Statin Suppresses Apoptosis in Osteoblastic Cells: Role of Transforming Growth Factor-β-Smad3 Pathway

Abstract

Statins possess pleiotropic effects in several tissues. Among them, their bone anabolic actions have been recently noted. We have proposed that Smad3, a TGF-beta-signaling molecule, is a promoter of bone formation. However, whether statins would affect TGF-beta-Smad3 pathway in osteoblasts is still unknown. The present study was performed to examine the effects of statin on Smad3 expression and cell apoptosis by employing mouse osteoblastic MC3T3-E1 and rat osteoblastic UMR-106 cells. Statins (pitavastatin, mevastatin, and simvastatin) as well as alendronate increased the levels of Smad3 in MC3T3-E1 cells. The effects of pitavastatin on Smad3 levels were observed from 3 hours and later. Pitavastatin induced the expression of TGF-beta, and cycloheximide, a protein synthesis inhibitor, antagonized the increased levels of pitavastatin on Smad3. On the other hand, pitavastatin antagonized dexamethasone- or etoposide-induced apoptosis in a dose-dependent manner, and Smad3 inactivation by dominant negative Smad3 or an inhibition of endogenous TGF-beta action by SB431542 antagonized anti-apoptotic effects of pitavastatin, indicating that pitavastatin suppressed osteoblast apoptosis partly through TGF-beta-Smad3 pathway. In conclusion, the present study has demonstrated for the first time that statin suppressed cell apoptosis partly through TGF-beta-Smad3 pathway in osteoblastic cells.

Osteogenic/Odontogenic Bioengineering with co-Administration of Simvastatin and Hydroxyapatite on Poly Caprolactone Based Nanofibrous Scaffold

“…34 There is strong evidence that statins increase the differentiation of osteoblasts and mineralization, resulting in osteogenesis. 35,36 In addition, statins increase osteogenesis indirectly by inhibiting inflammation which is responsible for an imbalance in the metabolism of bone. 37 Furthermore statins inhibit the activation of osteoclasts by inhibiting intracellular signaling pathways in osteoclasts 38 and have a role in maintaining the skeletal integrity.…”

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…The bone anabolic action of statins also involves an increased expression and synthesis of osteocalcin by reducing the inhibitory effect of Rho-associated kinase in human osteoblasts (Ohnaka et al, 2001). Statins are also able to partially suppress osteoblast apoptosis through a TGF-␤-Smad3 pathway (Kaji et al, 2008) and regulation of estrogen receptor ␣ expression . Moreover, the proliferation and recruitment of osteoprogenitor cells, critical steps in the early stages of bone healing, were enhanced by simvastatin-stimulated TGF-␤1 and bone morphogenetic protein-2 (Nyan et al, 2010).…”

Osteoporoza prouzrokovana lekovima

“…Povećanje rizika od fraktura kostiju kod pacijenata koji su na terapiji ovim lekovima može biti nezavisno od promene gustine mineralne strukture kostiju. To se objašnjava time da apoptoza osteocita brzo dovodi do slabljenja strukture kosti, što povećava rizik od preloma [9,10]. Visoke doze egzogeno unetih glukokortikoida dovode i do netraumatskih osteonekrotičnih promena u glavi butne kosti [11,12].…”