title: A naturally occurring naringenin derivative exerts potent bone anabolic effects by mimicking oestrogen action on osteoblasts.
abstract: OBJECTIVE
  Naringenin and its derivatives have been assessed in bone health for their oestrogen-'like' effects but low bioavailability impedes clinical potential. This study was aimed at finding a potent form of naringenin with osteogenic action.
  
  
  METHODS
  Osteoblast cultures were harvested from mouse calvaria to study differentiation by naringenin, isosakuranetin, poncirin, phloretin and naringenin-6-C-glucoside (NCG). Balb/cByJ ovariectomized (OVx) mice without or with osteopenia were given naringenin, NCG, 17β-oestradiol (E2) or parathyroid hormone (PTH). Efficacy was evaluated by bone microarchitecture using microcomputed tomography and determination of new bone formation by fluorescent labelling of bone. Plasma levels of NCG and naringenin were determined by HPLC.
  
  
  RESULTS
  NCG stimulated osteoblast differentiation more potently than naringenin, while isosakuranetin, poncirin or phloretin had no effect. NCG had better oral bioavailability than naringenin. NCG increased the mRNA levels of oestrogen receptors (ERs) and bone morphogenetic protein (an ER responsive gene) in vivo, more than naringenin. In OVx mice, NCG treatment in a preventive protocol increased bone formation rate (BFR) and improved trabecular microarchitecture more than naringenin or E2. In osteopenic mice, NCG but not naringenin, in a therapeutic protocol, increased BFR and improved trabecular microarchitecture, comparable with effects of PTH treatment. Stimulatory effects of NCG on osteoblasts were abolished by an ER antagonist. NCG transactivated ERβ but not ERα. NCG exhibited no uterine oestrogenicity unlike naringenin.
  
  
  CONCLUSIONS
  NCG is a potent derivative of naringenin that has bone anabolic action through the activation of osteoblast ERs and exhibited substantial oral bioavailability.
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Chattar Manzil, Lucknow, India.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Swarnkar
authors.forename: Kunal
authors.initials: K
authors.lastname: Sharan
authors.forename: Jawed A
authors.initials: JA
authors.lastname: Siddiqui
authors.forename: Jay Sharan
authors.initials: JS
authors.lastname: Mishra
authors.forename: Kainat
authors.initials: K
authors.lastname: Khan
authors.forename: Mohd Parvez
authors.initials: MP
authors.lastname: Khan
authors.forename: Varsha
authors.initials: V
authors.lastname: Gupta
authors.forename: Preeti
authors.initials: P
authors.lastname: Rawat
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.forename: Anil K
authors.initials: AK
authors.lastname: Dwivedi
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D044950:Flavanones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D005960:Glucosides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology; D010693:Phloretin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D012886:Skull / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D045930:Anabolic Agents; D019485:Bone Morphogenetic Proteins; D004967:Estrogens; D044950:Flavanones; D005419:Flavonoids; D005960:Glucosides; D010281:Parathyroid Hormone; D011960:Receptors, Estrogen; C066406:naringenin-6-C-glucoside; C119641:poncirin; C005273:naringenin; D010693:Phloretin; C538973:isosakuranetin