title: MicroRNA 874-3p Exerts Skeletal Anabolic Effects Epigenetically during Weaning by Suppressing Hdac1 Expression.
abstract: Embryonic skeletogenesis and postnatal bone development require the transfer of calcium from the mother to the offspring during pregnancy and lactation. Therefore, bone resorption in the mother becomes elevated during these periods, resulting in significant maternal skeletal loss. There follows an anabolic phase around weaning during which there is a remarkable recovery of the maternal skeleton. However, the mechanism(s) of this anabolic response remain(s) largely unknown. We identified eight differentially expressed miRNAs by array profiling, of which miR-874-3p was highly expressed at weaning, a time when bone loss was noted to recover. We report that this weaning-associated miRNA is an anabolic target. Therefore, an agomir of miR-874-3p induced osteoblast differentiation and mineralization. These actions were mediated through the inhibition of Hdac1 expression and enhanced Runx2 transcriptional activation. When injected in vivo, the agomir significantly increased osteoblastogenesis and mineralization, reversed bone loss caused by ovariectomy, and increased bone strength. We speculate that elevated miR-874-3p expression during weaning enhances bone formation and that this miRNA may become a therapeutic target for conditions of bone loss.
authors.affiliation: From the Endocrinology Division, Academy of Scientific and Innovative Research, and.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Kushwaha
authors.affiliation: From the Endocrinology Division.
authors.forename: Vikram
authors.initials: V
authors.lastname: Khedgikar
authors.affiliation: the Council of Scientific and Industrial Research-National Botanical Research Institute, Lucknow 226001, India.
authors.forename: Deepika
authors.initials: D
authors.lastname: Sharma
authors.affiliation: the The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, and.
authors.forename: Tony
authors.initials: T
authors.lastname: Yuen
authors.affiliation: From the Endocrinology Division.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Gautam
authors.affiliation: From the Endocrinology Division.
authors.forename: Naseer
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: From the Endocrinology Division.
authors.forename: Anirudha
authors.initials: A
authors.lastname: Karvande
authors.affiliation: Pharmaceutics Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Prabhat R
authors.initials: PR
authors.lastname: Mishra
authors.affiliation: the Council of Scientific and Industrial Research-National Botanical Research Institute, Lucknow 226001, India.
authors.forename: Prabodh K
authors.initials: PK
authors.lastname: Trivedi
authors.affiliation: the The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, and.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: the Department of Endocrinology and Metabolism, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Bhadada
authors.affiliation: the The Mount Sinai Bone Program, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, and mone.zaidi@mountsinai.org.
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
authors.affiliation: From the Endocrinology Division, ritu_trivedi@cdri.res.in.
authors.forename: Ritu
authors.initials: R
authors.lastname: Trivedi
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis / Q000235:genetics; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D014886:Weaning
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C586538:MIRN874 microRNA, mouse; D035683:MicroRNAs; C493716:Runx2 protein, mouse; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1
keywords: animal model; bone; bone morphogenetic protein (BMP); cell differentiation; drug discovery; gene silencing; histone deacetylase 1 (HDAC1); microRNA (miRNA); osteoblast; osteoporosis