Reduction of protein phosphatase 2A Cα promotes in vivo bone formation and adipocyte differentiation
Abstract
Serine/threonine protein phosphatase 2A (PP2A) regulates diverse physiological processes such as cell cycle, growth, apoptosis, and signal transduction. Previously, we demonstrated that silencing of the α-isoform of PP2A catalytic subunit (PP2A Cα) in osteoblasts accelerated osteoblast differentiation, whereas its overexpression suppressed differentiation. In this study, we examined the role of PP2A Cα in in vivo bone formation by generating transgenic mice (PP2A-Tg), in which the dominant negative form of PP2A Cα was specifically expressed in osteoblasts. PP2A-Tg mice exhibited an increase in body weight, cortical bone mineral density, and cortical bone thickness. Interestingly, they also displayed higher amounts of adipose tissue in the bone marrow of tibiae. The co-culture study showed that PP2A Cα-knockdown osteoblasts stimulated adipocyte differentiation from undifferentiated mesenchymal cells via upregulation of the adipocyte marker genes, such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα). These results indicated that the reduction of PP2A Cα levels in osteoblasts promoted bone formation in vivo. Additionally, PP2A Cα in osteoblasts was also potentially involved in controlling adipocyte differentiation through a paracrine mechanism.
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Osteoblast-specific overexpression of the dominant-negative L199P Cα mutant causes a 50% overall decrease in PP2A activity and is associated with larger and heavier mice.
“In bone, osteoblast-specific overexpression of the dominant-negative L199P Cα mutant, caused a 50% overall decrease in PP2A activity, associated with larger and heavier mice [96].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [96]
The increased bone marrow adipogenesis in L199P Cα mice is suspected to be caused by a paracrine mechanism.
“In addition, in the bone marrow, increased adipogenesis was observed, suspected to be caused by a paracrine mechanism.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [96]
In these mice, bone mineral density and thickness are significantly increased, while cartilage thickness is not affected.
“In the animals, bone mineral density and thickness were significantly increased, while cartilage thickness was not affected.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [96]
In the bone marrow of L199P Cα mice, increased adipogenesis is observed.
“In addition, in the bone marrow, increased adipogenesis was observed, suspected to be caused by a paracrine mechanism.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [96]
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References 38 · Cited by 7
- Authors
- Yoshida, K., Teramachi, J., Uchibe, K., Ikegame, M., Qiu, L., Yang, D., & Okamura, H.
- Affiliations
- Tokushima University (JP)
- Okayama University (JP)
- China Medical University (CN)
- Corresponding author
- Yang, Di
- Okamura, Hirohiko
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 470
- Pages
- 251-258
- ISSN
- 0303-7207 (ISSN-L)
- OpenAlex
- W2768029280
- Cited by
- 7
- References
- 38
- Citations by year
- 2025: 3 · 2021: 1 · 2020: 1 · 2018: 2
- FWCI
- 0.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (23592703)
- Takeda Science Foundation
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care (17KI255)
- Nakatomi Foundation
- Japan-China Medical Association
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- protein phosphatase 2A, bone formation, osteogenic differentiation, adipogenesis, bone marrow adipocytes, PPARγ, C/EBPα, paracrine signaling, mesenchymal cells, cortical bone mineral density, transgenic mice
- MeSH terms
- Cortical Bone, Animals, Cell Differentiation, Cell Line, Mice, Transgenic, Osteoblasts, Osteogenesis, Biomarkers, Bone Density, Up-Regulation, Adipocytes, Collagen Type I, Adipogenesis, Protein Phosphatase 2, Gene Knockdown Techniques
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