title: Methoxylated isoflavones, cajanin and isoformononetin, have non-estrogenic bone forming effect via differential mitogen activated protein kinase (MAPK) signaling.
abstract: Following a lead obtained from stem-bark extract of Butea monosperma, two structurally related methoxyisoflavones; cajanin and isoformononetin were studied for their effects in osteoblasts. Cajanin had strong mitogenic as well as differentiation-promoting effects on osteoblasts that involved subsequent activation of MEK-Erk and Akt pathways. On the other hand, isoformononetin exhibited potent anti-apoptotic effect in addition to promoting osteoblast differentiation that involved parallel activation of MEK-Erk and Akt pathways. Unlike genistein or daidzein, none of these two compounds appear to act via estrogen receptors in osteoblast. Once daily oral (by gavage) treatment for 30 consecutive days was given to recently weaned female Sprague-Dawley rats with each of these compounds at 10.0 mg kg(-1) day(-1) dose. Cajanin increased bone mineral density (BMD) at all skeletal sites studied, bone biomechanical strength, mineral apposition rate (MAR) and bone formation rate (BFR), compared with control. BMD levels at various anatomic positions were also increased with isoformononetin compared with control however, its effect was less potent than cajanin. Isoformononetin had no effect on the parameters of bone biomechanical strength although it enhanced MAR and BFR compared with control. Isoformononetin had very mild uterotrophic effect, whereas cajanin was devoid of any such effect. Our data suggest that cajanin is more potent than isoformononetin in accelerating peak bone mass achievement. To the best of our knowledge, this work represents the first attempt to elucidate structure-activity relationship between the two methoxylated isoflavones regarding their effects in osteoblasts and bone formation.
authors: Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, Uttar Pradesh, India.
authors: Biju
authors: B
authors: Bhargavan
authors: Abnish Kumar
authors: AK
authors: Gautam
authors: Divya
authors: D
authors: Singh
authors: Amit
authors: A
authors: Kumar
authors: Sumit
authors: S
authors: Chaurasia
authors: Abdul Malik
authors: AM
authors: Tyagi
authors: Dinesh Kumar
authors: DK
authors: Yadav
authors: Jay Sharan
authors: JS
authors: Mishra
authors: Amar Bahadur
authors: AB
authors: Singh
authors: Sabyasachi
authors: S
authors: Sanyal
authors: Atul
authors: A
authors: Goel
authors: Rakesh
authors: R
authors: Maurya
authors: Naibedya
authors: N
authors: Chattopadhyay
mesh_terms: D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D015519:Bone Density; D001854:Bone Marrow Cells / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004054:Diethylstilbestrol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism; D004965:Estrogen Antagonists / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D019833:Genistein / Q000031:analogs & derivatives*; D007529:Isoflavones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis; D048789:Phytoestrogens / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014599:Uterus / Q000166:cytology / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D007529:Isoflavones; D048789:Phytoestrogens; C541583:cajanine; C007768:formononetin; D004054:Diethylstilbestrol; D019833:Genistein