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Wnt and PPARγ signaling in osteoblastogenesis and adipogenesis

Abstract

Osteoblasts and adipocytes differentiate from a common pluripotent precursor, the mesenchymal stem cell (MSC). Studies have identified numerous transcription factors, and multiple extracellular and intracellular signaling pathways that regulate the closely linked processes of adipogenesis and osteoblastogenesis. Interestingly, inducers of differentiation along one lineage often inhibit differentiation along the other; for example, the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is a prime inducer of adipogenesis that inhibits osteoblastogenesis. The latest research has shown that inducers of osteoblastogenesis (such as bone morphogenetic protein 2 and Wnt ligands) use different mechanisms to suppress the transactivation function of PPARγ during osteoblastogenesis from MSCs. Signaling via the canonical Wnt–β-catenin pathway inhibits PPARγ mRNA expression, whereas signaling via the noncanonical Wnt pathway results in activation of a histone methyltransferase SETDB1 that represses PPARγ transactivation through histone H3K9 methylation of target genes. This article summarizes Wnt and PPARγ signaling in MSCs and the crosstalk between these pathways, and speculates on future clinical application of this knowledge as the basis of novel approaches for regeneration therapy.

Key Points

  • Bone marrow mesenchymal stem cells (MSCs) are pluripotent precursor cells capable of differentiating into many cell types, including adipocytes and osteoblasts

  • Many secreted and intracellular regulators, including peroxisome proliferator-activated receptor γ and Wnt ligands, govern MSC fate decisions

  • Canonical Wnt–β-catenin signaling supports osteoblastogenesis, while the role of noncanonical Wnt signaling in bone is less well understood

  • A noncanonical Wnt ligand, Wnt5a, potently suppresses adipogenesis through transcriptional suppression of PPARγ and subsequent activation of a histone methyltransferase SETDB1

  • SETDB1 is involved in epigenetic regulation of gene expression by inactivating chromatin and silencing the expression of downstream target genes

  • Crosstalk between noncanonical Wnt signals and the PPARγ-mediated gene cascade might represent one molecular aspect of the poorly characterized signaling networks in MSC fate decisions and differentiation

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Figure 1: Increased adipogenesis in the bone marrow of osteoporotic and aged bones.
Figure 2: Regulators of MSC differentiation.
Figure 3: Canonical and noncanonical Wnt signaling pathways.
Figure 4: The noncanonical Wnt ligand Wnt5a attenuates PPARγ-mediated adipogenesis, thereby favoring bone marrow MSC differentiation into osteoblasts.

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Acknowledgements

We thank Ms H. Yamazaki for manuscript preparation. This work was supported in part by a Grant-In-Aid for Basic Research Activities for Innovative Biosciences (BRAIN) and Priority Areas from the Ministry of Education, Science, Sports, and Culture of Japan (to S. Kato).

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Correspondence to Shigeaki Kato.

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Takada, I., Kouzmenko, A. & Kato, S. Wnt and PPARγ signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol 5, 442–447 (2009). https://doi.org/10.1038/nrrheum.2009.137

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  • DOI: https://doi.org/10.1038/nrrheum.2009.137

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