Abstract
Osteoporosis is a progressive systemic skeletal disease associated with decreased bone mineral density and deterioration of bone quality, and it affects millions of people worldwide. Currently, it is treated mainly using antiresorptive and osteoanabolic agents. However, these drugs have severe adverse effects. Cell replacement therapy using mesenchymal stem cells (MSCs) could serve as a treatment strategy for osteoporosis in the future. LIGHT (HVEM-L, TNFSF14, or CD258) is a member of the tumor necrosis factor superfamily. However, the effect of recombinant LIGHT (rhLIGHT) on osteogenesis in human bone marrow-derived MSCs (hBM-MSCs) is unknown. Therefore, we monitored the effects of LIGHT on osteogenesis of hBM-MSCs. Lymphotoxin-β receptor (LTβR), which is a LIGHT receptor, was constitutively expressed on the surface of hBM-MSCs. After rhLIGHT treatment, calcium and phosphate deposition in hBM-MSCs, stained by Alizarin red and von Kossa, respectively, significantly increased. We performed quantitative real-time polymerase chain reaction to examine the expressions of osteoprogenitor markers (RUNX2/CBFA1 and collagen I alpha 1) and osteoblast markers (alkaline phosphatase, osterix/Sp7, and osteocalcin) and immunoblotting to assess the underlying biological mechanisms following rhLIGHT treatment. We found that rhLIGHT treatment enhanced von Kossa- and Alizarin red-positive hBM-MSCs and induced the expression of diverse differentiation markers of osteogenesis in a dose-dependent manner. WNT/β-catenin pathway activation strongly mediated rhLIGHT-induced osteogenesis of hBM-MSCs, accelerating the differentiation of hBM-MSCs into osteocytes. In conclusion, the interaction between LIGHT and LTβR enhances osteogenesis of hBM-MSCs. Therefore, LIGHT might play an important role in stem cell therapy.
Highlights
LIGHT [tumor necrosis factor (TNF) superfamily protein 14 (TNFSF14), CD258, and lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry in Tcells] is a cytokine that is primarily expressed in immature dendritic cells (DCs), activated T-cells, monocytes, granulocytes, and spleen cells [15]
Lymphotoxin-β receptor (LTβR) was constitutively expressed on the surface of hBM-mesenchymal stem cells (MSCs) (S1C Fig)
In the sample on day 21, calcium deposition began to be observed in the control group, and the degree of calcium deposition was accelerated in the Recombinant human LIGHT (rhLIGHT) treatment group
Summary
Osteoporosis is a progressive systemic skeletal disease characterized by bone mineral density reduction and bone quality deterioration that affects millions of people worldwide [1]. MSCs are multipotent cells with tremendous potential as a new therapeutic drug [6, 7] These cells are present in various tissues and organs, including the bone marrow, umbilical cord, adipose tissues, dental pulp, and placenta [8, 9]. LIGHT [tumor necrosis factor (TNF) superfamily protein 14 (TNFSF14), CD258, and lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry in Tcells] is a cytokine that is primarily expressed in immature DCs, activated T-cells, monocytes, granulocytes, and spleen cells [15] It has three receptors: herpesvirus entry mediator (HVEM; TNFRSF14, CD270), lymphotoxin β receptor (LTβR; TNFRSF3), and decoy receptor-3 [16]. In this study, we investigated the role of LIGHT/LTβR interaction on osteogenesis of hBM-MSCs
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