ObjectiveTo test whether inhibition of sclerostin by a targeted monoclonal antibody (Scl-Ab) protects from bone and cartilage damage in inflammatory arthritis. Sclerostin is a potent inhibitor of bone formation and may be responsible for the low level of bone repair in patients with rheumatoid arthritis.MethodsHuman tumour necrosis factor transgenic mice (hTNFtg mice) developing inflammatory arthritis and local and bone loss were administered either vehicle, anti-TNF antibody, Scl-Ab, or a combination of both agents. Inflammation, systemic and periarticular bone loss, bone erosion and cartilage damage were evaluated at baseline (week 8) and after 3 weeks of treatment by clinical assessment, micro-CT and histology.ResultsScl-Ab did not affect joint swelling or synovitis. Systemic bone loss in the spine and periarticular bone loss in the proximal tibia were completely blocked and partially reversed by inhibition of sclerostin but not by inhibition of TNF. Moreover, Scl-Ab completely arrested the progression of bone erosion in hTNFtg mice and in combination with TNF inhibition even led to significant regression of cortical bone erosions. Protective effects of Scl-Ab were also observed for the articular cartilage.ConclusionsThese data suggest that sclerostin inhibition is a powerful tool to enhance bone repair in inflammatory arthritis.

Objective. To determine whether overexpression of the activator protein 1 (AP-1) transcription factor Fra-1 in adipose-derived stromal cells (ADSCs) is an effective treatment of collagenase-induced osteoarthritis (OA).Methods. OA was induced by injection of collagenase into the knee joints of male C57BL/6 mice. ADSCs were isolated from the inguinal fat pads of 8-week-old wild-type or Fra-1-transgenic mice and injected into the knee joints of mice with collagenase-induced OA 7 days after OA induction. Histologic analyses of cartilage destruction and chondrocyte cell death were performed. Adipogenic differentiation capacity was evaluated, gene expression was analyzed, and cytokine profiling was performed in stromal vascular fractions (SVFs) and ADSCs.Results. OA-related cartilage destruction and chondrocyte cell death were significantly reduced in mouse knee joints treated with ADSCs from Fra-1-transgenic mice compared to mouse knee joints treated with ADSCs from wild-type mice. This effect did not result from the higher number of adipogenic progenitors observed in SVFs from Fra-1-transgenic compared to wild-type mouse fat pads, since injection of wild-type mouse ADSCs enriched for adipogenic progenitors did not show any additional chondroprotective effects compared to nonsorted ADSCs. However, Fra-1-transgenic mouse ADSCs showed decreased adipogenic differentiation capacity. Moreover, Fra-1 significantly inhibited proinflammatory interleukin-6 and pentraxin 3 expression, while increasing the expression of extracellular matrix proteins, such as periostin and spondin 1. These findings suggest that Fra-1 overexpression leads to an increased chondroprotective effect of ADSCs in OA.Conclusion. ADSCs overexpressing Fra-1 effectively protect against OA. Our data indicate that genetic modifications of ADSCs, such as Fra-1 overexpression, may improve their potential to protect articular cartilage against OA-mediated damage.Osteoarthritis (OA) is the most common rheumatic disease, characterized by degeneration of articular cartilage. OA patients experience intense pain and impaired physical function. The high prevalence of OA, along with the severe disease burden, is also associated with high socioeconomic costs and loss of productivity (1,2). Mechanistically, it is thought that the balance between anabolic and catabolic factors in cartilage is disturbed, leading to a catabolic phenotype of articular chondrocytes. Different primary triggers eventually lead to a decrease in the capacity of chondrocytes to secrete specific components of the extracellular matrix, such as type IIB collagen or aggrecan, while at the same time the synthesis of catabolic enzymes, such as aggrecanases of the ADAMTS family and collagenases of the matrix

The difference in the increase of the mean degree of stenosis is probably not only important because of the resulting haemodynamic changes in myocardial perfusion. The quantitatively only slightly increased trend towards progression in the untreated groups can be interpreted as a marker for an active process of atherogenesis with a tendency of plaques to break off and of plaque thromboses.