title: Peroxisome proliferator-activated receptor delta agonist attenuates nicotine suppression effect on human mesenchymal stem cell-derived osteogenesis and involves increased expression of heme oxygenase-1.
abstract: Smoking has long been associated with osteoporosis, decreased bone mineral density, increased risk of bone fracture, and increased health costs. Nicotine, the main component of cigarette smoke, has major negative effects on bone metabolism and skeletal remodeling in vivo. Although osteoblasts and osteoblast-like cells have been used extensively to study the impact of nicotine, few studies have been performed on human mesenchymal stem cells (hMSCs). In this context, we examined the impact of nicotine on (a) hMSCs proliferation, (b) osteoblastic differentiation, (c) alkaline phosphatase (ALP) activity, and (d) expression of canonical genes during differentiation of hMSCs. MSCs isolated from human bone marrow were treated with different concentrations (0, 0.1, 1 and 10 μM) of nicotine for 7 days. Nicotine caused a dose-dependent decrease in cell proliferation, decreased heme oxygenase-1 (HO-1) expression (p < 0.05) and attenuated osteogenesis (p < 0.05) in hMSCs (45 % reduction at day 14). In addition, nicotine caused a dose-dependent decrease in alizarin red staining for calcium and staining for ALP. Induction of HO-1 by peroxisome proliferator-activated receptor delta agonist (GW0742) prevented the effect of nicotine. Nicotine caused a dose-dependent reduction in the expression of BMP-2, a well-known marker for bone formation; however, this was prevented by GW0742 treatment. Therefore, induction of HO-1 prevents the deleterious effects of nicotine on osteogenesis in hMSC. This offers insight into both how nicotine affects bone remodeling and a therapeutic approach to prevent fracture and osteoporosis in smokers.
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA. donghyun.kim@utoledo.edu
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Jiayong
authors.initials: J
authors.lastname: Liu
authors.forename: Samerna
authors.initials: S
authors.lastname: Bhat
authors.forename: Gregory
authors.initials: G
authors.lastname: Benedict
authors.forename: Beata
authors.initials: B
authors.lastname: Lecka-Czernik
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Peterson
authors.forename: Nabil A
authors.initials: NA
authors.lastname: Ebraheim
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Heck
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis; D016723:Bone Remodeling / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D009538:Nicotine / Q000009:adverse effects / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000009:adverse effects / Q000494:pharmacology*; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D010024:Osteoporosis / Q000378:metabolism / Q000517:prevention & control; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D000469:Alkaline Phosphatase; D055396:Bone Morphogenetic Protein 2; D002118:Calcium; D051547:Heme Oxygenase-1; D009538:Nicotine; D018722:Nicotinic Agonists; D047494:PPAR delta; D013844:Thiazoles; C525718:BMP2 protein, human; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C496541:HMOX1 protein, human