Identifying potential therapeutics for osteoporosis by exploiting the relationship between mevalonate pathway and bone metabolism

Wan N.W. Hasan, Chin Kok Yong, James J. Jolly, Norzana Abd. Ghafar, Ima Nirwana Soelaiman

Research output: Contribution to journalReview article

1 Citation (Scopus)

Abstract

Background: Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling. Objective: This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential. Discussion: Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans. Conclusion: Mevalonate pathway can be exploited to develop effective antiosteoporosis agents.

Original languageEnglish
Pages (from-to)450-457
Number of pages8
JournalEndocrine, Metabolic and Immune Disorders - Drug Targets
Volume18
Issue number5
DOIs
Publication statusPublished - 1 Jan 2018

Fingerprint

Mevalonic Acid
Osteoporosis
Bone and Bones
Protein Prenylation
Tocotrienols
Bone Remodeling
Bone Resorption
Osteogenesis
Oxidoreductases
Geranyltranstransferase
Cholesterol
Therapeutics
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Diphosphonates
Vitamin E
Bone Density
Enzymes

Keywords

  • Bone
  • Bone metabolism
  • Mevalonate pathway
  • Osteoporosis
  • Tocotrienol
  • Vitamin E

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Immunology and Allergy

Cite this

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title = "Identifying potential therapeutics for osteoporosis by exploiting the relationship between mevalonate pathway and bone metabolism",
abstract = "Background: Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling. Objective: This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential. Discussion: Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans. Conclusion: Mevalonate pathway can be exploited to develop effective antiosteoporosis agents.",
keywords = "Bone, Bone metabolism, Mevalonate pathway, Osteoporosis, Tocotrienol, Vitamin E",
author = "Hasan, {Wan N.W.} and {Kok Yong}, Chin and Jolly, {James J.} and {Abd. Ghafar}, Norzana and Soelaiman, {Ima Nirwana}",
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TY - JOUR

T1 - Identifying potential therapeutics for osteoporosis by exploiting the relationship between mevalonate pathway and bone metabolism

AU - Hasan, Wan N.W.

AU - Kok Yong, Chin

AU - Jolly, James J.

AU - Abd. Ghafar, Norzana

AU - Soelaiman, Ima Nirwana

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling. Objective: This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential. Discussion: Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans. Conclusion: Mevalonate pathway can be exploited to develop effective antiosteoporosis agents.

AB - Background: Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling. Objective: This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential. Discussion: Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans. Conclusion: Mevalonate pathway can be exploited to develop effective antiosteoporosis agents.

KW - Bone

KW - Bone metabolism

KW - Mevalonate pathway

KW - Osteoporosis

KW - Tocotrienol

KW - Vitamin E

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JO - Endocrine, Metabolic and Immune Disorders - Drug Targets

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