title: Differential effects of formononetin and cladrin on osteoblast function, peak bone mass achievement and bioavailability in rats.
abstract: Dietary soy isoflavones including genistein and daidzein have been shown to have favorable effects during estrogen deficiency in experimental animals and humans. We have evaluated osteogenic effect of cladrin and formononetin, two structurally related methoxydaidzeins found in soy food and other natural sources. Cladrin, at as low as 10 nM, maximally stimulated both osteoblast proliferation and differentiation by activating MEK-Erk pathway. On the other hand, formononetin maximally stimulated osteoblast differentiation at 100 nM that involved p38 MAPK pathway but had no effect on osteoblast proliferation. Unlike daidzein, these two compounds neither activated estrogen receptor in osteoblast nor had any effect on osteoclast differentiation. Daily oral administration of each of these compounds at 10.0 mg kg(-1) day(-1) dose to recently weaned female Sprague-Dawley rats for 30 consecutive days, increased bone mineral density at various anatomic positions studied. By dynamic histomorphometry of bone, we observed that rats treated with cladrin exhibited increased mineral apposition and bone formation rates compared with control, while formononetin had no effect. Cladrin had much better plasma bioavailability compared with formononetin. None of these compounds exhibited estrogen agonistic effect in uteri. Our data suggest that cladrin is more potent among the two in promoting parameters of peak bone mass achievement, which could be attributed to its stimulatory effect on osteoblast proliferation and better bioavailability. To the best of our knowledge, this is the first attempt to elucidate structure-activity relationship between the methoxylated forms of daidzein and their osteogenic effects.
authors.affiliation: Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, P.O. Box 173, Lucknow, India.
authors.forename: Abnish K
authors.initials: AK
authors.lastname: Gautam
authors.forename: Biju
authors.initials: B
authors.lastname: Bhargavan
authors.forename: Abdul M
authors.initials: AM
authors.lastname: Tyagi
authors.forename: Kamini
authors.initials: K
authors.lastname: Srivastava
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Yadav
authors.forename: Manmeet
authors.initials: M
authors.lastname: Kumar
authors.forename: Akanksha
authors.initials: A
authors.lastname: Singh
authors.forename: Jay S
authors.initials: JS
authors.lastname: Mishra
authors.forename: Amar Bahadur
authors.initials: AB
authors.lastname: Singh
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Manickavasagam
authors.forename: Sheelendra P
authors.initials: SP
authors.lastname: Singh
authors.forename: Wahajuddin
authors.initials: W
authors.lastname: Wahajuddin
authors.forename: Girish K
authors.initials: GK
authors.lastname: Jain
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
mesh_terms: D000818:Animals; D001682:Biological Availability; D015519:Bone Density / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D007529:Isoflavones / Q000097:blood / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology*; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007529:Isoflavones; C558945:cladrin; C007768:formononetin; C004742:daidzein