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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.

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Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Orthopaedic Surgery, Brown Institute for Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail, CO, USA and.
Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, Medical Academy, Kaunas, Lithuania.
Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA


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.

[Indexed for MEDLINE]
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