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Arterial calcification is driven by RAGE in Enpp1-/- mice
Denise L Cecil1, Robert A Terkeltaub
1Department of Medicine, Rheumatology Section, VA Health Care System/UCSD, San Diego, CA 92161, USA.
Background/Aims:
Ectopic osteochondral differentiation, driven by ENPP1-catalyzed generation of the chondrogenesis and calcification inhibitor inorganic pyrophosphate (PP(i)), promotes generalized arterial calcification of infancy. The multiligand receptor for advanced glycation end-products (RAGE), which promotes atherosclerosis and diabetic cardiovascular and renal complications, also mediates chondrocyte differentiation in response to RAGE ligand calgranulins such as S100A11. Here, we tested RAGE involvement in ENPP1 deficiency-associated arterial calcification.
Methods:
Because ectopic artery calcification in Enpp1-/- mice is P(i)-dependent and mediated by PP(i) deficiency, in vitro studies on effects of S100A11 and RAGE on mouse aortic explants were conducted using exogenous P(i), as well as alkaline phosphatase to hydrolyze ambient PP(i).
Results:
S100A11 induced cartilage-specific collagen IX/XI expression and calcification dependent on RAGE in mouse aortic explants that was inhibited by the endogenous RAGE signaling inhibitor soluble RAGE (sRAGE). Enpp1-/- aortic explants demonstrated decreased P(i)-stimulated release of sRAGE, and increased calcification and type IX/XI collagen expression that were suppressed by exogenous sRAGE and by Rage knockout. Last, Rage knockout suppressed spontaneous aortic calcification in situ in Enpp1-/- mice.
Conclusion:
Cultured Enpp1-/- aortic explants have decreased P(i)-stimulated release of sRAGE, and RAGE promotes ectopic chondrogenic differentiation and arterial calcification in Enpp1-/- mice.
Insights
The receptor for advanced glycation end-products (RAGE) promotes arterial calcification in ENPP1 deficiency by driving ectopic chondrogenesis. Blocking RAGE signaling significantly reduces calcification in Enpp1-/- mice.
Area of Science:
- Vascular Biology
- Mineral Metabolism
- Chondrogenesis
Background:
- Generalized arterial calcification of infancy (GACI) is driven by ENPP1 deficiency, leading to reduced inorganic pyrophosphate (PP(i)) and ectopic osteochondral differentiation.
- The receptor for advanced glycation end-products (RAGE) mediates chondrocyte differentiation and is implicated in atherosclerosis and diabetic complications.
- Calgranulins, such as S100A11, are ligands for RAGE and can induce chondrocyte differentiation.
Purpose of the Study:
- To investigate the role of RAGE in ENPP1 deficiency-associated arterial calcification.
- To determine if RAGE mediates S100A11-induced chondrogenesis and calcification in the context of ENPP1 deficiency.
Main Methods:
- In vitro studies using mouse aortic explants exposed to exogenous phosphate and alkaline phosphatase.
- Assessment of collagen IX/XI expression and calcification in response to S100A11, RAGE, and soluble RAGE (sRAGE).
- In vivo studies using Enpp1-/- mice with and without Rage knockout to evaluate spontaneous aortic calcification.
Main Results:
- S100A11 induced RAGE-dependent chondrogenic differentiation and calcification in mouse aortic explants, which was inhibited by sRAGE.
- Enpp1-/- aortic explants showed reduced sRAGE release, increased calcification, and elevated type IX/XI collagen expression, all suppressed by sRAGE or Rage knockout.
- Rage knockout in Enpp1-/- mice significantly reduced spontaneous aortic calcification.
Conclusions:
- RAGE plays a critical role in promoting ectopic chondrogenic differentiation and arterial calcification in ENPP1 deficiency.
- Reduced sRAGE release in Enpp1-/- aortic explants contributes to RAGE-mediated calcification.
- Targeting RAGE signaling represents a potential therapeutic strategy for ENPP1 deficiency-associated arterial calcification.
