FAK Promotes Early Osteoprogenitor Cell Proliferation by Enhancing mTORC1 Signaling.
FAK
OSTEOBLAST
OSTEOPROGENITOR
PYK2
mTORC1
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
16
10
2019
revised:
16
03
2020
accepted:
05
04
2020
pubmed:
15
4
2020
medline:
7
7
2021
entrez:
15
4
2020
Statut:
ppublish
Résumé
Focal adhesion kinase (FAK) has important functions in bone homeostasis but its role in early osteoprogenitor cells is unknown. We show herein that mice lacking FAK in Dermo1-expressing cells exhibited low bone mass and decreased osteoblast number. Mechanistically, FAK-deficient early osteoprogenitor cells had decreased proliferation and significantly reduced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, a central regulator of cell growth and proliferation. Furthermore, our data showed that the pharmacological inhibition of FAK kinase-dependent function alone was sufficient to decrease the proliferation and compromise the mineralization of early osteoprogenitor cells. In contrast to the Fak deletion in early osteoprogenitor cells, FAK loss in Col3.6 Cre-targeted osteoblasts did not cause bone loss, and Fak deletion in osteoblasts did not affect proliferation, differentiation, and mTORC1 signaling but increased the level of active proline-rich tyrosine kinase 2 (PYK2), which belongs to the same non-receptor tyrosine kinase family as FAK. Importantly, mTORC1 signaling in bone marrow stromal cells (BMSCs) was reduced if FAK kinase was inhibited at the early osteogenic differentiation stage. In contrast, mTORC1 signaling in BMSCs was not affected if FAK kinase was inhibited at a later osteogenic differentiation stage, in which, however, the concomitant inhibition of both FAK kinase and PYK2 kinase reduced mTORC1 signaling. In summary, our data suggest that FAK promotes early osteoprogenitor cell proliferation by enhancing mTORC1 signaling via its kinase-dependent function and the loss of FAK in osteoblasts can be compensated by the upregulated active PYK2. © 2020 American Society for Bone and Mineral Research.
Identifiants
pubmed: 32286710
doi: 10.1002/jbmr.4029
pmc: PMC7486225
mid: NIHMS1606628
doi:
Substances chimiques
Focal Adhesion Kinase 1
EC 2.7.10.2
Focal Adhesion Kinase 2
EC 2.7.10.2
Focal Adhesion Protein-Tyrosine Kinases
EC 2.7.10.2
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1798-1811Subventions
Organisme : NIAMS NIH HHS
ID : P30 AR069620
Pays : United States
Organisme : NIH HHS
ID : AR 69620
Pays : United States
Informations de copyright
© 2020 American Society for Bone and Mineral Research.
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