title: A novel quercetin analogue from a medicinal plant promotes peak bone mass achievement and bone healing after injury and exerts an anabolic effect on osteoporotic bone: the role of aryl hydrocarbon receptor as a mediator of osteogenic action.
abstract: We recently reported that extracts made from the stem bark of Ulmus wallichiana promoted peak bone mass achievement in growing rats and preserved trabecular bone mass and cortical bone strength in ovariectomized (OVX) rats. Further, 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-3',4',5,7-tetrahydroxyflavanol (GTDF), a novel flavonol-C-glucoside isolated from the extracts, had a nonestrogenic bone-sparing effect on OVX rats. Here we studied the effects of GTDF on osteoblast function and its mode of action and in vivo osteogenic effect. GTDF stimulated osteoblast proliferation, survival, and differentiation but had no effect on osteoclastic or adipocytic differentiation. In cultured osteoblasts, GTDF transactivated the aryl hydrocarbon receptor (AhR). Activation of AhR mediated the stimulatory effect of GTDF on osteoblast proliferation and differentiation. Furthermore, GTDF stimulated cAMP production, which mediated osteogenic gene expression. GTDF treatments given to 1- to 2-day-old rats or adult rats increased the mRNA levels of AhR target genes in calvaria or bone marrow stromal cells. In growing female rats, GTDF promoted parameters of peak bone accrual in the appendicular skeleton, including increased longitudinal growth, bone mineral density, bone-formation rate (BFR), cortical deposition, and bone strength. GTDF promoted the process of providing newly generated bone to fill drill holes in the femurs of both estrogen-sufficient and -deficient rats. In osteopenic OVX rats, GTDF increased BFR and significantly restored trabecular bone compared with the ovaries-intact group. Together our data suggest that GTDF stimulates osteoblast growth and differentiation via the AhR and promotes modeling-directed bone accrual, accelerates bone healing after injury, and exerts anabolic effects on osteopenic rats likely by a direct stimulatory effect on osteoprogenitors. Based on these preclinical data, clinical evaluation of GTDF as a potential bone anabolic agent is warranted.
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Kunal
authors.initials: K
authors.lastname: Sharan
authors.forename: Jay Sharan
authors.initials: JS
authors.lastname: Mishra
authors.forename: Gaurav
authors.initials: G
authors.lastname: Swarnkar
authors.forename: Jawed Akhtar
authors.initials: JA
authors.lastname: Siddiqui
authors.forename: Kainat
authors.initials: K
authors.lastname: Khan
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kumari
authors.forename: Preeti
authors.initials: P
authors.lastname: Rawat
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001861:Bone Regeneration / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology*; D002113:Calcification, Physiologic / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D010024:Osteoporosis / Q000188:drug therapy / Q000473:pathology*; D010946:Plants, Medicinal / Q000737:chemistry; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D045930:Anabolic Agents; D018336:Receptors, Aryl Hydrocarbon; D011794:Quercetin; D000242:Cyclic AMP