Abstract
Guanylate Binding Proteins (GBPs) are a group of cytokine-inducible large guanosine triphosphatase. Previous studies have shown high expression of GBP1 in circulating monocytes of premenopausal subjects was correlated to extremely low peak bone mass, which is considered as an important determinant of osteoporosis. However, whether GBPs play a role in regulation of osteogenesis of mesenchymal stromal cells (MSCs) remains largely unknown. In the present study, we found that mRNA expression of GBP1 was highest among all the GBPs, and it was dramatically downregulated during osteogenic differentiation of human MSCs derived from bone marrow (hBM-MSCs). While siRNA-mediated knockdown of GBP1 promoted osteogenesis, overexpression of GBP1 suppressed osteogenesis of hBM-MSCs. Furthermore, we found GBP1 is required for expression of indoleamine 2,3 dioxygenase (IDO), Interleukin 6 (IL-6) and IL-8 induced by treatment with Interferon-γ (IFN-γ). Depletion of GBP1 rescued the inhibited osteogenesis induced by IFN-γ treatment, at least in part. Collectively, our findings indicate GBP1 inhibits osteogenic differentiation of MSCs, and inhibition of GBP1 expression may prevent development of osteoporosis and facilitate MSC-based bone regeneration.
Highlights
The Guanylate Binding Proteins (GBPs) are a subfamily of cytokine-induced dynamin superfamily of large guanosine triphosphatase (GTPases)[13,14,15]
We examined the expression of GBP1 to GBP5 during the osteogenic differentiation of hBM-mesenchymal stromal cells (MSCs)
While GBP2 expression was upregulated after 7 days of osteogenic differentiation, expression of GBP3, GBP4, and GBP5 seemed to be unchanged during osteogenic differentiation of hBM-MSCs (Fig. 1C to F)
Summary
The GBPs are a subfamily of cytokine-induced dynamin superfamily of large guanosine triphosphatase (GTPases)[13,14,15]. HGBP-1 through -5 and all the mGBPs can be induced by interferon-gamma(IFN-γ). In regard to MSCs, previous study has shown that hGBP1 can be induced by IFN-γ, and play an important role in the immunity of hMSCs against Toxoplasma gondii[20]. A recent study has revealed that mGbp[2] was downregulated during osteogenic differentiation of mouse MC3T3 cells, an osteoblast precursor cell line[22]. The role of GBPs in osteogenic differentiation of MSCs remains largely unknown. We evaluated the expression levels of hGBPs during osteogenic differentiation of MSCs derived from human bone marrow (hBM-MSCs), and investigated the changes in osteogenic differentiation potential of BMSCs in response to knockdown and overexpression of hGBP1, respectively. We found hGBP1 was induced by IFN-γ treatment, and was required for the upregulation of the target genes induced by IFN-γ in hBM-MSCs
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