Background: MGP inhibits tissue calcification, but underlying mechanisms are understudied. Results: In MGP null mice, TG2 ablation prevents calcifying cartilaginous vascular lesions but does not affect elastocalcinosis and elastin fragmentation associated with increased elastase adipsin. Conclusion: MGP acts via two distinct mechanisms. Significance: Our study identifies TG2 and adipsin as potential therapeutic targets in vascular disease linked to MGP deficiency.