Mechanisms of ankylosis in a mouse model of ankylosing spondylitis

Spondyloarthritis (SpA) is a group of common inflammatory and chronic musculoskeletal diseases with an estimated prevalence between 0.3 and 1%. Ankylosing spondylitis (AS) is the best-known form and prototype of SpA. It is a remodeling arthritis characterized by two characterisic phenomena: chronic inflammation and bone formation. Inflammation in the spine and sacroiliac joints presents as osteitis, enthesitis and synovitis, together triggering inflammatory back pain and stiffness. In the long-term, ankylosis of the axial skeleton and sacroiliac joints leads to an impairment of spinal mobility and permanent poor physical function. The structural damage is associated with increased health related costs and mortality rates. The introduction of targeted therapies, in particular anti-tumor necrosis factor (TNF) drugs, has met unprecedented success in the treatment of AS signs and symptoms. However, current radiographic follow-up data suggest that these drugs do not stop new bone formation. Hence, the concept that effective control of inflammation automatically leads to delayed ankylosis does not hold true for this disease, suggesting the need for alternative or complementary drugs. On the other hand, continuous use of nonsteroidal anti-inflammatory (NSAIDs) drugs does appear to influence ankylosis. These observations strongly emphasize that insights into the molecular mechanisms of ankylosis and into the relationship between inflammation and new tissue formation are essential. The relation of inflammation to new bone formation has been controversial and the link between these two disease processes has therefore become a central focus in AS research.Increasing evidence supports the concept that pathways involved in embryonic bone development are active during pathological new bone formation. Bone morphogenetic proteins (BMPs) have critical roles in skeletal development and joint morphogenesis, but also in postnatal joint homeostasis and tissue remodeling. They are known as factors that can induce a complete cascade of endochondral bone formation. Furthermore, the BMP pathway has been defined as an attractive therapeutic target to restore joint function as demonstrated by its targeted inhibition in a mouse model of AS. The main goal of this PhD project was to further unravel the role of BMP signaling in the onset and progression of ankylosis and to further explore their role in the entheseal stress hypothesis, which proposes that inflammation and ankylosis are linked but largely independent processes. The work was therefore mainly focused on molecular signaling pathways influencing the process of entheseal cartilage and bone formation and their interactions with inflammatory pathways.To investigate molecular aspects of ankylosis, we used the spontaneous mouse model of arthritis in ageing male DBA/1 mice; one of the best-studied experimental models for AS. We showed that this model is very sensitive to external stress and sensory factors that potentially affect the behavior of the male mice. These observations highlighted the importance of optimizing the environmental factors in housing conditions of these mice.The first part of this thesis aimed to study the role of p38 MAPK signaling in in vitro and in vivo chondrogenesis, since this cascade has been associated with both BMP and pro-inflammatory cytokine signaling. We showed that not only canonical SMAD pathways, but also alternative activation of p38 contribute to the process of chondrogenesis in vitro. Surprisingly, in vivo experiments using a chemical inhibitor of p38 demonstrated accelerated new bone formation. We hypothesized that this paradox can be explained by the relatively short half-life of the compound in vivo resulting in compensatory mechanisms leading to increased MAPK activation. This observation propose an important lesson for the development of therapies that aim to control structural progression of the disease by suggesting that continuous suppression of bone forming processes may be of importance.Next, we demonstrated that treatment with glucocorticoids, drugs with strong anti-inflammatory and anti-bone anabolic effects, did affect inflammation without direct impact on joint ankylosis. These results parallel our earlier results and strengthen the entheseal stress hypothesis in which we propose that both inflammation and new tissue formation are secondary to a common trigger. Our data at least suggested that activation of BMP signaling cascades could contribute to these two phenomena. Finally, we investigated the effect of currently available therapies on ankylosis. In contrast to earlier studies in the spontaneous mouse model using etanercept, a soluble TNF receptor, we found that mouse specific TNF antibody therapy was effective in inhibiting the disease. In conclusion, this PhD research supports the notion that BMP signaling has an important role in the structural progression of AS and provides further insights in the complex regulation of BMP signaling in joint diseases. However, further research efforts should try to better understand basic disease mechanisms and the relationship between inflammation, bone formation and remodeling. Only when full understanding of AS disease is achieved, novel drugs and strategies can be introduced.

Publication year:2012

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