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Hum Mol Genet. 2016 Aug 1;25(15):3216-3231. doi: 10.1093/hmg/ddw172. Epub 2016 Jun 27.

Cyclooxygenase-2 deficiency impairs muscle-derived stem cell-mediated bone regeneration via cellular autonomous and non-autonomous mechanisms.

Gao X1,2,3, Usas A1,4, Lu A1,2,3, Kozemchak A1, Tang Y1, Poddar M1, Sun X2, Cummins JH1,2,3, Huard J5,2,3.

Author information

1
Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
2
Department of Orthopaedic Surgery, Brown Institute for Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
3
Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail, CO, USA and.
4
Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, Medical Academy, Kaunas, Lithuania.
5
Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA johnny.huard@uth.tmc.edu.

Abstract

This study investigated the role of cyclooxygenase-2 (COX-2) expression by donor and host cells in muscle-derived stem cell (MDSC)-mediated bone regeneration utilizing a critical size calvarial defect model. We found that BMP4/green fluorescent protein (GFP)-transduced MDSCs formed significantly less bone in COX-2 knock-out (Cox-2KO) than in COX-2 wild-type (WT) mice. BMP4/GFP-transduced Cox-2KO MDSCs also formed significantly less bone than transduced WT MDSCs when transplanted into calvarial defects created in CD-1 nude mice. The impaired bone regeneration in the Cox-2KO MDSCBMP4/GFP group is associated with downregulation of BMP4-pSMAD1/5 signaling, decreased osteogenic differentiation and lowered proliferation capacity after transplantation, compared with WT MDSCBMP4/GFP cells. The Cox-2KO MDSCBMP4/GFP group demonstrated a reduction in cell survival and direct osteogenic differentiation in vitro These effects were mediated in part by the downregulation of Igf1 and Igf2. In addition, the Cox-2KO MDSCBMP4/GFP cells recruited fewer macrophages than the WT MDSC/BMP4/GFP cells in the early phase after injury. We concluded that the bone regeneration capacity of Cox-2KO MDSCs was impaired because of a reduction in cell proliferation and survival capacities, reduction in osteogenic differentiation and a decrease in the ability of the cells to recruit host cells to the injury site.

PMID:
27354351
PMCID:
PMC5179923
DOI:
10.1093/hmg/ddw172
[Indexed for MEDLINE]
Free PMC Article

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