limiting repair through enhanced inflammation. FASEB J. 26, 1423‐1430 (2012). www.fasebj.org