PT  - JOURNAL ARTICLE
AU  - Csukasi, Fabiana
AU  - Duran, Ivan
AU  - Barad, Maya
AU  - Barta, Tomas
AU  - Gudernova, Iva
AU  - Trantirek, Lukas
AU  - Martin, Jorge H.
AU  - Kuo, Caroline Y.
AU  - Woods, Jeremy
AU  - Lee, Hane
AU  - Cohn, Daniel H.
AU  - Krejci, Pavel
AU  - Krakow, Deborah
TI  - The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling
AID  - 10.1126/scitranslmed.aat9356
DP  - 2018 Sep 19
TA  - Science Translational Medicine
PG  - eaat9356
VI  - 10
IP  - 459
4099  - http://stm.sciencemag.org/content/10/459/eaat9356.short
4100  - http://stm.sciencemag.org/content/10/459/eaat9356.full
AB  - Skeletal dysplasias are rare genetic disorders affecting bone and cartilage growth during development. Csukasi et al. identified two patients with developmental delay and a skeletal phenotype similar to Jansen metaphyseal chondrodysplasia, a disorder caused by altered parathyroid hormone signaling. They identified a genetic mutation in SIK3 as the cause of the of the patients’ dysplasia. The SIK3 mutation altered mTOR signaling, and parathyroid hormone signaling was found to regulate SIK3 activity. This study identifies a common signaling pathway underlying two distinct skeletal disorders, suggesting it plays an important role during skeletal development.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.