2. Academic Validation
  3. The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling

The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling

  • Sci Transl Med. 2018 Sep 19;10(459):eaat9356. doi: 10.1126/scitranslmed.aat9356.
Fabiana Csukasi 1,  Ivan Duran 1,  Maya Barad 1,  Tomas Barta 2,  Iva Gudernova 3,  Lukas Trantirek 4,  Jorge H Martin 1,  Caroline Y Kuo 5,  Jeremy Woods 5,  Hane Lee 6,  Daniel H Cohn 1 7 8,  Pavel Krejci 1 3 9 10,  Deborah Krakow 11 7 12 13
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, University of California-Los Angeles, Los Angeles, CA 90095, USA.
  • 2 Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
  • 3 Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
  • 4 Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic.
  • 5 Department of Pediatrics, University of California-Los Angeles, Los Angeles, CA 90095, USA.
  • 6 Department of Pathology and Laboratory Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA.
  • 7 Orthopaedic Institute for Children, University of California-Los Angeles, Los Angeles, CA 90095, USA.
  • 8 Department of Molecular, Cell and Developmental Biology, University of California-Los Angeles, Los Angeles, CA 90095, USA.
  • 9 International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
  • 10 Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, 60200 Brno, Czech Republic.
  • 11 Department of Orthopaedic Surgery, University of California-Los Angeles, Los Angeles, CA 90095, USA. dkrakow@mednet.ucla.edu.
  • 12 Department of Human Genetics, University of California-Los Angeles, Los Angeles, CA 90095, USA.
  • 13 Department of Obstetrics and Gynecology, University of California-Los Angeles, Los Angeles, CA 90095, USA.
PMID: 30232230 DOI: 10.1126/scitranslmed.aat9356
Abstract

Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)-salt-inducible kinase 3 (SIK3)-mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis.

Figures