Arterial calcification is driven by RAGE 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.