Simvastatin induces adverse effects on proliferation and mineralization of human primary osteoblasts

Abstract

Background: Frequently statins were administered to reduce the LDL-concentration in circulating blood. Especially simvastatin (SV) is an often prescribed statin. Pleiotropic effects of these drugs were reported. Thus, the aim of this study was to evaluate effects of SV on osteoblastic mineralization. Methods: After informed consent primary osteoblasts were collected from tissue surplus after treatment of 14 individuals in the Department of Cranio-Maxillofacial Surgery, University Hospital Münster. The cells were passaged according to established protocols. Viability, mineralization capability and osteoblastic marker (alkaline phosphatase) were determined at day 9, 13 and 16 after adding various SV concentrations (0.05 μM, 0.1 μM, 0.5 μM, 1.0 μM). Statistical analysis was performed using the Kruskal-Wallis-test. Results: The cell cultures showed a time and dose-dependent significantly decreased viability (p < 0.01) and a significantly increased mineralization (p < 0.01) in a late mineralization stage after adding SV. The typical alteration of the alkaline phosphatase (ALP) levels during osteogenic differentiation was not recognizable. Conclusions: The pleiotropic effects found for different SV concentrations were possibly originated from other mineralization pathways beside the ALP induced one. Additionally, possible alterations of protein expression levels during mineralization and investigation of possible deviating application of SV in other treatment fields can be considered after gaining a deeper insight in the affected mechanisms.

Simvastatin Induces In Vitro Mineralization Effects of Primary Human Odontoblast-Like Cells

“…Significantly decreased cell viability, increased phosphate turnover and significant (p < 0.01) increase of the mineralization capability of the odontoblast-like cells point to a linkage between SV and the ability of biomineralization of odontoblast-like cells especially at a later stage of culture in the current study (day 21) (Figure 4) [30,34,35,37]. Although cytotoxic effects of SV are recognizable in a time and dose-dependent manner upon human osteoblasts, odontoblast-like cells and likewise other cell types [23,24,46,47] the application of SV induced a 2 times elevated median value of the ALP conversion in the group with 2 µM SV compared to the control group (Figure 3). Additionally, the median value of the mineralization capability of the group with the same concentration was approximately 3 times higher compared with the control group (Figure 4).…”

“…Several studies investigated the effects of simvastatin on human osteoblasts [20,23,24,40]. Influence of SV on mineralization, alteration of the expression of osteogenic markers and viability were shown but the toxicity levels of osteoblasts were in general lower compared to those of odontoblast-like cells [20,24,39].…”

“…Due to reported adverse effects, some studies investigated such effects in the cells of other tissues than those originally targeted. Different human cell types had been investigated, such as adipose tissue cells [18,19], osteoblasts [20][21][22][23] and bone marrow cells [24].…”

“…Compared to bisphosphonates, statins also influence the mevalonate pathway by inhibiting the HMG-CoA reductase [25]. Beside these observational studies, both in vitro [23,24,26,27] and in vivo studies [28] proved mineralization effects of SV to be bone-related cells like osteoblasts. Besides the typical bone-related cells, other mineralizing cells like human odontoblast-like cells or dental pulp cells were also investigated [29][30][31][32][33][34][35][36][37].…”

Pleiotropic effects on proliferation and mineralization of primary human adipose tissue-derived stromal cells induced by simvastatin

“…In previous studies mineralization potential [6,27], expression of osteogenic markers on gene and protein level [10,14,27] and osteoblastic differentiation and proliferation [9,14,27] were investigated under influence of SV. The used human cells were, for instance, obtained from tissues like bone marrow and mesenchymal stem cells [14], periodontal ligament [10,27], odontoblast-like cells [11], cells from adipose tissues [5,28] and osteoblasts from bone chips [8]. The used SV concentrations in animal studies of rodent origin [6,7,[15][16][17][18][19][20][29][30][31][32][33] were quiet equal.…”