title: Cyclooxygenase-2 deficiency impairs muscle-derived stem cell-mediated bone regeneration via cellular autonomous and non-autonomous mechanisms.
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.
authors.affiliation: 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.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.|Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, Medical Academy, Kaunas, Lithuania.
authors.forename: Arvydas
authors.initials: A
authors.lastname: Usas
authors.affiliation: 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.
authors.forename: Aiping
authors.initials: A
authors.lastname: Lu
authors.affiliation: Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Kozemchak
authors.affiliation: Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Poddar
authors.affiliation: Department of Orthopaedic Surgery, Brown Institute for Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Xuying
authors.initials: X
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: James H
authors.initials: JH
authors.lastname: Cummins
authors.affiliation: Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA johnny.huard@uth.tmc.edu.|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.
authors.forename: Johnny
authors.initials: J
authors.lastname: Huard
mesh_terms: D000818:Animals; D001861:Bone Regeneration; D002454:Cell Differentiation; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D032446:Myoblasts / Q000378:metabolism / Q000637:transplantation; D012886:Skull / Q000293:injuries*; D033581:Stem Cell Transplantation
chemical_list: C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2