BoneKEy Reports | BoneKEy Watch
Inhibiting PHOSPHO1 reduces calcification in smooth muscle cells
DOI:10.1038/bonekey.2012.216
Chronic kidney disease, ageing and obesity can all lead to the deposition of hydroxyapatite crystals within the medial layers of arterial walls, a condition known as medial vascular calcification (MVC). This study identified PHOSPHO1, the phosphatase that catalyses the first mineralization step that leads to endochondral ossification, as a key factor involved in the development of MVC.
The group then used high-throughput screening to discover potential potent inhibitors of PHOSPHO1, identifying several benzoisothiazolone compounds. The most potent were then used to demonstrate that inhibition was competitive and specific; there was minimal cross-inhibition of tissue-nonspecific alkaline phosphatase (TNAP) and virtually no inhibition of ectonucleotidepyrophosphatase/phosphodiesterase 1 (ENPP1) activity.
The therapeutic potential of the inhibitors identified was then explored. Using the most potent PHOSPHO1 inhibitor in combination with a known TNAP inhibitor reduced calcification in an in vitro model of vascular smooth muscle cell (VSMC) mineralization by 20.9 ± 0.74% compared to controls. This dual inhibition also increased expression of Acta 2, a smooth muscle cell marker, and reduced the expression of other enzymes known to play a part in mineralization.
Editor's comment: This study of selective inhibitors in cultured VSMCs provides new insights into how the enzymes TNAP, PHOSPHO1 and ENPP1 interact during VSMC mineralization.
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