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Updated: May 22, 2026
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Mice lacking the calcineurin inhibitor Rcan2 have an isolated defect of osteoblast function
J H Duncan Bassett1, John G Logan, Alan Boyde
1Molecular Endocrinology Group, Department of Medicine, Imperial College London, Hammersmith Campus, London W12 0NN, United Kingdom.
Abstract:
Calcineurin-nuclear factor of activated T cells signaling controls the differentiation and function of osteoclasts and osteoblasts, and regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of this pathway. Rcan2 expression is regulated by T(3), which also has a central role in skeletal development and bone turnover. To investigate the role of Rcan2 in bone development and maintenance, we characterized Rcan2(-/-) mice and determined its skeletal expression in T(3) receptor (TR) knockout and thyroid-manipulated mice. Rcan2(-/-) mice had normal linear growth but displayed delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual during development as well as increased mineralization of adult bone. These abnormalities resulted from an isolated defect in osteoblast function and are similar to skeletal phenotypes of mice lacking the type 2 deiodinase thyroid hormone activating enzyme or with dominant-negative mutations of TRα, the predominant TR isoform in bone. Rcan2 mRNA was expressed in primary osteoclasts and osteoblasts, and its expression in bone was differentially regulated in TRα and TRβ knockout and thyroid-manipulated mice. However, in primary osteoblast cultures, T(3) treatment did not affect Rcan2 mRNA expression or nuclear factor of activated T cells c1 expression and phosphorylation. Overall, these studies establish that Rcan2 regulates osteoblast function and its expression in bone is regulated by thyroid status in vivo.
Insights
Regulator of calcineurin-2 (Rcan2) impacts bone development by affecting osteoblast function. Rcan2 expression in bone is influenced by thyroid status, highlighting its role in skeletal maintenance.
Area of Science:
- Bone biology
- Endocrinology
- Cell signaling
Background:
- Calcineurin-nuclear factor of activated T cells (NFAT) signaling is crucial for osteoclast and osteoblast differentiation and function.
- Regulator of calcineurin-2 (Rcan2) is a physiological inhibitor of the calcineurin-NFAT pathway.
- Thyroid hormone (T3) regulates Rcan2 expression and plays a key role in skeletal development and bone turnover.
Purpose of the Study:
- To investigate the role of Rcan2 in bone development and maintenance.
- To characterize the skeletal phenotypes of Rcan2 knockout mice.
- To determine Rcan2's skeletal expression in relation to thyroid hormone signaling.
Main Methods:
- Characterization of Rcan2 knockout (Rcan2-/-) mice.
- Analysis of skeletal expression in thyroid hormone receptor (TR) knockout and thyroid-manipulated mice.
- Primary osteoblast and osteoclast culture experiments.
Main Results:
- Rcan2-/- mice exhibited delayed intramembranous ossification, impaired cortical bone formation, and reduced bone mineral accrual.
- Adult Rcan2-/- mice showed increased bone mineralization.
- These skeletal abnormalities were linked to isolated osteoblast dysfunction and resembled phenotypes seen in thyroid hormone-related bone disorders.
- Rcan2 mRNA was expressed in osteoblasts and osteoclasts and its expression was differentially regulated by thyroid status in vivo.
- In vitro, T3 did not affect Rcan2 or NFATc1 expression in osteoblasts.
Conclusions:
- Rcan2 plays a significant role in regulating osteoblast function.
- Rcan2 expression in bone is regulated by thyroid status in vivo.
- These findings establish Rcan2 as a key mediator in thyroid hormone's regulation of bone metabolism.
