Mevalonate-suppressive dietary isoprenoids for bone health

Huanbiao Mo, Hoda Yeganehjoo, Anureet Shah, Warren K. Mo, Ima Nirwana Soelaiman, Chwan Li Shen

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Osteoclastogenesis and osteoblastogenesis, the balancing acts for optimal bone health, are under the regulation of small guanosine triphosphate-binding proteins (GTPases) including Ras, Rac, Rho and Rab. The activities of GTPases require post-translational modification with mevalonate-derived prenyl pyrophosphates. Mevalonate deprivation induced by competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (e.g., statins) prevents the activation of GTPases, suppresses the expression of the receptor for activation of nuclear factor kappa B (NFκB) ligand (RANKL) and activation of NFκB and, consequently, inhibits osteoclast differentiation and induces osteoclast apoptosis. In contrast, statin-mediated inactivation of GTPases enhances alkaline phosphatase activity and the expression of bone morphogenetic protein-2, vascular epithelial growth factor, and osteocalcin in osteoblasts and induces osteoblast proliferation and differentiation. Animal studies show that statins inhibit bone resorption and increase bone formation. The anabolic effect of statins and other mevalonate pathway-suppressive pharmaceuticals resembles the anti-osteoclastogenic and bone-protective activities conferred by dietary isoprenoids, secondary products of plant mevalonate metabolism. The tocotrienols, vitamin E molecules with HMG CoA reductase-suppressive activity, induce mevalonate deprivation and concomitantly suppress the expression of RANKL and cyclooxygenase-2, the production of prostaglandin E2 and the activation of NFκB. Accordingly, tocotrienols inhibit osteoclast differentiation and induce osteoclast apoptosis, impacts reminiscent of those of statins. In vivo studies confirm the bone protective activity of tocotrienols at nontoxic doses. Blends of tocotrienols, statins and isoprenoids widely found in fruits, vegetables, grains, herbs, spices, and essential oils may synergistically suppress osteoclastogenesis while promoting osteoblastogenesis, offering a novel approach to bone health that warrants clinical studies.

Original languageEnglish
Pages (from-to)1543-1551
Number of pages9
JournalJournal of Nutritional Biochemistry
Volume23
Issue number12
DOIs
Publication statusPublished - Dec 2012

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Mevalonic Acid
Terpenes
Tocotrienols
Bone
GTP Phosphohydrolases
Health
Osteoclasts
Bone and Bones
NF-kappa B
Chemical activation
Osteogenesis
Osteoblasts
Oxidoreductases
Apoptosis
Anabolic Agents
ras Proteins
Bone Morphogenetic Protein 2
Spices
Diphosphates

Keywords

  • HMG CoA reductase
  • Isoprenoid
  • Mevalonate
  • Osteoblast
  • Osteoclast
  • Tocotrienol

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

Cite this

Mevalonate-suppressive dietary isoprenoids for bone health. / Mo, Huanbiao; Yeganehjoo, Hoda; Shah, Anureet; Mo, Warren K.; Soelaiman, Ima Nirwana; Shen, Chwan Li.

In: Journal of Nutritional Biochemistry, Vol. 23, No. 12, 12.2012, p. 1543-1551.

Research output: Contribution to journalArticle

Mo, Huanbiao ; Yeganehjoo, Hoda ; Shah, Anureet ; Mo, Warren K. ; Soelaiman, Ima Nirwana ; Shen, Chwan Li. / Mevalonate-suppressive dietary isoprenoids for bone health. In: Journal of Nutritional Biochemistry. 2012 ; Vol. 23, No. 12. pp. 1543-1551.
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AB - Osteoclastogenesis and osteoblastogenesis, the balancing acts for optimal bone health, are under the regulation of small guanosine triphosphate-binding proteins (GTPases) including Ras, Rac, Rho and Rab. The activities of GTPases require post-translational modification with mevalonate-derived prenyl pyrophosphates. Mevalonate deprivation induced by competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (e.g., statins) prevents the activation of GTPases, suppresses the expression of the receptor for activation of nuclear factor kappa B (NFκB) ligand (RANKL) and activation of NFκB and, consequently, inhibits osteoclast differentiation and induces osteoclast apoptosis. In contrast, statin-mediated inactivation of GTPases enhances alkaline phosphatase activity and the expression of bone morphogenetic protein-2, vascular epithelial growth factor, and osteocalcin in osteoblasts and induces osteoblast proliferation and differentiation. Animal studies show that statins inhibit bone resorption and increase bone formation. The anabolic effect of statins and other mevalonate pathway-suppressive pharmaceuticals resembles the anti-osteoclastogenic and bone-protective activities conferred by dietary isoprenoids, secondary products of plant mevalonate metabolism. The tocotrienols, vitamin E molecules with HMG CoA reductase-suppressive activity, induce mevalonate deprivation and concomitantly suppress the expression of RANKL and cyclooxygenase-2, the production of prostaglandin E2 and the activation of NFκB. Accordingly, tocotrienols inhibit osteoclast differentiation and induce osteoclast apoptosis, impacts reminiscent of those of statins. In vivo studies confirm the bone protective activity of tocotrienols at nontoxic doses. Blends of tocotrienols, statins and isoprenoids widely found in fruits, vegetables, grains, herbs, spices, and essential oils may synergistically suppress osteoclastogenesis while promoting osteoblastogenesis, offering a novel approach to bone health that warrants clinical studies.

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