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.

MicroRNA-183 increases osteoclastogenesis by repressing heme oxygenase-1

“…Additional medium containing M-CSF and RANKL (40 ng/ml) was added, and the medium was replaced on day 3. After incubation for the indicated times, cells were fixed in 10% formalin for 10 min, and stained for TRAP as described [24]. Numbers of TRAP-positive multinucleated cells (MNC) (three or more nuclei) were scored.…”

Sirt3&ndash;MnSOD axis represses nicotine-induced mitochondrial oxidative stress and mtDNA damage in osteoblasts

“…Nicotine, one of the main compounds in cigarette, influences the biological activity, proliferation, and differentiation of osteoblasts [3][4][5]. In addition, nicotine can also suppress the osteoblast differentiation from human mesenchymal stem cell (MSC) [6]. However, the mechanisms by which nicotine induces dysfunction of osteoblasts are not fully understood.…”

“…Several reports have shown the negative effects of smoking or nicotine on bone homeostasis [1,6]. Furthermore, nicotine could also induce dysfunction and death of osteoblasts [3,4].…”

Role of Heme Oxygenase-1 in Postnatal Differentiation of Stem Cells: A Possible Cross-Talk with MicroRNAs

“…Similar effect was observed when HO-1-overexpressing primary osteoblasts were stimulated with IL-1b (41). HO-1 was also suggested to be a mediator of in vitro osteoblastogenesis of primary rat or human MSCs induced by curcumin (64) and osteoprotegerin (221), or as a factor protecting MSCs from nicotine-dependent inhibition of osteogenic differentiation (92).…”