title: Mevalonate-suppressive dietary isoprenoids for bone health.
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.
authors.affiliation: Department of Nutrition and Food Sciences, Texas Woman's University, Denton, TX 76204, USA. hmo@twu.edu
authors.forename: Huanbiao
authors.initials: H
authors.lastname: Mo
authors.forename: Hoda
authors.initials: H
authors.lastname: Yeganehjoo
authors.forename: Anureet
authors.initials: A
authors.lastname: Shah
authors.forename: Warren K
authors.initials: WK
authors.lastname: Mo
authors.forename: Ima Nirwana
authors.initials: IN
authors.lastname: Soelaiman
authors.forename: Chwan-Li
authors.initials: CL
authors.lastname: Shen
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019587:Dietary Supplements; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors; D004164:Diphosphonates / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010010:Osteoclasts / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D053245:RANK Ligand / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*; D024505:Tocopherols / Q000494:pharmacology; D024508:Tocotrienols; D024482:Vitamin K 2 / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D055396:Bone Morphogenetic Protein 2; D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053245:RANK Ligand; D013729:Terpenes; D024508:Tocotrienols; D024482:Vitamin K 2; D051546:Cyclooxygenase 2; D004122:Dimethylallyltranstransferase; D024505:Tocopherols; D008798:Mevalonic Acid