Autocrine fibroblast growth factor 18 mediates dexamethasone‐induced osteogenic differentiation of murine mesenchymal stem cells

Abstract

The potential of mesenchymal stem cells (MSC) to differentiate into functional bone forming cells provides an important tool for bone regeneration. The identification of factors capable of promoting osteoblast differentiation in MSCs is therefore critical to enhance the osteogenic potential of MSCs. Using microarray analysis combined with biochemical and molecular approach, we found that FGF18, a member of the FGF family, is upregulated during osteoblast differentiation induced by dexamethasone in murine MSCs. We showed that overexpression of FGF18 by lentiviral (LV) infection, or treatment of MSCs with recombinant human (rh)FGF18 increased the expression of the osteoblast specific transcription factor Runx2, and enhanced osteoblast phenotypic marker gene expression and in vitro osteogenesis. Molecular silencing using lentiviral shRNA demonstrated that downregulation of FGFR1 or FGFR2 abrogated osteoblast gene expression induced by either LV-FGF18 or rhFGF18, indicating that FGF18 enhances osteoblast differentiation in MSCs via activation of FGFR1 or FGFR2 signaling. Biochemical and pharmacological analyses showed that the induction of phenotypic osteoblast markers by LV-FGF18 is mediated by activation of ERK1/2-MAPKs and PI3K signaling in MSCs. These results reveal that FGF18 is an essential autocrine positive regulator of the osteogenic differentiation program in murine MSCs and indicate that osteogenic differentiation induced by FGF18 in MSCs is triggered by FGFR1/FGFR2-mediated ERK1/2-MAPKs and PI3K signaling.

Bioinformatics analysis on the differentiation of bone mesenchymal stem cells into osteoblasts and adipocytes

“…Osteoblastic or adipocytic differentiation occurs when MSCs are cultured in three conditions in vitro : i) Three-dimensional culture format; ii) serum-free nutrient medium; and iii) with the addition of inducible factors, such as bone morphogenetic protein 6 (BMP-6) and dexamethasone (4). BMP-6 or dexamethasone may induce osteoblastic or adipocytic differentiation of MSCs, respectively, via crosstalk with signaling pathways, including mitogen-activated protein kinase, Wnt, Notch and nuclear factor-kappa B (5–7). …”

Controlled release of dexamethasone from peptide nanofiber gels to modulate inflammatory response

“…In addition, Dex is known to be an important signaling molecule to promote differentiation in bone marrow-derived stromal cells and mesenchymal stem cells [17–21]. In order to harness its anti-inflammatory function or to stimulate differentiation, non-covalent Dex incorporation and release has been included in the design of a number of biomaterials [22–27].…”

Investigating the Role of FGF18 in the Cultivation and Osteogenic Differentiation of Mesenchymal Stem Cells

“…4). Osteogenic differentiation by FGF18 has been previously reported in murine MSCs [23]. FGF18 is an essential positive autocrine regulator of the osteogenic differentiation in murine MSCs, and the osteogenic differentiation induced by FGF18 in MSCs was found to be triggered by FGFR1/FGFR2-mediated ERK1/2-MAPKs and PI3K signaling, which indicates that FGF18 is required for osteogenesis.…”

“…In addition, rhFGF18 has been shown to participate in limb bud mesenchymal cells by suppressing the proliferation and promoting differentiation in cartilage matrix [22]. Notably, rhFGF18 has been also involved in osteogenic differentiation by inducing the osteoblast gene expression on murine MSCs including BMC10 murine mesencymal stem cell and murine C3H10T1/2 stem cells [23]. Taken together, FGF18 may play a crucial role in proliferation and differentiation on MSCs.…”