Enpp1 inhibits ectopic joint calcification and maintains articular chondrocytes by repressing Hedgehog signaling

The differentiated phenotype of articular chondrocytes of synovial joints needs to be maintained throughout life. Disruption of the articular cartilage, frequently associated with chondrocyte hypertrophy and calcification, is a central feature in osteoarthritis (OA). However, the molecular mechanisms whereby phenotypes of articular chondrocytes are maintained and pathological calcification is inhibited remain poorly understood. Recently, 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. Here we found that Hedgehog signaling activation contributes to ectopic joint calcification in the Enpp1^−/- mice. In the Enpp1^−/- joints, Hedgehog signaling was upregulated. Further activation of Hedgehog signaling by removing Patched 1 in the Enpp1^−/- mice enhanced ectopic joint calcification, while removing Gli2 partially rescued the ectopic calcification phenotype. Additionally, reduction of Gα_s in the Enpp1^−/- mice also enhanced joint calcification, suggesting Enpp1 inhibited Hedgehog signaling and chondrocyte hypertrophy by activating Gα_s-PKA signaling. Our findings provide new insights in the mechanisms underlying Enpp1 regulation of joint integrity.