Medial vascular calcification (MVC) is a pathological condition common to a variety of diseases, including chronic kidney disease, diabetes, obesity, generalized arterial calcification of infancy, arterial calcification due to deficiency of CD73, and Keutel syndrome. These diseases share the common feature of tissue-nonspecific alkaline phosphatase (TNAP) upregulation in the vasculature. We developed a mouse model that overexpresses human TNAP in vascular smooth muscle cells, in an X-linked manner. As early as 7 days of age, mice showed strong TNAP expression in the aorta and, by 14 days, distinct aortic calcification was visible by X-ray. Hemizygous overexpressor male mice (TaglnCre/WT; HprtALPLflox/Y) exhibit severe cardiac hypertrophy and have a median age of death of 44 days, whereas the hypertrophy is less pronounced and life expectancy is normal in heterozygous females (TaglnCre/WT; HprtALPLflox/WT). Gene expression analysis showed upregulation of classical markers of MVC (Bmp2, Mgp and Spp1) and osteoblast (Runx2 and Col1a1) and chondrocyte (Acan and Sox9) markers and a decrease in expression of the smooth muscle marker Tagln indicating that altering the local Pi/PPi balance is sufficient to initiate the transdifferentiation of smooth muscle cells, a hallmark of MVC and that TNAP overexpression is sufficient to cause MVC. Through medicinal chemistry efforts, we developed inhibitors of TNAP with drug-like characteristics. Overexpressor mice were injected i.p. once daily with 10 mg/kg of the TNAP inhibitor SBI-425 or vehicle from day 7 to day 30 and day 60 respectively. Heart weight to body weight ratios were significantly lower in both male and female treated mice, indicating improvement in cardiac hypertrophy. SBI-425 treatment also significantly increased the median life expectancy of affected male mice from 44 to 68 days. No secondary effects were observed in the skeleton of treated mice. These results indicate that SBI-425 can effectively reach and inhibit TNAP in the vasculature reducing the calcium loads, preventing the cardiovascular consequences of MVC and increasing the survival of overexpressor mice. Pharmacological inhibition of TNAP appears to be a viable treatment option for MVC.
17 May 2014 - 20 May 2014