Open AccessEnpp1 inhibits ectopic joint calcification and maintains articular chondrocytes by repressing Hedgehog signaling
Author(s) -
Yunyun Jin,
Cong Qi,
Jelena Gvozdenović-Jeremić,
Jiajie Hu,
Yiqun Zhang,
Robert Terkeltaub,
Yingzi Yang
Publication year - 2018
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.164830
Subject(s) - ectopic calcification , calcification , indian hedgehog , chondrocyte , ectopic expression , biology , synovial joint , hedgehog signaling pathway , microbiology and biotechnology , hedgehog , cartilage , phenotype , signal transduction , patched , chondrogenesis , osteoarthritis , endocrinology , medicine , anatomy , pathology , biochemistry , articular cartilage , genetics , cell culture , alternative medicine , gene
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 Gαs in the Enpp1−/- mice also enhanced joint calcification, suggesting Enpp1 inhibited Hedgehog signaling and chondrocyte hypertrophy by activating Gαs-PKA signaling. Our findings provide new insights in the mechanisms underlying Enpp1 regulation of joint integrity.