The effects of PPAR-γ inhibition on gene expression and the progression of induced osteogenic differentiation of human mesenchymal stem cells.
Mesenchymal stem cells (MSCs) can differentiate into several cell types, such as osteoblasts and adipocytes, both in vitro and in vivo. Although these two differentiation pathways are distinct from each other, cross-communication between cells of the two lineages exists both systemically and peripherally in the tissue. The transcription factor PPAR-γ, the main switch in adipogenic differentiation of MSCs, has previously been described to have a negative effect on osteogenic differentiation. The aim of this study was to investigate the effect of PPAR-γ inhibition on osteogenic differentiation of human MSCs, in vitro. Extracellular matrix analysis and quantification of osteogenic markers, revealed how these cells respond when the adipogenic differentiation pathway is blocked during induction of osteogenic differentiation. The inhibition leads to a significant increase in mineralization of the extracellular matrix, as well as an increased activity or up-regulated gene expression of alkaline phosphatase, the key enzyme involved in matrix mineralization. Furthermore, it was also demonstrated by microarray analysis, that PPAR-γ inhibition during osteogenic induction leads to a significant up-regulation of a number of genes related to both osteogenesis and adipogenesis such as c10orf10, leptin, GDF5 and KLF15. In conclusion, inhibition of PPAR-γ during induction of osteogenesis leads to increased osteogenic differentiation of human MSCs.
Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg , Gothenburg , Sweden .
Cecilia
C
Granéli
Camilla
C
Karlsson
Helena
H
Brisby
Anders
A
Lindahl
Peter
P
Thomsen
D050156:Adipogenesis; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000943:Antigens, Differentiation; D047495:PPAR gamma
Adipogenic differentiation; PPAR-γ; leptin; mesenchymal stem cells; osteogenic differentiation