In synovial cells, iron increases human synovial cell proliferation and induces c-myc expression, and inducing mdm2 gene expression. This latter effect decreases p53 activity, resulting in abrogation of synovial apoptosis and/or increased cellular proliferation (Fig. 8) [37–39]. BTK inhibitor datasheet A study investigating the role of angiogenic mediators in synovial changes [40] identified several contributing factors. These investigators observed elevations in proangiogenic factors such as vascular endothelial growth factor A (VEGF-A) and stromal cell-derived factor 1, elevated levels of proangiogenic macrophages and monocytes, and increased numbers of endothelial and haematopoietic progenitor cells. Sera

from patients with haemophilia and joint disease induced an angiogenic response in endothelial SAHA HDAC mw cells that was abrogated by blocking VEGF. Peripheral blood mononuclear cells from these patients stimulated synovial cell proliferation, which was blocked by the anti-VEGF antibody bevacizumab. Lastly, human synovial cells, when incubated with haemophilic sera, elicited upregulation of hypoxia-inducible factor 1-alpha (HIF-1α)

mRNA, implicating hypoxia in the neo-angiogenesis process [40]. To summarize, blood and its breakdown products stimulates synovial proliferation, leading to hypoxia and the release of HIF-1α and producing active synovitis (Fig. 9). Another interesting observation regarding musculoskeletal bleeding disorders is that some patients with haemophilia develop severe joint disease despite the lack of clinically identified bleeding into the joints. Conversely, other patients appear to be protected from the onset of arthritis despite many episodes of haemarthrosis. Manco-Johnson and colleagues [41] examined the relationship between Magnetic Resonance Imaging (MRI) score (0 = normal, 7–10 = cartilage damage) and number of clinically evident joint haemorrhages. It is very interesting that some patients with high MRI scores have never experienced a clinically evident joint haemorrhage,

medchemexpress whereas others with bleeding episodes have low MRI scores and no joint damage. One explanation is given by Rodriguez-Merchan and colleagues [42] and illustrated in Fig. 10. The authors proposed that the oval seen in the figure represents the normal distribution of patients and provides evidence for a correlation between bleeding and MRI score. The dotted line indicates the threshold for patients to develop arthropathy. Within the upper green rectangle are patients with a genetic propensity protecting them from haemarthrosis, while the lower red rectangle includes patients who suffer severe bleeding with no change in MRI score. These results suggest that as yet unidentified genetic and environmental factors lead to arthropathy in patients with haemophilia. The ability to identify these factors may permit the rational design of therapies to target treatment and prevention of blood-induced joint disease.