The BHD protein folliculin (FLCN) plays a role in numerous signalling pathways and cellular processes. Although mutations in FLCN are only firmly linked to the development of fibrofolliculomas, pulmonary cysts and renal tumours it is possible that disruption of these pathways also plays a role in other phenotypes. Recently Kapoor et al., (2015) reported three cases studies of women with BHD who presented with intracranial vascular pathologies. There are few other reports of vascular pathologies in BHD and further studies would be required to determine any causative link. Kapoor et al. proposed two hypotheses to link BHD to aneurysms and vascular malformations: aberrant HIF-1α signalling and increased matrix metalloproteinase 9 (MMP-9) activity.
MMP-9 is a proteolytic enzyme that cleaves several connective tissue proteins and has multiple roles in tissue extra-cellular matrix (ECM) remodelling, angiogenesis and cell migration. Regulation of MMP-9 is predominantly transcriptional; low background levels result from inhibition by SMAD7 (Kim et al., 2012, Yu et al., 2013). A significant reduction in SMAD7 expression, alongside other TGF-β signalling targets, was reported in FLCN-null cells (Hong et al., 2010), supporting a link between reduced FLCN and increased MMP-9.
MMPs are important for vascular wall matrix remodelling and increased activity is associated with potentially-pathogenic increased degradation of structural proteins in vascular walls (Maradni et al., 2013). Increased levels of MMP-9 have been seen in extra- and intra-cerebral, abdominal aortic and intracranial aneurysm walls (Pannu et al., 2006, Maradni et al., 2013). The expression of MMP9 is locally, rather than systemically, perturbed in such patients as healthy vascular tissue from aneurysm patients shows no increase in MMP-9 compared to healthy controls (Kim et al., 1997). Although an increase in MMP-9 has not been investigated in aneurysm wall samples from BHD patients, a role for FLCN in the control of MMP9 expression could support the potential for increased risk of intracranial vascular pathologies in BHD.
Aberrant MMP-9 activity has also been associated with a number of pulmonary disorders and previously been discussed in the context of BHD. MMP9 is expressed at low levels in healthy adult lung tissue but marked increases have been reported in cystic fibrosis (Sagel et al., 2005), asthma, IPF, and COPD (Atkinson & Senior, 2003) associated with airway and vascular remodelling. Increased MMP-9 expression is also seen in Lymphangioleiomyomatosis (LAM) patients associated with ECM breakdown and cystic lesions (McCormack, 2008).
In BHD patients increased MMP9 expression has been reported in alveolar epithelial cells, macrophages and neutrophils (Hayashi et al., 2010, Pimenta et al., 2012). However, these reports are not conclusive as there was a lack of comparison to healthy tissue (Hayashi et al., 2010) or no published genetic confirmation of BHD (Pimenta et al., 2012). Additionally increased production of MMP-9 as a result of increased pulmonary inflammation has been reported in mouse models of BHD (Goncharova et al., 2014). Contrary to these reports Nishii et al., (2013) found that MMP-9 levels were unchanged in their patient’s lung samples suggesting that further, large-scale analysis of expression is required in BHD patients.
The patient reported by Pimenta et al. (2012) was initially misdiagnosed with LAM and received standard treatment with the MMP-inhibitor doxycycline. Although this patient was subsequently suspected to have BHD she did show an improvement in pulmonary function during the treatment. Further research is required to understand the role, if any, that MMP-9 or other MMPs play in the pathology of BHD. If disruption of TGF-β signalling is resulting in a pathogenic activation of MMP-9 then it may be possible to utilise the well-established inhibitors such as doxycycline for the treatment of BHD pathologies.
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