A novel therapeutic approach with Caviunin-based isoflavonoid that en routes bone marrow cells to bone formation via BMP2/Wnt-β-catenin signaling

• Published in: Cell death & disease Vol. 5; no. 9; p. e1422
• Main Authors: Kushwaha, P, Khedgikar, V, Gautam, J, Dixit, P, Chillara, R, Verma, A, Thakur, R, Mishra, D P, Singh, D, Maurya, R, Chattopadhyay, N, Mishra, P R, Trivedi, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-09-2014; Nature Publishing Group
• Subjects: 13; 13/1; 13/109; 13/2; 13/95; 14; 14/19; 38; 38/77; 631/80/82/23; 631/80/86; 692/699/1670/316/801; 692/700/565/1436; 82; 82/51; 82/80; Animals; Animals, Newborn; Antibodies; beta Catenin - genetics; beta Catenin - metabolism; Biochemistry; Biomedical and Life Sciences; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone and Bones - pathology; Bone and Bones - physiopathology; Bone Diseases, Metabolic - drug therapy; Bone Diseases, Metabolic - genetics; Bone Diseases, Metabolic - metabolism; Bone Diseases, Metabolic - pathology; Bone Diseases, Metabolic - physiopathology; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Bone Morphogenetic Protein 2 - genetics; Bone Morphogenetic Protein 2 - metabolism; Cell Biology; Cell Culture; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Chondrogenesis - drug effects; Dalbergia sissoo; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Genistein - pharmacology; Glycosides - pharmacology; HEK293 Cells; Humans; Immunology; Isoflavones - pharmacology; Life Sciences; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - metabolism; Mesenchymal Stromal Cells - pathology; Mice, Inbred BALB C; Original; original-article; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoblasts - pathology; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Osteogenesis - drug effects; Ovariectomy; Time Factors; Transfection; Wnt Signaling Pathway - drug effects; Wnt Signaling Pathway - genetics
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.350

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.