Increased canonical WNT/β-catenin signalling and myxomatous valve disease

This editorial refers to ‘Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease’ by A. Hulin et al ., doi: 10.1093/cvr/cvw229. Myxomatous valve disease (MVD) is a common form of valvular heart disease which causes severe valvular regurgitation.1 Increased accumulation of glycosaminoglycans (GAG), disrupted collagen fiber organization, increased cell proliferation, increased presence of inflammatory cells, and induction of Wingless-type MMTV integration site family (WNT), Transforming Growth Factor-beta (TGFβ), and Bone Morphogenetic Protein (BMP) signalling is reported in late stage human MVD.2–4 Valve development involves cell–cell and cell–matrix interactions ( Figure 1 ). Recent studies suggest that defects in heart valve development can lead to heart valve disease in adults.5 Valve formation starts with an epithelial mesenchymal transition (EMT) (E9.5–E10.5) that gives rise to mesenchymal cushions in both the atrioventricular and outflow tract regions of the developing heart. Cardiac cushions become mature valves through mesenchymal expansion (E10.5–E12.5), differentiation (E12.5–E14.5), and maturation (E14.5-postnatal stages). Although heart valve remodelling can be conceptually or arbitrarily organized into multiple processes based on the molecular and cellular markers, it is very difficult to establish precisely when a developmental event (such as EMT) in valvulogenesis formally ends. In fact, it has been demonstrated that valvulogenesis continues after birth to adjust to the postnatal maturation of the heart. Figure 1 Valve development and homeostasis and valve pathogenesis. Elucidation of the WNT/β-catenin mechanisms through which loss of Axin2 affects the developmental transition during valvulogenesis, from cushion formation – cushion remodeling – valve maturation – adult valve homeostasis, will improve basic understanding of the etiology of MVD. WNT/β-catenin signalling is active during heart valve development6 and has been reported in human MVD.2,7 There are 19 WNT family members which signal through the canonical (via β-catenin) pathway but can also signal through non-canonical …