title: A novel therapeutic approach with Caviunin-based isoflavonoid that en routes bone marrow cells to bone formation via BMP2/Wnt-β-catenin signaling.
abstract: Recently, we reported that extract of Dalbergia sissoo made from leaves and pods have antiresorptive and bone-forming effects. The positive skeletal effect attributed because of active molecules present in the extract of Dalbergia sissoo. Caviunin 7-O-[β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside] (CAFG), a novel isoflavonoid show higher percentage present in the extract. Here, we show the osteogenic potential of CAFG as an alternative for anabolic therapy for the treatment of osteoporosis by stimulating bone morphogenetic protein 2 (BMP2) and Wnt/β-catenin mechanism. CAFG supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur and decreased bone turnover markers better than genistein. Oral administration of CAFG to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased the expression of osteogenic genes in femur and show new bone formation without uterine hyperplasia. CAFG increased mRNA expression of osteoprotegerin in bone and inhibited osteoclast activation by inhibiting the expression of skeletal osteoclastogenic genes. CAFG is also an effective accelerant for chondrogenesis and has stimulatory effect on the repair of cortical bone after drill-hole injury at the tissue, cell and gene level in mouse femur. At cellular levels, CAFG stimulated osteoblast proliferation, survival and differentiation. Signal transduction inhibitors in osteoblast demonstrated involvement of p-38 mitogen-activated protein kinase pathway stimulated by BMP2 to initiate Wnt/β-catenin signaling to reduce phosphorylation of GSK3-β and subsequent nuclear accumulation of β-catenin. Osteogenic effects were abrogated by Dkk1, Wnt-receptor blocker and FH535, inhibitor of TCF-complex by reduction in β-catenin levels. CAFG modulated MSC responsiveness to BMP2, which promoted osteoblast differentiation via Wnt/β-catenin mechanism. CAFG at 1 mg/kg(/)day dose in ovariectomy mice (human dose ∼0.081 mg/kg) led to enhanced bone formation, reduced bone resorption and bone turnover better than well-known phytoestrogen genistein. Owing to CAFG's inherent properties for bone, it could be positioned as a potential drug, food supplement, for postmenopausal osteoporosis and fracture repair.
authors.affiliation: Division of Endocrinology, Center for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: P
authors.initials: P
authors.lastname: Kushwaha
authors.affiliation: Division of Endocrinology, Center for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: V
authors.initials: V
authors.lastname: Khedgikar
authors.affiliation: Division of Endocrinology, Center for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: J
authors.initials: J
authors.lastname: Gautam
authors.affiliation: Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow 226031, India.
authors.forename: P
authors.initials: P
authors.lastname: Dixit
authors.affiliation: Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow 226031, India.
authors.forename: R
authors.initials: R
authors.lastname: Chillara
authors.affiliation: India Division of Pharmaceutics, Central Drug Research Institute, CSIR-CDRI, Lucknow 226031, India.
authors.forename: A
authors.initials: A
authors.lastname: Verma
authors.affiliation: Division of Endocrinology, Center for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: R
authors.initials: R
authors.lastname: Thakur
authors.affiliation: Division of Endocrinology, Center for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: D P
authors.initials: DP
authors.lastname: Mishra
authors.affiliation: Division of Endocrinology, Center for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: D
authors.initials: D
authors.lastname: Singh
authors.affiliation: Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow 226031, India.
authors.forename: R
authors.initials: R
authors.lastname: Maurya
authors.affiliation: Division of Endocrinology, Center for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: N
authors.initials: N
authors.lastname: Chattopadhyay
authors.affiliation: India Division of Pharmaceutics, Central Drug Research Institute, CSIR-CDRI, Lucknow 226031, India.
authors.forename: P R
authors.initials: PR
authors.lastname: Mishra
authors.affiliation: Division of Endocrinology, Center for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: R
authors.initials: R
authors.lastname: Trivedi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D019833:Genistein / Q000494:pharmacology; D006027:Glycosides / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D013997:Time Factors; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; C495267:CTNNB1 protein, mouse; D006027:Glycosides; D007529:Isoflavones; D051176:beta Catenin; C000591514:caviunin; D019833:Genistein