http://orcid.org/0000-0002-9987-7093
Repeated episodes of joint bleeding in hemophilic patients cause hemophilic arthropathy (HA), which is a chronic joint disease. Recurrent bleeding causes joint swelling and pain as well as muscular spasms (short-term complications). Following frequent articular bleeding in long term, crippling and decrease in range of motion observe mostly in knee, ankle, and elbow, which is one the most common complications in hemophilic patients [Citation1]. Angiogenesis is the formation of new blood vessels from existing ones, which is seen in different pathological conditions. This phenomenon is highly dependent on proliferation and migration of endothelial cells (ECs) of which both are affected by angiogenic and inflammatory cytokines [Citation2,Citation3].
I have read the interesting paper by Dr Rodriguez-Merchan, which reviewed the role of angiogenesis in HA. In this article, different angiogenic factors, such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1 (HIF-1), were reviewed [Citation4]. I found it very useful, but I would like to mention that we could consider some other angiogenic molecular pathways in this pathology. Angiogenesis and inflammation are nearly related in some pathologies. As Acharya et al. mentioned, CD68+ and CD11b+ cells are highly presented in synovium of patients with HA in comparison to normal controls. According to their report, CD66+ cells are colocalized with VEGF in tissue staining, which shows possible role of macrophages in angiogenesis. Also it has been shown that both VEGF and HIF-1 are elevated in synovium and sera of HA patients [Citation5]. All of these data were presented by Dr Rodriguez-Merchan in his review [Citation4].
HIF-1 is able to induce the expression of VEGF that is one the most important and potent angiogenic inducers and regulators [Citation2]. In hypoxic situations under the effect of HIF-1, macrophages secrete cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6 [Citation6], which are considered as angiogenic inducers [Citation2,Citation3]. In 1998, when studies first began on the role of inflammation in patients with HA, it was showed that the levels of TNF- α, IL-1, and IL-6 are highly elevated in sera of these patients as well as overexpression of them in their synovium in comparison to normal healthy controls which supports their role in pathogenesis of HA [Citation7].
TNF-α is responsible for the expression of different angiogenic factors such as VEGF and metalloproteinase-9 (MMP-9) [Citation8]. Also, IL-1 is able to upregulate the expression of VEGF and VEGF receptors on ECs as well as releasing of MMPs [Citation9]. IL-6 could induce migration and proliferation (two main steps of angiogenesis) to ECs as well as VEGF overexpression [Citation10]. Moreover, it has been proved that IL-1, IL-6, and TNF-α could be released by macrophages during inflammation [Citation6].
I think, although those five papers, which were the main source of the mentioned review by Dr Rodriguez-Merchan, are only the documents focused on the role of angiogenesis in HA, we can’t ignore other articles. In HA patients, presence and activity of CD68+ macrophages in articular space is proved [Citation5] as well as increased levels of IL-1, IL-6, and TNF-α in sera and synovium [Citation7] which could be released form macrophages during inflammation. Also I think one of the important molecules involved in angiogenesis is missed in the review article: MMP-9. This metalloproteinase was upregulated in synovium vascular culture of HA patients in comparisons to controls as well as elevation in their sera. This elevation was also detected for stromal cell-derived factor-1 (SDF-1) [Citation5] which induces neo-angiogenesis [Citation11]. Together all it seems we can consider IL-1, IL-6, TNF-α, MPP-9, and SDF-1 as involved angiogenic cytokines in HA pathogenesis.
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References
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