sFRP2 activates Wnt/β-catenin signaling in cardiac fibroblasts: differential roles in cell growth, energy metabolism, and extracellular matrix remodeling.

Secreted Frizzled-related protein 2 (sFRP2) plays a key role in chronic fibrosis after myocardial infarction and in heart failure. The aim of this study was to elucidate the mechanisms through which sFRP2 may regulate the growth and extracellular matrix (ECM) remodeling of adult mouse cardiac fibroblasts (CFs). We found that sFRP2 activates CFs in part through canonical Wnt/β-catenin signaling, as evidenced by increased expression of Axin2 and Wnt3a, but not Wnt5a, as well as accumulation of nuclear β-catenin.

Tissue-nonspecific alkaline phosphatase as a target of sFRP2 in cardiac fibroblasts.

Recent studies of myocardial infarction in secreted Frizzled-related protein 2 (sFRP2) knockout mice and our hamster heart failure therapy based on sFRP2 blockade have established sFRP2 as a key profibrotic cytokine in the heart. The failing hamster heart is marked by prominent fibrosis and calcification with elevated expression of sFRP2. Noting the involvement of tissue-nonspecific alkaline phosphatase (TNAP) in bone mineralization and vascular calcification, we determined whether sFRP2 might be an upstream regulator of TNAP.