title: Pharmacological activation of aldehyde dehydrogenase 2 promotes osteoblast differentiation via bone morphogenetic protein-2 and induces bone anabolic effect.
abstract: Aldehyde dehydrogenases (ALDHs) are a family of enzymes involved in detoxifying aldehydes. Previously, we reported that an ALDH inhibitor, disulfiram caused bone loss in rats and among ALDHs, osteoblast expressed only ALDH2. Loss-of-function mutation in ALDH2 gene is reported to cause bone loss in humans which suggested its importance in skeletal homeostasis. We thus studied whether activating ALDH2 by N-(1, 3-benzodioxol-5-ylmethyl)-2, 6-dichlorobenzamide (alda-1) had osteogenic effect. We found that alda-1 increased and acetaldehyde decreased the differentiation of rat primary osteoblasts and expressions of ALDH2 and bone morphogenetic protein-2 (BMP-2). Silencing ALDH2 in osteoblasts abolished the alda-1 effects. Further, alda-1 attenuated the acetaldehyde-induced lipid-peroxidation and oxidative stress. BMP-2 is essential for bone regeneration and alda-1 increased its expression in osteoblasts. We then showed that alda-1 (40mg/kg dose) augmented bone regeneration at the fracture site with concomitant increase in BMP-2 protein compared with control. The osteogenic dose (40mg/kg) of alda-1 attained a bone marrow concentration that was stimulatory for osteoblast differentiation, suggesting that the tissue concentration of alda-1 matched its pharmacologic effect. In addition, alda-1 promoted modeling-directed bone growth and peak bone mass achievement, and increased bone mass in adult rats which reiterated its osteogenic effect. In osteopenic ovariectomized (OVX) rats, alda-1 reversed trabecular osteopenia with attendant increase in serum osteogenic marker (procollagen type I N-terminal peptide) and decrease in oxidative stress. Alda-1 has no effect on liver and kidney function. We conclude that activating ALDH2 by alda-1 had an osteoanabolic effect involving increased osteoblastic BMP-2 production and decreased OVX-induced oxidative stress.
authors.affiliation: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Monika
authors.initials: M
authors.lastname: Mittal
authors.affiliation: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Subhashis
authors.initials: S
authors.lastname: Pal
authors.affiliation: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Shyamsundar Pal
authors.initials: SP
authors.lastname: China
authors.affiliation: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Konica
authors.initials: K
authors.lastname: Porwal
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Kapil
authors.initials: K
authors.lastname: Dev
authors.affiliation: Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Shrivastava
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Kanumuri Siva Rama
authors.initials: KS
authors.lastname: Raju
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Mamunur
authors.initials: M
authors.lastname: Rashid
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Trivedi
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
authors.affiliation: Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Wahajuddin
authors.affiliation: Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Smrati
authors.initials: S
authors.lastname: Bhaduria
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.affiliation: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: n_chattopadhyay@cdri.res.in.
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
mesh_terms: D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000819:agonists / Q000096:biosynthesis*; D001861:Bone Regeneration / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001549:Benzamides; D052117:Benzodioxoles; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D020536:Enzyme Activators; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat
keywords: Alda-1; Bone regeneration; Osteoanabolic; Peak bone mass; Pharmacokinetics; Post-menopausal osteoporosis