1. Academic Validation
  2. Enpp1 inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling

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

  • Development. 2018 Sep 20;145(18):dev164830. doi: 10.1242/dev.164830.
Yunyun Jin 1 2 Qian Cong 1 Jelena Gvozdenovic-Jeremic 3 Jiajie Hu 1 Yiqun Zhang 1 Robert Terkeltaub 4 Yingzi Yang 5
Affiliations

Affiliations

  • 1 Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Stem Cell Institute, Boston, MA 02115, USA.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 3 Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
  • 4 Department of Medicine, Veterans Affairs Healthcare System, University of California San Diego, 111K, 3350 La Jolla Village Dr., San Diego, CA 92161, USA.
  • 5 Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Stem Cell Institute, Boston, MA 02115, USA yingzi_yang@hsdm.harvard.edu.
Abstract

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 (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. In addition, reduction of Gαs in the Enpp1-/- mice enhanced joint calcification, suggesting that Enpp1 inhibits Hh signaling and chondrocyte hypertrophy by activating Gαs-PKA signaling. Our findings provide new insights into the mechanisms underlying Enpp1 regulation of joint integrity.

Keywords

Ectopic calcification; Enpp1; Gnas; Hedgehog signaling; Mouse; Osteoarthritis.

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