Disruption of the articular cartilage, frequently associated with chondrocyte hypertrophy and calcification, is a central feature in osteoarthritis (OA). The ecto-enzyme Enpp1, a suppressor of pathological calcification, was reported to be decreased in joint cartilage with OA in both human and mouse, and Enpp1 deficiency causes joint calcification. hedgehog (Hh) signaling activation contributes to ectopic joint calcification in the Enpp1-/- mice. In the Enpp1-/- joints, Hh signaling was upregulated. Further activation of Hh signaling by removing the patched 1 gene in the Enpp1-/- mice enhanced ectopic joint calcification, whereas removing Gli2 partially rescued the ectopic calcification phenotype. Enpp1 inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling.