title: Isoformononetin, a methoxydaidzein present in medicinal plants, reverses bone loss in osteopenic rats and exerts bone anabolic action by preventing osteoblast apoptosis.
abstract: OBJECTIVE
  Daidzein (Daid) has been implicated in bone health for its estrogen-'like' effects but low bioavailability, unfavorable metabolism and uterine estrogenicity impede its clinical potential. This study was aimed at assessing isoformononetin (Isoformo), a naturally occurring methoxydaidzein, for bone anabolic effect by overcoming the pitfalls associated with Daid.
  
  
  METHODS
  Sprague-Dawley ovariectomized (OVx) rats with established osteopenia were administered Isoformo, 17β-oestradiol (E2) or human parathyroid hormone. Efficacy was evaluated by bone microarchitecture using microcomputed tomography and determination of new bone formation by fluorescent labeling of bone. Osteoblast apoptosis was measured by co-labeling of bone sections with Runx-2 and TUNEL. Biochemical markers of bone metabolism were measured by ELISA. Plasma and bone marrow levels of Isoformo and Daid were determined by LC-MS-MS. Rat bone marrow stromal cells were harvested to study osteoblastic differentiation by Isoformo and Daid. New born rat pups were injected with Isoformo and Daid to study the effect of the compounds on the expression of osteogenic genes in the calvaria by real time PCR.
  
  
  RESULTS
  In osteopenic rats, Isoformo treatment restored trabecular microarchitecture, increased new bone formation, increased the serum osteogenic marker (procollagen N-terminal propeptide), decreased resorptive marker (urinary C-terminal teleopeptide of type I collagen) and diminished osteoblast apoptosis in bone. At the most effective osteogenic dose of Isoformo, plasma and bone marrow levels were comprised of ~90% Isoformo and the rest, Daid. Isoformo at the concentration reaching the bone marrow achieved out of its most effective oral dosing induced stromal cell mineralization and osteogenic gene expression in the calvaria of neonatal rats. Isoformo exhibited uterine safety.
  
  
  CONCLUSIONS
  Our study demonstrates that Isoformo reverses established osteopenia in adult OVx rats likely via its pro-survival effect on osteoblasts. Given its bone anabolic and anti-catabolic effects accompanied with safety at uterine level we propose its potential in the management of postmenopausal osteoporosis.
authors: Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Chattar Manzil, Lucknow, India.
authors: K
authors: K
authors: Srivastava
authors: A M
authors: AM
authors: Tyagi
authors: K
authors: K
authors: Khan
authors: M
authors: M
authors: Dixit
authors: S
authors: S
authors: Lahiri
authors: A
authors: A
authors: Kumar
authors: B
authors: B
authors: Changkija
authors: M P
authors: MP
authors: Khan
authors: G K
authors: GK
authors: Nagar
authors: D K
authors: DK
authors: Yadav
authors: R
authors: R
authors: Maurya
authors: S P
authors: SP
authors: Singh
authors: G K
authors: GK
authors: Jain
authors: Wahajuddin
authors: R
authors: R
authors: Trivedi
authors: N
authors: N
authors: Chattopadhyay
authors: D
authors: D
authors: Singh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood / Q000652:urine; D050071:Bone Density Conservation Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D001862:Bone Resorption / Q000517:prevention & control; D001842:Bone and Bones / Q000187:drug effects*; D002113:Calcification, Physiologic / Q000187:drug effects; D005260:Female; D007529:Isoflavones / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008660:Metabolism / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D010024:Osteoporosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D010052:Ovariectomy; D048789:Phytoestrogens / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D014599:Uterus / Q000187:drug effects
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D007529:Isoflavones; D048789:Phytoestrogens; D010936:Plant Extracts; C007768:formononetin; C004742:daidzein