Geranylgeraniol (GGOH) as a Mevalonate Pathway Activator in the Rescue of Bone Cells Treated with Zoledronic Acid: An In Vitro Study

Fliefel, Riham; Entekhabi, S.; Ehrenfeld, Michael; Otto, Sven

doi:10.1155/2019/4351327

Cited by 24 publications

(32 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The immobilization of species such as lutein or geranylgeraniol in the synthesized samples is not harmful since they are no toxic and present therapeutic properties. [63][64][65] The radical scavenger capacity of norbixin solutions and LDH-Norbix materials was evaluated by reaction with the stable DPPH free radical. This probe species supports an odd electron in the nitrogen atom that is reduced to hydrazine by an antioxidant that transfers hydrogen atom.…”

Section: Resultsmentioning

confidence: 99%

Intercalation of Apocarotenoids from Annatto (Bixa orellana L.) into Layered Double Hydroxides

Perotti¹,

Silva²,

Couto³

et al. 2020

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

Synthetic conditions were evaluated to intercalate norbixin into layered double hydroxides (LDH). Norbixin was isolated from a hydrosoluble commercial annatto extract. LDH samples comprising M 2+ /Al 3+ (M = Mg, Zn) were synthesized by coprecipitation and characterized by X-ray diffraction, thermal analysis coupled to mass spectrometry, vibrational spectroscopies, and solid-state 13 C nuclear magnetic resonance. Radical scavenging activity of LDH hybrids was monitored by electron paramagnetic resonance towards the stable radical DPPH (1,1-diphenyl-2-picrylhydrazyl). LDH hosts presented more than 50 wt.% of norbixin and d-spacing (003) values of about 2.5 or 3.0 nm depending of the cation LDH composition. Vibrational spectra assignment (supported by density functional theory calculations) confirmed the chemical integrity of norbixin after intercalation into LDH. The inorganic layers were found to enhance the thermal stability of norbixin upon intercalation. The free radical scavenging capacity of norbixin was retained when immobilized into LDH. Considering that zinc and magnesium-LDH matrices are biocompatible and that norbixin presents biological activity, the hybrid materials appear as promising systems for biomedical assessment.

show abstract

Section: Resultsmentioning

confidence: 99%

Intercalation of Apocarotenoids from Annatto (Bixa orellana L.) into Layered Double Hydroxides

Perotti¹,

Silva²,

Couto³

et al. 2020

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

show abstract

“…[6] Additionally the protein prenylation function of osteoclasts has recently been shown to be restored by GGOH in osteoclasts exposed to zoledronate. [8] To our knowledge GGOH induced rescue of osteoclast function as measured by their ability to resorb calcium phosphate from a substrate has not been shown.…”

Section: Discussionmentioning

confidence: 89%

Geranylgeraniol in Bone Cement Rescues Osteoclasts from the Toxic Effects of Pamidronate and Restores Function

Feldman¹,

Yagnik²,

Taub³

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundExposed intraoral bone in medically related osteonecrosis of the jaw (MRONJ) is a devastatingly side effect of treatment with nitrogen containing bisphosphonates(NBPs) The pathogenesis of the condition is thought to be caused by NBP inhibition of farnesyl diphosphate synthase (FDPS), a critical enzyme in the mevalonate pathway. This block suppresses the prenylation of factors necessary for the maintenance and survival of osteoclasts. Geranylgeraniol (GGOH), a metabolite in the mevalonate pathway downstream of FDPS, reverses the block NBPs impose on osteoclasts. However, no effective method currently exists to deliver GGOH locally to NBP-induced lesions in the mouth. The purpose of this study is to develop a biocompatible, resorbable and tunable carrier to deliver GGOH intraorally and thereby reverse the damaging effects of MRONJ.MethodsPrimary human oral fibroblasts and RAW264.7 osteoclasts were exposed to pamidronate in vitro and GGOH contained within a bone cement pellet and survival of the cells was measured. The kinetics of release of 3HGGOH from the bone cement was measured.. The resorptive function of osteoclasts exposed to pamidronate with or without GGOH was quantitated by measuring the release of bound fluorescent dye from a CaPO4 coated plate. Resorption areas on this plate were photographed.ResultsHuman gingival fibroblasts exposed to pamidronate (100uM) alone decreased survival by 49% (p<0.001) over 72 hours, 2mM GGOH incorporated into bone cement rescued these cells from the toxic effect of NBP (p=0.0024).Exposure of osteoclasts to 400 and 800uM pamidronate over 72 hours showed a 49% and 69% loss of viability respectively. (p<0.0001 for each concentration). 2mM GGOH incorporated into bone cement increased survival by 247% (p=0.0001) for the cells treated with 800uM pamidronate and 4mM GGOH by 450% (p<0.0001). Pamidronate at both concentrations reduced osteoclast function and 4mM GGOH completely restored resorbtive function. At a powder to liquid ration of 2.5:1 92% of the loaded metabolite was released into medium after in 96 hours.ConclusionsGGOH contained in a bone cement carrier can rescue osteoclast function from the toxic effects of pamidronate. This carrier may be the first step in local delivery of this metabolite in the oral cavity.

show abstract

“…8: 202066 geranylgeranylated. Decreased prenylation of other small GTPases, such as Rap, Ras and Cdc42, has been linked to some effects of ZA [40][41][42][43]. These proteins are essential for multiple cellular processes, including cell proliferation, cell movement, cytoskeletal rearrangement and apoptosis [19,44,45].…”

Section: Discussionmentioning

confidence: 99%

Geranylgeraniol prevents zoledronic acid-mediated reduction of viable mesenchymal stem cells via induction of Rho-dependent YAP activation

2021

View full text Add to dashboard Cite

Long-term use of zoledronic acid (ZA) increases the risk of medication-related osteonecrosis of the jaw (MRONJ). This may be attributed to ZA-mediated reduction of viable mesenchymal stem cells (MSCs). ZA inhibits protein geranylgeranylation, thus suppressing cell viability and proliferation. Geranylgeraniol (GGOH), which is a naturally found intermediate compound in the mevalonate pathway, has positive effects against ZA. However, precise mechanisms by which GGOH may help preserve stem cell viability against ZA are not fully understood. The objective of this study was to investigate the cytoprotective mechanisms of GGOH against ZA. The results showed that while ZA dramatically decreased the number of viable MSCs, GGOH prevented this negative effect. GGOH-rescued ZA-exposed MSCs formed mineralization comparable to that produced by normal MSCs. Mechanistically, GGOH preserved the number of viable MSCs by its reversal of ZA-mediated Ki67 + MSC number reduction, cell cycle arrest and apoptosis. Moreover, GGOH prevented ZA-suppressed RhoA activity and YAP activation. The results also established the involvement of Rho-dependent YAP and YAP-mediated CDK6 in the cytoprotective ability of GGOH against ZA. In conclusion, GGOH preserves a pool of viable MSCs with osteogenic potency against ZA by rescuing the activity of Rho-dependent YAP activation, suggesting GGOH as a promising agent and YAP as a potential therapeutic target for MRONJ.

show abstract

Geranylgeraniol (GGOH) as a Mevalonate Pathway Activator in the Rescue of Bone Cells Treated with Zoledronic Acid: An In Vitro Study

Cited by 24 publications

References 40 publications

Intercalation of Apocarotenoids from Annatto (Bixa orellana L.) into Layered Double Hydroxides

Intercalation of Apocarotenoids from Annatto (Bixa orellana L.) into Layered Double Hydroxides

Geranylgeraniol in Bone Cement Rescues Osteoclasts from the Toxic Effects of Pamidronate and Restores Function

Geranylgeraniol prevents zoledronic acid-mediated reduction of viable mesenchymal stem cells via induction of Rho-dependent YAP activation

Contact Info

Product

Resources

About