Adipocyte induced arterial calcification is prevented with sodium thiosulfate.
BACKGROUND
Calcification can occur in fat in multiple clinical conditions including in the dermis, breasts and in the abdomen in calciphylaxis. All of these are more common in patients with advanced kidney disease. Clinically, hyperphosphatemia and obesity are risk factors. Thus we tested the hypothesis that adipocytes can calcify in the presence of elevated phosphorus and/or that adipocytes exposed to phosphorus can induce vascular smooth muscle cell (VSMC) calcification.


METHODS
3T3-L1 preadipocytes were induced into mature adipocytes and then treated with media containing high phosphorus. Calcification was assessed biochemically and PCR performed to determine the expression of genes for osteoblast and adipocyte differentiation. Adipocytes were also co-cultured with bovine VSMC to determine paracrine effects, and the efficacy of sodium thiosulfate was determined.


RESULTS
The results demonstrated that high phosphorus induced the calcification of differentiated adipocytes with increased expression of osteopontin, the osteoblast transcription factor Runx2 and decreased expression of adipocyte transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (CEBPα), indicating that high phosphorus led to a phenotypic switch of adipocytes to an osteoblast like phenotype. Sodium thiosulfate, dose dependently decreased adipocyte calcification and inhibited adipocyte induced increase of VSMC calcification. Co-culture studies demonstrated that adipocytes facilitated VSMC calcification partially mediated by changes of secretion of leptin and vascular endothelial growth factor (VEGF) from adipocytes.


CONCLUSIONS
High phosphorus induced calcification of mature adipocytes, and adipocytes exposed to elevated phosphorus can induce calcification of VSMC in a paracrine manner. Sodium thiosulfate inhibited this calcification and decreased the secretin of leptin and VEGF from adipocytes. These results suggest that adipocyte exposure to elevated phosphorus may be a pathogenic factor in calcification observed in the skin in calciphylaxis and other diseases.
Divison of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: xuechen@iupui.edu.
Neal X
NX
Chen
Divison of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA.
Kalisha
K
O'Neill
Divison of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA.
Nader Kassis
NK
Akl
Divison of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush VA Medical Center, Indianapolis, IN, USA.
Sharon M
SM
Moe
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013885:Thiosulfates / Q000494:pharmacology*; D016896:Treatment Outcome
D013885:Thiosulfates; C017717:sodium thiosulfate; D002118:Calcium
Adipocytes; Calcification; Calciphylaxis; Leptin; Sodium thiosulfate; Vascular smooth muscle cells