Canonical FGFs Prevent Osteogenic Lineage Commitment and Differentiation of Human Bone Marrow Stromal Cells Via ERK1/2 Signaling.
Controlling the adipo-osteogenic lineage decision of trabecular human bone marrow stromal cells (hBMSCs) in favor of osteogenesis represents a promising approach for osteoporosis therapy and prevention. Previously, Fibroblast Growth Factor 1 (FGF1) and its subfamily member FGF2 were scored as leading candidates to exercise control over skeletal precursor commitment and lineage decision albeit literature results are highly inconsistent. We show here that FGF1 and 2 strongly prevent the osteogenic commitment and differentiation of hBMSCs. Mineralization of extracellular matrix (ECM) and mRNA expression of osteogenic marker genes Alkaline Phosphatase (ALP), Collagen 1A1 (COL1A1), and Integrin-Binding Sialoprotein (IBSP) were significantly reduced. Furthermore, master regulators of osteogenic commitment like Runt-Related Transcription Factor 2 (RUNX2) and Bone Morphogenetic Protein 4 (BMP4) were downregulated. When administered under adipogenic culture conditions, canonical FGFs did not support osteogenic marker expression. Moreover despite the presence of osteogenic differentiation factors, FGFs even disabled the pro-osteogenic lineage decision of pre-differentiated adipocytic cells. In contrast to FGF Receptor 2 (FGFR2), FGFR1 was stably expressed throughout osteogenic and adipogenic differentiation and FGF addition. Moreover, FGFR1 and Extracellular Signal-Regulated Kinases 1 and 2 (ERK1/2) were found to be responsible for underlying signal transduction using respective inhibitors. Taken together, we present new findings indicating that canonical FGFR-ERK1/2 signaling entrapped hBMSCs in a pre-committed state and arrested further maturation of committed precursors. Our results might aid in unraveling and controlling check points relevant for ageing-associated aberrant adipogenesis with consequences for the treatment of degenerative diseases such as osteoporosis and for skeletal tissue engineering strategies. J. Cell. Biochem. 118: 263-275, 2017. © 2016 Wiley Periodicals, Inc.
Department of Orthopedics, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
Meike
M
Simann
Department of Orthopedics, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
Solange
S
Le Blanc
Chair Tissue Engineering & Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany.
Verena
V
Schneider
Department of Orthopedics, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
Viola
V
Zehe
Orthopedic Department König-Ludwig-Haus, Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
Martin
M
Lüdemann
Department of Orthopedics, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
Norbert
N
Schütze
Department of Orthopedics, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
Franz
F
Jakob
Department of Orthopedics, Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
Tatjana
T
Schilling
D000328:Adult; D000368:Aged; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
D000943:Antigens, Differentiation; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
ADIPOGENIC; DIFFERENTIATION; FGF1; FGF2; MSC; OSTEOGENIC; hBMSC