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.

Central European Institute of Technology Masaryk University 62500 Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Department of Histology and Embryology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Department of Human Genetics University of California Los Angeles Los Angeles CA 90095 USA

Department of Molecular Cell and Developmental Biology University of California Los Angeles Los Angeles CA 90095 USA

Department of Obstetrics and Gynecology University of California Los Angeles Los Angeles CA 90095 USA

Department of Orthopaedic Surgery University of California Los Angeles Los Angeles CA 90095 USA

Department of Pathology and Laboratory Medicine University of California Los Angeles Los Angeles CA 90095 USA

Department of Pediatrics University of California Los Angeles Los Angeles CA 90095 USA

Institute of Animal Physiology and Genetics of the Czech Academy of Sciences 60200 Brno Czech Republic

International Clinical Research Center St Anne's University Hospital 65691 Brno Czech Republic

Orthopaedic Institute for Children University of California Los Angeles Los Angeles CA 90095 USA

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