Funding sources: Ministry of Health and Family Welfare, Council of Scientific and Industrial Research, Department of Biotechnology, Government of India. Fellowship grants from Council of Scientific and Industrial Research (GS, PR and VG), the Department of Biotechnology (KS & KK), University Grants Commission (JAS & JSM), Indian Council of Medical Research (MPK), Government of India.
A naturally occurring naringenin derivative exerts potent bone anabolic effects by mimicking oestrogen action on osteoblasts
Article first published online: 10 FEB 2012
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Volume 165, Issue 5, pages 1526–1542, March 2012
How to Cite
Swarnkar, G., Sharan, K., Siddiqui, J. A., Mishra, J. S., Khan, K., Khan, M. P., Gupta, V., Rawat, P., Maurya, R., Dwivedi, A. K., Sanyal, S. and Chattopadhyay, N. (2012), A naturally occurring naringenin derivative exerts potent bone anabolic effects by mimicking oestrogen action on osteoblasts. British Journal of Pharmacology, 165: 1526–1542. doi: 10.1111/j.1476-5381.2011.01637.x
- Issue published online: 10 FEB 2012
- Article first published online: 10 FEB 2012
- Accepted manuscript online: 22 AUG 2011 10:23AM EST
- Received; 8 June 2011; Revised; 13 July 2011; Accepted; 5 August 2011
- oestrogen deficiency;
- osteoblast differentiation;
- bone marrow;
- bone microarchitecture;
- preclinical development;
- parathyroid hormone
BACKGROUND AND PURPOSE Naringenin and its derivatives have been assessed in bone health for their oestrogen-‘like’ effects but low bioavailability impedes clinical potential. This study was aimed at finding a potent form of naringenin with osteogenic action.
EXPERIMENTAL APPROACH Osteoblast cultures were harvested from mouse calvaria to study differentiation by naringenin, isosakuranetin, poncirin, phloretin and naringenin-6-C-glucoside (NCG). Balb/cByJ ovariectomized (OVx) mice without or with osteopenia were given naringenin, NCG, 17β-oestradiol (E2) or parathyroid hormone (PTH). Efficacy was evaluated by bone microarchitecture using microcomputed tomography and determination of new bone formation by fluorescent labelling of bone. Plasma levels of NCG and naringenin were determined by HPLC.
KEY RESULTS NCG stimulated osteoblast differentiation more potently than naringenin, while isosakuranetin, poncirin or phloretin had no effect. NCG had better oral bioavailability than naringenin. NCG increased the mRNA levels of oestrogen receptors (ERs) and bone morphogenetic protein (an ER responsive gene) in vivo, more than naringenin. In OVx mice, NCG treatment in a preventive protocol increased bone formation rate (BFR) and improved trabecular microarchitecture more than naringenin or E2. In osteopenic mice, NCG but not naringenin, in a therapeutic protocol, increased BFR and improved trabecular microarchitecture, comparable with effects of PTH treatment. Stimulatory effects of NCG on osteoblasts were abolished by an ER antagonist. NCG transactivated ERβ but not ERα. NCG exhibited no uterine oestrogenicity unlike naringenin.
CONCLUSIONS AND IMPLICATIONS NCG is a potent derivative of naringenin that has bone anabolic action through the activation of osteoblast ERs and exhibited substantial oral bioavailability.