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Calreticulin regulates a switch between osteoblast and chondrocyte lineages derived from murine embryonic stem cells.

ABSTRACT: Calreticulin is a highly conserved, ubiquitous Ca²⁺-buffering protein in the endoplasmic reticulum that controls transcriptional activity of various developmental programs and also of embryonic stem cell (ESC) differentiation. Calreticulin activates calcineurin, which dephosphorylates and induces the nuclear import of the osteogenic transcription regulator nuclear factor of activated T cells 1 (NFATC1). We investigated whether calreticulin controls a switch between osteogenesis and chondrogenesis in mouse ESCs through NFATC1. We found that in the absence of calreticulin, intranuclear transport of NFATC1 is blocked and that differentiation switches from osteogenic to chondrogenic, a process that could be mimicked by chemical inhibition of NFAT translocation. Glycogen synthase kinase 3? (GSK3?) deactivation and nuclear localization of ?-catenin critical to osteogenesis were abrogated by calreticulin deficiency or NFAT blockade. Chemically induced GSK3? inhibition bypassed the calreticulin/calcineurin axis and increased osteoblast output from both control and calreticulin-deficient ESCs, while suppressing chondrogenesis. Calreticulin-deficient ESCs or cells treated with an NFAT blocker had enhanced expression of dickkopf WNT-signaling pathway inhibitor 1 (Dkk1), a canonical Wnt pathway antagonist that blocks GSK3? deactivation. The addition of recombinant mDKK1 switched osteogenic ESC differentiation toward chondrogenic differentiation. The results of our study indicate a role for endoplasmic reticulum calcium signaling via calreticulin in the differentiation of ESCs to closely associated osteoblast or chondrocyte lineages.

SUBMITTER: Pilquil C

PROVIDER: S-EPMC7242707 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Calreticulin regulates a switch between osteoblast and chondrocyte lineages derived from murine embryonic stem cells.

Pilquil Carlos C Alvandi Zahra Z Opas Michal M

The Journal of biological chemistry 20200327 20

Calreticulin is a highly conserved, ubiquitous Ca<sup>2+</sup>-buffering protein in the endoplasmic reticulum that controls transcriptional activity of various developmental programs and also of embryonic stem cell (ESC) differentiation. Calreticulin activates calcineurin, which dephosphorylates and induces the nuclear import of the osteogenic transcription regulator nuclear factor of activated T cells 1 (NFATC1). We investigated whether calreticulin controls a switch between osteogenesis and ch ...[more]

PMID: 32220932

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Dataset Information

Calreticulin regulates a switch between osteoblast and chondrocyte lineages derived from murine embryonic stem cells.

Publications

Calreticulin regulates a switch between osteoblast and chondrocyte lineages derived from murine embryonic stem cells.

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