Abstract
Long-term or high-dose use of glucocorticoids causes bone loss and low bone formation.
We previously demonstrated that dexamethasone (Dex) administration caused the shifted
differentiation balance of mesenchymal stromal cells (MSCs) to favor adipogenic lineage
over osteoblastic lineage, which is one of the key mechanisms for Dex-induced osteoporosis
(DIO). These findings indicate that supplementing functional allogeneic MSCs could
be a therapeutic strategy for DIO. Here, we found that transplanting MSCs by intramedullary
injection had little effect in promoting new bone formation. Fluorescent-labeled lineage
tracing revealed that 1 week after transplantation, green fluorescent protein (GFP)-MSCs
were found to migrate to the bone surface (BS) in control mice but not in DIO mice.
As expected, GFP-MSCs on the BS were mostly Runx2-positive; however, GFP-MSCs located
away from the BS failed to differentiate into osteoblasts. We further discovered that
the levels of transforming growth factor beta 1 (TGF-β1), one of the main chemokines
for MSC migration, is significantly decreased in the bone marrow fluid of DIO mice,
which is insufficient to direct MSC migration. Mechanistically, Dex inhibits TGF-β1
expression by down-regulating its promoter activity, which decreases bone matrix–deposited
TGF-β1 as well as active TGF-β1 released during osteoclast-mediated bone resorption.
This study indicates that blocking MSC migration in osteoporotic BM contributes to
bone loss and suggests that MSC mobilization to the BS may be a promising target for
treating osteoporosis.
Key Words
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Article info
Publication history
Published online: February 28, 2023
Accepted:
January 7,
2023
Received:
May 3,
2022
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.
