Methoxylated isoflavones, cajanin and isoformononetin, have non-estrogenic bone forming effect via differential mitogen activated protein kinase (MAPK) signaling.
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.
Bhargavan
Biju
B
Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, Uttar Pradesh, India.
Gautam
Abnish Kumar
AK
Singh
Divya
D
Kumar
Amit
A
Chaurasia
Sumit
S
Tyagi
Abdul Malik
AM
Yadav
Dinesh Kumar
DK
Mishra
Jay Sharan
JS
Singh
Amar Bahadur
AB
Sanyal
Sabyasachi
S
Goel
Atul
A
Maurya
Rakesh
R
Chattopadhyay
Naibedya
N
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
D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D007529:Isoflavones; D048789:Phytoestrogens; C541583:cajanine; C007768:formononetin; D004054:Diethylstilbestrol; D019833:Genistein