A peptide from wheat germ abolishes the senile osteoporosis by regulating OPG/RANKL/RANK/TRAF6 signaling pathway

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Phytomedicine 104 (2022) 154304

Available online 30 June 2022

Original Article

A peptide from wheat germ abolishes the senile osteoporosis by regulating

OPG/RANKL/RANK/TRAF6 signaling pathway

Fang Wang

, Gaohong Yang

, Yu Li

, Zhijuan Tang

, Jiayi Du

, Haizhao Song

, Ling Xiong

Luanfeng Wang

, Zebin Weng

, Xinchun Shen

College of Food Science and Engineering/Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control

and Processing, Nanjing University of Finance and Economics, Nanjing 210046, China

School of Traditional Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China

ARTICLE INFO

Keywords:

Wheat germ peptide

ADWGGPLPH

Senile osteoporosis

TRAF6 pathway

ABSTRACT

Background: Oxidative stress played a key role in the development of bone brittleness and is an important

pathogenic factor of senile osteoporosis. A variety of animal and plant-derived peptides have been shown to have

signicant anti-osteoporosis effects in vivo and in vitro.

Purpose: In this study, we aim to explore the possible mechanism of wheat germ peptide ADWGGPLPH on senile

osteoporosis.

Study design: Naturally, aged rats were used as animal models of senile osteoporosis.

Methods: Wheat germ peptide ADWGGPLPH was administered from 9-months-old to 21-months-old, and the

effect of ADWGGPLPH on preventing senile osteoporosis was evaluated by measuring serum biochemical in-

dexes, bone histomorphometry, bone biomechanics, and other indexes to elucidate the mechanism of

ADWGGPLPH in delaying senile osteoporosis by detecting the expression of osteoporosis-related proteins.

Results: The results showed that ADWGGPLPH could effectively reduce the level of oxidative stress and improve

the microstructure and bone mineral density in senile osteoporosis rats. In addition, ADWGGPLPH could improve

the proliferation and differentiation activity of osteoblasts and effectively inhibit osteoclasts’ differentiation by

regulating the OPG/RANKL/RANK/TRAF6 pathway.

Conclusion: ADWGGPLPH from wheat germ exhibited a notably effect on senile osteoporosis and has a high

potential in the development of the nutrient regimen to against senile osteoporosis.

Introduction

Osteoporosis is a degenerative metabolic disease characterized by

reduced bone mass, destruction of bone microstructure, increased bone

fragility, and predisposition to fracture (Compston et al., 2019). Estro-

gen deciency is commonly thought to cause osteoporosis, but bone loss

occurs long before menopause (around age 30), so this age-related bone

loss cannot be explained by estrogen deciency alone (Ullah et al., 2022;

Johnston and Dagar, 2020). With age, the body’s antioxidant capacity

decreases while the activity of NADPH oxidase increases, leading to the

accumulation of excessive free radicals and oxidative stress (Luo et al.,

2020). Recent studies have shown that oxidative stress played a key role

in the development of bone brittleness and is an important pathogenic

factor of senile osteoporosis (Kimball et al., 2021; Zhou et al., 2016).

Reactive oxygen species (ROS) can regulate the phosphorylation of

Serine (Ser36) of P66 shc by activating PKC and passing it from the

cytoplasm into the mitochondria. It acts as an oxidoreductase to reduce

to H

during electron transfer, and the production of H

acti-

vates the JNK pathway to induce osteoblast (OB) apoptosis (An et al.,

2019; Li et al., 2021). If the production of ROS is greater than the free

radical scavenging capacity, oxidative stress will occur, which will

further cause oxidative damage to OBs, affect their proliferation and

differentiation activities, and ultimately lead to the disruption of the

balance of bone reconstruction (Shahriarpour et al., 2021). Therefore,

Abbreviations: ADW, ADWGGPLPH; ALP, alkaline phosphatase; BAPs, Bioactive peptides; FWL, Femur weight per unit length; OB, osteoblast; OPG, osteopro-

tegerin, RANK, receptor activator of nuclear factor-κB; ROS, Reactive oxygen species; TRAF6, tumor necrosis factor receptor-associated factor 6; TRAP, tartrate-

resistant acid phosphatase.

* Corresponding authors.

E-mail address: wangfang8875@163.com (F. Wang).

Contents lists available at ScienceDirect

Phytomedicine

journal homepage: www.elsevier.com/locate/phymed

https://doi.org/10.1016/j.phymed.2022.154304

Received 20 April 2022; Received in revised form 19 June 2022; Accepted 26 June 2022

Phytomedicine 104 (2022) 154304

senile osteoporosis can be effectively improved by reducing the level of

oxidative stress.

With the aggravation of global aging, nutritional intervention for

maintaining bone homeostasis in the elderly is of great signicance

(Daly, 2017; Mu˜

noz-Garach et al., 2020; Ortega et al., 2021). Bioactive

peptides (BAPs) are a series of peptides separated from animals, plants,

and microorganisms with different compositions and arrangements from

dipeptides to complex linear and ring structures. BAP showed a variety

of physiological activities such as antioxidant, antibacterial,

immune-enhancing, and anti-osteoporosis activities (Chakrabarti et al.,

2018; Chatterjee et al., 2018). Previous studies revealed that bovine

collagen peptide combined with calcium citrate could restrain bone loss

in osteoporosis rats. Peptide TQS169 extracted from cattle prevents

osteoporosis and promotes osteoblast differentiation and calcium ab-

sorption (Wang et al., 2020b). In addition, a variety of animal and

plant-derived peptides have been shown to have signicant

anti-osteoporosis effects in vivo and in vitro (Chen et al., 2020; Min et al.,

2022; Pujia et al., 2017; Tella and Gallagher, 2014; Zdzieblik et al.,

2021).

Wheat germ is rich in protein, tocopherol, thiamine, riboavin, and

niacin, which is regarded by nutritionists as "the natural nutritional

treasure of human beings" (Weng et al., 2021). In previous studies, we

prepared a highly active wheat germ peptide with high free radical

scavenging ability by using two-step enzymatic hydrolysis (Chen et al.,

2017; Wang et al., 2020a). The chemical structure of the peptide was

shown in Fig. 1, the amino acid sequence of the peptide was

Ala-Asp-Trp-Gly-Gly-Pro-Leu-Pro-His (ADWGGPLPH). Therefore, in the

present study, we use spontaneously aged rats to explore the effect and

mechanism of ADWGGPLPH on senile osteoporosis to provide a protocol

for the nutritional intervention of senile osteoporosis and the develop-

ment of new pharmaceutical preparations.

Materials and methods

Reagents

The peptide ADW was chemically synthesized by Jinsirui Biotech-

nology (Nanjing, China). The purity is ≥95%. T-AOC, GSH-Px, MDA,

and SOD were purchased from Jiancheng Institute of Biotechnology

(Nanjing, China). Alendronate sodium were purchased from Savio In-

dustrial S.r. L (Hangzhou, China). Antibodies against phospho-PKCζ

(Thr410) were from Cell Signaling Technology, Inc. (Beverly, MA, USA).

The anti-OPG, anti-RANKL, anti-RANK and anti-TRAF6 antibodies were

purchased from BBI Life Sciences Corporation (Hongkong, China).

β-actin was purchased from Abcam (Cambridge, MA, USA).

Animals and treatment

Thirty 9-month-old female Sprague-Dawley rats (body weight 300.0

±20.0 g) were provided by Qinglongshan Animal Breeding Farm

(Nanjing, China). The experimental animals were received humane care

and the experiments carried out according to the guidelines of the An-

imal Care Committee of Nanjing University of Chinese Medicine. The

protocol approval number was 201905A031 (May 01, 2019). The ani-

mals were housed in a facility at 23 ±2 ◦C with 12 h / 12 h light / dark

cycle conditions and 50 ±5 % relative humidity. All animals were

allowed free access to distilled water and fed on a standard rodent basic

diet that contained 1.0% calcium and 0.6% phosphate. After a week of

adaptive feeding, random grouping was initiated. Rats were randomly

divided into ve groups (n =6): 9-month-old blank group (Con-9), 21-

month-old blank group (Con-21), 21-month-old low-dose wheat germ

peptide group (Con-21+L-ADW), 21-month-old high-dose wheat germ

peptide group (Con-21 +H-ADW), alendronate sodium group (ALN). On

the rst day of the experiment, rats in Con-9 were sacriced as longi-

tudinal control. The two groups were treated with L-ADW (1.5 mg/kg),

H-ADW (6.0 mg/kg) through intraperitoneal injections, one group was

treated with ALN (60 mg/kg/7d) through Intragastric administration,

and one group was treated with an equal amount of normal saline. From

the rst day of the experiment, the rats were treated every day according

to the experimental groups until 21 months of age. During the experi-

mental period, body weight, diet, and water intake were recorded

weekly and the serum of each rat at the 9

, 13

, and 21

months

was collected for the detection of serum biochemical indices.

Determination of serum biochemical indices

Serum alkaline phosphatase (ALP), tartrate-resistant acid phospha-

tase (TRAP), and oxidative stress indexes including T-AOC, GSH-Px,

MDA, and SOD were determined using rat ELISA kits following the

manufacturer’s instruction (Jiancheng Institute of Biotechnology,

Nanjing, China).

Analysis of the Micro-CT scans and histopathology of the femur

The right distal femur from each group was subjected to micro-CT

scanning (Skyscan Model 1174 Micro-CT, Bruker, German) for the

analysis of trabecular bone microarchitecture. The scanned images were

analyzed by the Scanner software (Bruker, German). The scanning pa-

rameters were set at the energy of 50 kV with a scan range of 1304 ×

1024 eld size and 12

m scan resolution. The 1 mm below the femoral

knee lateral growth plate was set as the scanning reference line, and the

Fig. 1. The chemical structure of ADWGGPLPH.

F. Wang et al.

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A peptide from wheat germ abolishes the senile osteoporosis by regulating OPG/RANKL/RANK/TRAF6 signaling pathway

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