Matrix Metalloproteinase signalling

Conflicting results have suggested that the metalloproteinases, particularly matrix metalloproteinase 9 (MMP9), which are known to cause lung cyst formation in a range of cystic lung diseases, may also promote lung cyst formation in BHD syndrome.

Hayashi et al. (2010) showed immunohistochemical staining of MMP9 in alveolar epithilal cells, macrophages and neutrophils lining cysts in a confirmed case of BHD, but crucially did not perform this experiment in matched healthy lung tissue or in control lung tissue making the significance of this finding unclear. More recently, Pimenta et al. (2012) also found that that macrophages and neutrophils lining cysts walls were stained positively for MMP9 in a suspected case of BHD. Additionally, their patient – who was initially diagnosed with LAM – was treated with the metalloproteinase inhibitor doxycycline with some success, as measured by improved pulmonary function (Pimenta et al., 2012). However, genetic testing was not performed in this patient, meaning that BHD cannot be conclusively diagnosed, so these results must be treated with caution.

Conversely, Niishi et al. (2013) also analysed MMP9 expression in lung cysts of a BHD patient and did not find any increase in expression compared to control lung tissue. Thus the role of MMP9 is BHD lung cyst formation is still uncertain and needs to be investigated in a larger data set of confirmed BHD cases, and including appropriate controls.

Abberrant MMP activity has also been linked to several vascular pathologies (Maradni et al., 2013) and has been suggested to provide a link between BHD and a case series of patients with cranial vascular pathologies (Kapoor et al.,2015).

Mice lacking FLCN in their alveolar epithelial type II cells displayed an increased inflammatory response in vivo, as measured by increased MMP3 and MMP9 expression (Goncharova et al., 2014).

Heterozygous loss of FLCN was also reported to lead to increased MMP9 expression in a high grade oncocytic carcinoma. However, there were additional genomic rearrangements seen in this tumour, suggesting that additional factors may have contributed to this signalling dysregulation (Sirintrapun et al., 2014).