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Degenerative and inflammatory joint diseases lead to a destruction of the joint architecture. Whereas degenerative osteoarthritis results in the formation of new bone, rheumatoid arthritis leads to bone resorption. The molecular basis of these different patterns of joint disease is unknown. By inhibiting Dickkopf-1 (DKK-1), a regulatory molecule of the Wnt pathway, we were able to reverse the bone-destructive pattern of a mouse model of rheumatoid arthritis to the bone-forming pattern of osteoarthritis. In this way, no overall bone erosion resulted, although bony nodules, so-called osteophytes, did form. We identified tumor necrosis factor-[alpha] (TNF) as a key inducer of DKK-1 in the mouse inflammatory arthritis model and in human rheumatoid arthritis. These results suggest that the Wnt pathway is a key regulator of joint remodeling., Author(s): Danielle Diarra [1, 2, 5]; Marina Stolina [3, 5]; Karin Polzer [1]; Jochen Zwerina [1]; Michael S Ominsky [3]; Denise Dwyer [3]; Adelheid Korb [2]; Josef Smolen [2]; Markus [...]

Churg-Strauss syndrome (CSS) is a rare systemic necrotizing vasculitis associated with granuloma formation and severe blood and tissue eosinophilia. CSS occurs almost exclusively in patients with asthma. Its pathogenesis remains largely unknown, as triggering factors for CSS development have not been identified so far. AAb, such as anti-neutrophil cytoplasmic autoantibodies, are found in less than half of patients and possibly constitute a subtype of CSS with different clinical behaviour. On a cellular level, CSS is characterized by a strong Th2-type immune response. Th2-associated cytokines such as IL-4, IL-13 and IL-5 may precipitate the severe eosinophilia in CSS, while migration of Eos to inflammatory sites is possibly mediated by eotaxin-3. This review summarizes recent advances in the knowledge on epidemiology, clinical features, and pathogenesis of CSS. [ABSTRACT FROM AUTHOR]

Inflammatory joint disease typically provokes progressive cartilage damage. The proliferative synovial inflammatory tissue directly invades the cartilage and induces the expression and activation of degrading enzymes such as matrix metalloproteases (MMPs) and aggrecanases. However, also chondrocyte apoptosis has been observed in cartilage samples of inflamed joints. It remains unclear whether this is a secondary phenomenon due to cartilage damage or a primary event initiated by the synovial inflammation. To determine the presence or absence of chondrocyte death in experimental arthritis, we longitudinally assessed proteoglycan depletion and chondrocyte apoptosis in paw sections from human tumor necrosis factor transgenic (hTNFtg) mice and wild-type littermates. Whereas, wild-type mice showed no signs of cartilage damage, hTNFtg mice exhibited progressive proteoglycan loss starting at clinical onset of arthritis. However, we already found the first apoptotic chondrocytes well before cartilage matrix breakdown occurred indicating that chondrocyte death can be induced before matrix resorption. Chondrocyte death could constantly be observed until late stages of arthritis causing a continuous increase in the number of empty cartilage lacunae. As apoptotic cells in cartilage cannot be cleared by phagocytes due to their spatial isolation in the avascular lacunae of cartilage, having no contact to professional or amateur phagocytes. The dying cells are compelled to undergo a "lonely death" inevitable ending up in secondary necrosis giving rise to perpetuation of a pro-inflammatory cascade. These data indicate that chondrocyte death may play a primary role in inflammatory arthritis fuelling cartilage inflammation and damage due to secondary necrosis. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the function of inflammatory bone marrow infiltrates found in vicinity to joints affected by inflammatory arthritis. These bone marrow infiltrates are rich in B cells and emerge at the interphase between bone marrow and synovial inflammatory tissue, where cortical bone has been broken. We deleted an essential molecule of B-cell development, Brutońs tyrosine kinase (Btk), in arthritic TNF-transgenic mice and studied its effect on bone marrow inflammation. Although antigen responses, immunoglobulin levels, and autoantibody production were diminished in Btk(-/-)hTNFtg mice, synovial inflammation developed normally. However, bone marrow infiltrates were significantly diminished in Btk(-/-)hTNFtg mice, which lead to impaired bone formation at endosteal sites underneath bone erosions and an increased invasion of synovial inflammatory cells into the bone marrow. Expression of bone morphogenic protein-7 was dramatically decreased in Btk(-/-)hTNFtg mice. These results do not only indicate that bone formation at endosteal regions next to bone marrow infiltrates is driven by B cells but also show that bone marrow aggregates in the vicinity of inflamed joint appear as an attempt to counter the invasion of inflammatory tissue into the bone marrow.