Kaempferitrin prevents bone lost in ovariectomized rats

doi:10.1016/j.phymed.2015.09.003

Phytomedicine

Volume 22, Issue 13, 1 December 2015, Pages 1159-1162

https://doi.org/10.1016/j.phymed.2015.09.003 Get rights and content

Abstract

Background

Podocarpium podocarpum (DC.), an edible and medicinal plant popularly used for the treatment of bruises and fracture in Chinese folk medicine, has been proved to possess significant antiosteoporotic effect in our latest research.

Purpose

Our study aimed to investigate the in vitro and in vivo antiosteoporotic effect of kaempfertrin (KN), a principal flavonoid in P. podocarpum obtained through bio-guided isolation.

Methods

An ovariectomized (OVX) rat model of osteoporosis as well as in vitro osteoblast and osteoclast cell lines were employed to evaluate the antiosteoporotic potency of KN.

Results

KN significantly improved the bone mass and microarchitecture in OVX rats, with little estrogen-like side effect compared with estradiol valerate. KN also exhibited stimulatory effect on osteoblastic cells and inhibitory action on osteoclastic cells, which down-regulated the phosphorylation level of I-κB.

Conclusion

KN possessed significant antiosteoporotic activity. Combined with its limited estrogen-like side effect, KN can be regarded as an idealistic antiosteoporotic candidate for human osteoporosis diseases.

Graphical abstract

Introduction

Osteoporosis is a kind of metabolic disorders characterized by the imbalance between osteoblastic formation and osteoclastic resorption. It is a stealthy and unpredictable disease that does not become symptomatic until the advanced stages, thus termed a “silent killer” (Kanis et al. 1994). The prevalence of this bone remodeling disease was estimated to be more than 200 million people worldwide in 2006 with attendant costs exceeding 10 billion dollars per annum (Reginster and Burlet 2006), which highlights the large medical input for new treatment options and strategies. Among those treatments, natural compounds with antiosteoporotic activity but few side effects are worth of exploring.

Flavonoids represent a large group of phenolic compounds commonly found in daily nutrition with proven health benefits as well as antiosteoporotic properties (Léotoing et al. 2014). Among this group, kaempferitrin (KN, 3,5,7,4′-tetrahydroxy-flavonoid 3,7-L-dirhamnoside) (Fig. 1A), a natural flavonoid glycoside, has been isolated from several edible and medicinal plants (Fang et al. 2005), suggested to possess antioxidant, antimicrobial, anti-inflammatory and anti-diabetic activities (Abdel-Ghani et al., 2001, Cazarolli et al., 2013). Recently, our lab performed bio-guided isolation on an antiosteoporotic plant, Podocarpium podocarpum (DC.) Yang et Huang, and found the abundance of KN (Ma et al. 2011), which implied that this natural flavonoid may be responsible for the antiosteoporotic activity of P. podocarpum and can be used as a potential agent to treat osteoporosis disease. Here we demonstrated the efficacy of KN on bone loss prevention both in ovariectomized rats of osteoporosis and in osteoclastic cell line. Futhermore, we revealed its effects on the phosphorylation of I-κB, JNK, p38 and ERK to elucidate the possible antiosteoporotic mechanisms.

Section snippets

Instruments and reagents

A total of 12.2 g KN (>95% pure) was isolated from P. podocarpum (DC.) Yang et Huang (13 kg) according to the method of our previous published paper (Urgaonkar and Shaw, 2007, Ye et al., 2015). The structure was elucidated mainly by NMR and MS spectra data analyses, which was consistent with reported data (Kader and Alqasoumi 2007). Its purity can be deduced by the HPLC area normalization method and evidenced by its clear ¹³C NMR spectrum (Fig. S1).

Estradiol valerate (1 mg, Delpharm Lille SAS,

Results and discussion

Low bone mass is a major risk factor for fractures. Ovariectomy significantly decreased trabecular structural parameters (Li et al. 2013). As showed in Fig. 1B, 12 weeks after ovariectomy, the total bone mineral density (BMD) of those OVX rats were declined by 7.4% in comparison to that of the Sham rats (P < 0.01). Administrated orally, the high dose of KN (KH, 16 mg/kg) increased the BMD by 6.4% (p < 0.01). And in micro-CT experiments, as shown in Fig. 1C1–C5, the bone mineral content (BMC),

Conclusion

In summary, our findings demonstrated that KN possessed significant antiosteoporotic activity mainly through bone resorption suppression, by inhibiting the I-κB phosphorylation and activation of NF-κB signal pathway. Combined with its limited estrogen-like side effect, KN may be regarded as an idealistic antiosteoporotic candidate for human osteoporosis diseases.

Conflict of interest

We confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

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The data of present experiments demonstrated that with CSE treatment, the total BMD of OVX rats was significantly enhanced and the trabecular bone microarchitecture was partially improved. Our previous studies have shown that ovariectomy induced osteoporosis leading to a significant deteriorations in distal femur morphometric parameters including BMC, TMC, Tb.N, BVF and Tb.Sp [3,21]. Now, our data obtained from micro-CT determination of distal femur of OVX rats have shown that, treatment of CSE (100 and 300 mg/kg) significantly enhanced the BMC, TMC, Tb.N, BVF and decreased the Tb.Sp of the bone trabecular microarchitecture as compared to OVX group, thus implying CSE was effective in ameliorating bone mass and trabecular microarchitecture in OVX rats.
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After 12 weeks of continues orally intervention, the decreases of bone mineral density, bone mineral content, tissue mineral content, as well as the increases of bone trabecular separation and bone resorption markers were significantly reversed by CSE in the OVX rats, and in particular, a contradictory phenomenon on calcium and phosphorus contents was observed and elucidated. Mechanistically, the expressions of tumor-necrosis factor receptor-associated factor 6 (TRAF 6), nuclear factor kappa B (RANK) and its ligand (RANKL), as well as the nuclear factor kappa B (NF-κB), phosphoinositide 3‑kinase (PI3K) and protein kinase B (AKT) levels were significantly down-regulated by CSE intervention, whereas the osteoprotegerin (OPG) was significantly up-regulated by CSE as compared to the control.
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^¹: These authors contributed equally to this manuscript.

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Kaempferitrin prevents bone lost in ovariectomized rats

Abstract

Background

Purpose

Methods

Results

Conclusion

Graphical abstract

Introduction

Section snippets

Instruments and reagents

Results and discussion

Conclusion

Conflict of interest

Eur. J. Pharmacol.

Bioorg. Med. Chem.

Phytomedicine

Phytochem. Lett.

J Ethnopharmacol

Eur. J. Pharmacol.

Phytomedicine

J. Pharm. Biomed. Anal.

Bone