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
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Bone marrow mesenchymal stem cells (MSCs) are pluripotent precursor cells capable of differentiating into many cell types, including adipocytes and osteoblasts
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Many secreted and intracellular regulators, including peroxisome proliferator-activated receptor γ and Wnt ligands, govern MSC fate decisions
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Canonical Wnt–β-catenin signaling supports osteoblastogenesis, while the role of noncanonical Wnt signaling in bone is less well understood
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A noncanonical Wnt ligand, Wnt5a, potently suppresses adipogenesis through transcriptional suppression of PPARγ and subsequent activation of a histone methyltransferase SETDB1
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SETDB1 is involved in epigenetic regulation of gene expression by inactivating chromatin and silencing the expression of downstream target genes
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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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References
Dorheim, M. A. et al. Osteoblastic gene expression during adipogenesis in hematopoietic supporting murine bone marrow stromal cells. J. Cell. Physiol. 154, 317–328 (1993).
Beresford, J. N., Bennett, J. H., Devlin, C., Leboy, P. S. & Owen, M. E. Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. J. Cell Sci. 102, 341–351 (1992).
Schwartz, A. V. et al. Thiazolidinedione use and bone loss in older diabetic adults. J. Clin. Endocrinol. Metab. 91, 3349–3354 (2006).
Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I. & Spiegelman, B. M. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 8, 1224–1234 (1994).
Gimble, J. M. et al. Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells. Mol. Pharmacol. 50, 1087–1094 (1996).
Hamada, H. et al. Mesenchymal stem cells (MSC) as therapeutic cytoreagents for gene therapy. Cancer Sci. 96, 149–156 (2005).
Arthur, A., Zannettino, A. & Gronthos, S. The therapeutic applications of multipotential mesenchymal/stromal stem cells in skeletal tissue repair. J. Cell. Physiol. 218, 237–245 (2009).
Quarto, R. et al. Repair of large bone defects with the use of autologous bone marrow stromal cells. N. Engl. J. Med. 344, 385–386 (2001).
Horwitz, E. M. et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc. Natl Acad. Sci. USA 99, 8932–8937 (2002).
Suzawa, M. et al. Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade. Nat. Cell Biol. 5, 224–230 (2003).
Takada, I. et al. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat. Cell Biol. 9, 1273–1285 (2007).
Muruganandan, S., Roman, A. A. & Sinal, C. J. Adipocyte differentiation of bone marrow-derived mesenchymal stem cells: cross talk with the osteoblastogenic program. Cell. Mol. Life Sci. 66, 236–253 (2009).
Fontaine, C., Cousin, W., Plaisant, M., Dani, C. & Peraldi, P. Hedgehog signaling alters adipocyte maturation of human mesenchymal stem cells. Stem Cells 26, 1037–1046 (2008).
Davis, R. L., Weintraub, H. & Lassar, A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987–1000 (1987).
Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755–764 (1997).
Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L. & Karsenty, G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89, 747–754 (1997).
Enomoto, H. et al. Cbfa1 is a positive regulatory factor in chondrocyte maturation. J. Biol. Chem. 275, 8695–8702 (2000).
Christy, R. J. et al. Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes. Genes Dev. 3, 1323–1335 (1989).
Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007).
Hong, J. H. et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309, 1074–1078 (2005).
Akune, T. et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J. Clin. Invest. 113, 846–855 (2004).
Chang, J. et al. Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK. J. Biol. Chem. 282, 30938–30948 (2007).
Chambon, P. The nuclear receptor superfamily: a personal retrospect on the first two decades. Mol. Endocrinol. 19, 1418–1428 (2005).
Evans, R. M. The nuclear receptor superfamily: a rosetta stone for physiology. Mol. Endocrinol. 19, 1429–1438 (2005).
Rosenfeld, M. G., Lunyak, V. V. & Glass, C. K. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 20, 1405–1428 (2006).
Hu, E., Kim, J. B., Sarraf, P. & Spiegelman, B. M. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science 274, 2100–2103 (1996).
Krishnan, V., Bryant, H. U. & Macdougald, O. A. Regulation of bone mass by Wnt signaling. J. Clin. Invest. 116, 1202–1209 (2006).
Baron, R., Rawadi, G. & Roman-Roman, S. Wnt signaling: a key regulator of bone mass. Curr. Top. Dev. Biol. 76, 103–127 (2006).
Veeman, M. T., Axelrod, J. D. & Moon, R. T. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev. Cell 5, 367–377 (2003).
Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001).
Glass, D. A. Jr et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev. Cell 8, 751–764 (2005).
Manolagas, S. C. & Almeida, M. Gone with the Wnts: beta-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism. Mol. Endocrinol. 21, 2605–2614 (2007).
Bennett, C. N. et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc. Natl Acad. Sci. USA 102, 3324–3329 (2005).
Yadav, V. K. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825–837 (2008).
Harada, H. et al. Cbfa1 isoforms exert functional differences in osteoblast differentiation. J. Biol. Chem. 274, 6972–6978 (1999).
Fujino, T. et al. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc. Natl Acad. Sci. USA 100, 229–234 (2003).
Ishitani, T. et al. The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature 399, 798–802 (1999).
Ishitani, T. et al. The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Mol. Cell Biol. 23, 131–139 (2003).
Yang, L. et al. Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. Oncogene 21, 148–152 (2002).
Margueron, R., Trojer, P. & Reinberg, D. The key to development: interpreting the histone code? Curr. Opin. Genet. Dev. 15, 163–176 (2005).
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).
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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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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