Tags

Type your tag names separated by a space and hit enter

Effects of farnesyl pyrophosphate accumulation on calvarial osteoblast differentiation.
Endocrinology. 2011 Aug; 152(8):3113-22.E

Abstract

Statins, drugs commonly used to lower serum cholesterol, have been shown to stimulate osteoblast differentiation and bone formation. Statins inhibit 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase (HMGCR), the first step of the isoprenoid biosynthetic pathway, leading to the depletion of the isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). The effects of statins on bone have previously been attributed to the depletion of GGPP, because the addition of exogenous GGPP prevented statin-stimulated osteoblast differentiation in vitro. However, in a recent report, we demonstrated that the specific depletion of GGPP did not stimulate but, in fact, inhibited osteoblast differentiation. This led us to hypothesize that isoprenoids upstream of GGPP play a role in the regulation of osteoblast differentiation. We demonstrate here that the expression of HMGCR and FPP synthase decreased during primary calvarial osteoblast differentiation, correlating with decreased FPP and GGPP levels during differentiation. Zaragozic acid (ZGA) inhibits the isoprenoid biosynthetic pathway enzyme squalene synthase, leading to an accumulation of the squalene synthase substrate FPP. ZGA treatment of calvarial osteoblasts led to a significant increase in intracellular FPP and resulted in inhibition of osteoblast differentiation as measured by osteoblastic gene expression, alkaline phosphatase activity, and matrix mineralization. Simultaneous HMGCR inhibition prevented the accumulation of FPP and restored osteoblast differentiation. In contrast, specifically inhibiting GGPPS to lower the ZGA-induced increase in GGPP did not restore osteoblast differentiation. The specificity of HMGCR inhibition to restore osteoblast differentiation of ZGA-treated cultures through the reduction in isoprenoid accumulation was confirmed with the addition of exogenous mevalonate. Similar to ZGA treatment, exogenous FPP inhibited the mineralization of primary calvarial osteoblasts. Interestingly, the effects of FPP accumulation on osteoblasts were found to be independent of protein farnesylation. Our findings are the first to demonstrate that the accumulation of FPP impairs osteoblast differentiation and suggests that the depletion of this isoprenoid may be necessary for normal and statin-induced bone formation.

Authors+Show Affiliations

Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242-1009, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21586555

Citation

Weivoda, Megan M., and Raymond J. Hohl. "Effects of Farnesyl Pyrophosphate Accumulation On Calvarial Osteoblast Differentiation." Endocrinology, vol. 152, no. 8, 2011, pp. 3113-22.
Weivoda MM, Hohl RJ. Effects of farnesyl pyrophosphate accumulation on calvarial osteoblast differentiation. Endocrinology. 2011;152(8):3113-22.
Weivoda, M. M., & Hohl, R. J. (2011). Effects of farnesyl pyrophosphate accumulation on calvarial osteoblast differentiation. Endocrinology, 152(8), 3113-22. https://doi.org/10.1210/en.2011-0016
Weivoda MM, Hohl RJ. Effects of Farnesyl Pyrophosphate Accumulation On Calvarial Osteoblast Differentiation. Endocrinology. 2011;152(8):3113-22. PubMed PMID: 21586555.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of farnesyl pyrophosphate accumulation on calvarial osteoblast differentiation. AU - Weivoda,Megan M, AU - Hohl,Raymond J, Y1 - 2011/05/17/ PY - 2011/5/19/entrez PY - 2011/5/19/pubmed PY - 2011/9/22/medline SP - 3113 EP - 22 JF - Endocrinology JO - Endocrinology VL - 152 IS - 8 N2 - Statins, drugs commonly used to lower serum cholesterol, have been shown to stimulate osteoblast differentiation and bone formation. Statins inhibit 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase (HMGCR), the first step of the isoprenoid biosynthetic pathway, leading to the depletion of the isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). The effects of statins on bone have previously been attributed to the depletion of GGPP, because the addition of exogenous GGPP prevented statin-stimulated osteoblast differentiation in vitro. However, in a recent report, we demonstrated that the specific depletion of GGPP did not stimulate but, in fact, inhibited osteoblast differentiation. This led us to hypothesize that isoprenoids upstream of GGPP play a role in the regulation of osteoblast differentiation. We demonstrate here that the expression of HMGCR and FPP synthase decreased during primary calvarial osteoblast differentiation, correlating with decreased FPP and GGPP levels during differentiation. Zaragozic acid (ZGA) inhibits the isoprenoid biosynthetic pathway enzyme squalene synthase, leading to an accumulation of the squalene synthase substrate FPP. ZGA treatment of calvarial osteoblasts led to a significant increase in intracellular FPP and resulted in inhibition of osteoblast differentiation as measured by osteoblastic gene expression, alkaline phosphatase activity, and matrix mineralization. Simultaneous HMGCR inhibition prevented the accumulation of FPP and restored osteoblast differentiation. In contrast, specifically inhibiting GGPPS to lower the ZGA-induced increase in GGPP did not restore osteoblast differentiation. The specificity of HMGCR inhibition to restore osteoblast differentiation of ZGA-treated cultures through the reduction in isoprenoid accumulation was confirmed with the addition of exogenous mevalonate. Similar to ZGA treatment, exogenous FPP inhibited the mineralization of primary calvarial osteoblasts. Interestingly, the effects of FPP accumulation on osteoblasts were found to be independent of protein farnesylation. Our findings are the first to demonstrate that the accumulation of FPP impairs osteoblast differentiation and suggests that the depletion of this isoprenoid may be necessary for normal and statin-induced bone formation. SN - 1945-7170 UR - https://www.unboundmedicine.com/medline/citation/21586555/Effects_of_farnesyl_pyrophosphate_accumulation_on_calvarial_osteoblast_differentiation_ L2 - https://academic.oup.com/endo/article-lookup/doi/10.1210/en.2011-0016 DB - PRIME DP - Unbound Medicine ER -