title: Medicarpin, a legume phytoalexin, stimulates osteoblast differentiation and promotes peak bone mass achievement in rats: evidence for estrogen receptor β-mediated osteogenic action of medicarpin.
abstract: Dietary isoflavones including genistein and daidzein have been shown to have favorable bone conserving effects during estrogen deficiency in experimental animals and humans. We have evaluated osteogenic effect of medicarpin (Med); a phytoalexin that is structurally related to isoflavones and is found in dietary legumes. Med stimulated osteoblast differentiation and mineralization at as low as 10⁻¹⁰ M. Studies with signal transduction inhibitors demonstrated involvement of a p38 mitogen activated protein kinase-ER-bone morphogenic protein-2 pathway in mediating Med action in osteoblasts. Co-activator interaction studies demonstrated that Med acted as an estrogen receptor (ER) agonist; however, in contrast to 17β-estradiol, Med had no uterine estrogenicity and blocked proliferation of MCF-7 cells. Med increased protein levels of ERβ in osteoblasts. Selective knockdown of ERα and ERβ in osteoblasts established that osteogenic action of Med is ERβ-dependent. Female Sprague-Dawley (weaning) rats were administered Med at 1.0- and 10.0 mg.kg⁻¹ doses by gavage for 30 days along with vehicle control. Med treatment resulted in increased formation of osteoporgenitor cells in the bone marrow and osteoid formation (mineralization surface, mineral apposition/bone formation rates) compared with vehicle group. In addition, Med increased cortical thickness and bone biomechanical strength. In pharmacokinetic studies, Med exhibited oral bioavailability of 22.34% and did not produce equol. Together, our results demonstrate Med stimulates osteoblast differentiation likely via ERβ, promotes achievement of peak bone mass, and is devoid of uterine estrogenicity. In addition, given its excellent oral bioavailability, Med can be potential osteogenic agent.
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: Biju
authors.initials: B
authors.lastname: Bhargavan
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
authors.forename: Abnish K
authors.initials: AK
authors.lastname: Gautam
authors.forename: Jay Sharan
authors.initials: JS
authors.lastname: Mishra
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Atul
authors.initials: A
authors.lastname: Goel
authors.forename: Manish
authors.initials: M
authors.lastname: Dixit
authors.forename: Rashmi
authors.initials: R
authors.lastname: Pandey
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Manickavasagam
authors.forename: Shailendra D
authors.initials: SD
authors.lastname: Dwivedi
authors.forename: Bandana
authors.initials: B
authors.lastname: Chakravarti
authors.forename: Girish K
authors.initials: GK
authors.lastname: Jain
authors.forename: Ravishankar
authors.initials: R
authors.lastname: Ramachandran
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.forename: Arun
authors.initials: A
authors.lastname: Trivedi
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
mesh_terms: D000818:Animals; D001682:Biological Availability; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects; D036343:Pterocarpans / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000493:pharmacokinetics / Q000494:pharmacology; D012886:Skull / Q000166:cytology / Q000187:drug effects; D014599:Uterus / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000094162:Phytoalexins
chemical_list: D055396:Bone Morphogenetic Protein 2; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D036343:Pterocarpans; D012717:Sesquiterpenes; C047353:medicarpin; D048051:p38 Mitogen-Activated Protein Kinases; D000094162:Phytoalexins