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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 (Hh) signaling activation contributes to ectopic joint calcification in the Enpp1\u2212\/\u2212 mice. In the Enpp1\u2212\/\u2212 joints, Hh signaling was upregulated. Further activation of Hh signaling by removing the patched 1 gene in the Enpp1\u2212\/\u2212 mice enhanced ectopic joint calcification, whereas removing Gli2 partially rescued the ectopic calcification phenotype. In addition, reduction of G\u03b1s in the Enpp1\u2212\/\u2212 mice enhanced joint calcification, suggesting that Enpp1 inhibits Hh signaling and chondrocyte hypertrophy by activating G\u03b1s-PKA signaling. Our findings provide new insights into the mechanisms underlying Enpp1 regulation of joint integrity.<\/jats:p>","DOI":"10.1242\/dev.164830","type":"journal-article","created":{"date-parts":[[2018,8,15]],"date-time":"2018-08-15T09:35:15Z","timestamp":1534325715000},"source":"Crossref","is-referenced-by-count":30,"title":["<i>Enpp1<\/i> inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling"],"prefix":"10.1242","volume":"145","author":[{"given":"Yunyun","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Developmental Biology 1 , , Boston, MA 02115 , USA"},{"name":"Harvard School of Dental Medicine, Harvard Stem Cell Institute 1 , , Boston, MA 02115 , USA"},{"name":"Institute of Biomedical Sciences and School of Life Sciences, East China Normal University 2 Shanghai Key Laboratory of Regulatory Biology , , Shanghai 200241 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Cong","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology 1 , , Boston, MA 02115 , USA"},{"name":"Harvard School of Dental Medicine, Harvard Stem Cell Institute 1 , , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Gvozdenovic-Jeremic","sequence":"additional","affiliation":[{"name":"Genetic Disease Research Branch, National Human Genome Research Institute 3 , Bethesda, MD 20892 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology 1 , , Boston, MA 02115 , USA"},{"name":"Harvard School of Dental Medicine, Harvard Stem Cell Institute 1 , , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology 1 , , Boston, MA 02115 , USA"},{"name":"Harvard School of Dental Medicine, Harvard Stem Cell Institute 1 , , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Terkeltaub","sequence":"additional","affiliation":[{"name":"University of California San Diego 4 Department of Medicine, Veterans Affairs Healthcare System , , 111K, 3350 La Jolla Village Dr., San Diego, CA 92161 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3933-887X","authenticated-orcid":false,"given":"Yingzi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology 1 , , Boston, MA 02115 , USA"},{"name":"Harvard School of Dental Medicine, Harvard Stem Cell Institute 1 , , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2018,9,20]]},"reference":[{"key":"2024061400015306100_DEV164830C1","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.cell.2004.07.023","article-title":"Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning","volume":"118","author":"Ahn","year":"2004","journal-title":"Cell"},{"key":"2024061400015306100_DEV164830C2","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.1242\/dev.119065","article-title":"Wnt5a and Wnt11 regulate mammalian anterior-posterior axis elongation","volume":"142","author":"Andre","year":"2015","journal-title":"Development"},{"key":"2024061400015306100_DEV164830C3","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.joca.2004.05.001","article-title":"Effect of adenovirus-mediated overexpression of bovine ADAMTS-4 and human ADAMTS-5 in primary bovine articular chondrocyte pellet culture system","volume":"12","author":"Arai","year":"2004","journal-title":"Osteoarthritis Cartilage"},{"key":"2024061400015306100_DEV164830C4","doi-asserted-by":"publisher","first-page":"1552","DOI":"10.1359\/jbmr.090417","article-title":"New variants in the Enpp1 and Ptpn6 genes cause low BMD, crystal-related arthropathy, and vascular calcification","volume":"24","author":"Babij","year":"2009","journal-title":"J Bone Miner. 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