Grape Seed Proanthocyanidin Extract Prevents Bone Loss via Regulation of Osteoclast Differentiation, Apoptosis, and Proliferation.

Sung Chul Kwak,Yoon-Hee Cheon,Hong Young Jun,Chang Hoon Lee,Ju-Young Kim,Kwon-Ha Yoon,Myeung Su Lee

doi:10.3390/nu12103164

Abstract

Dietary procyanidin has been shown to be an important bioactive component that regulates various pharmacological activities to maintain metabolic homeostasis. In particular, grape seed proanthocyanidin extract (GSPE) is a commercially available medicine for the treatment of venous and lymphatic dysfunction. This study aimed to investigate whether GSPE protects against lipopolysaccharide (LPS)-induced bone loss in vivo and the related mechanism of action in vitro. The administration of GSPE restored the inflammatory bone loss phenotype stimulated by acute systemic injection of LPS in vivo. GSPE strongly suppressed receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and bone resorption activity of mature osteoclasts by decreasing the RANKL-induced nuclear factor-κB transcription activity. GSPE mediates this effect through decreased phosphorylation and degradation of NF-κB inhibitor (IκB) by IκB kinaseβ, subsequently inhibiting proto-oncogene cellular Fos and nuclear factor of activated T cells. Additionally, GSPE promotes osteoclast proliferation by increasing the phosphorylation of components of the Akt and mitogen-activated protein kinase signaling pathways and it also inhibits apoptosis by decreasing the activity of caspase-8, caspase-9, and caspase-3, as corroborated by a decrease in the Terminal deoxynucleotidyl transferase dUTP nick end labeling -positive cells. Our study suggests a direct effect of GSPE on the proliferation, differentiation, and apoptosis of osteoclasts and reveals the mechanism responsible for the therapeutic potential of GSPE in osteoclast-associated bone metabolism disease.

Highlights

Bone diseases are caused by disharmony in the bone remodeling process, which is mediated by bone-formative osteoblasts and bone-resorbing osteoclasts [1]
We studied its effects on the proliferation, differentiation, and apoptosis of osteoclasts and the related mechanism of action in vitro
Treatment with grape seed proanthocyanidin extract (GSPE)+LPS increased the BV/TV, Tb.Th, and Tb.N. compared to LPS alone; on the other hand, GSPE alone did not exhibit any significant difference compared to the control (Figure 1A,B)

Summary

Introduction

Bone diseases are caused by disharmony in the bone remodeling process, which is mediated by bone-formative osteoblasts and bone-resorbing osteoclasts [1]. Excessive activation of osteoclasts, which leads to excessive bone destruction, is associated with low concentration levels of estrogen in post-menopausal women or excessive inflammatory responses in pathological circumstances [2,3]. Osteoclasts are derived from bone-marrow macrophages and are responsible for the removal of old bone tissue by secreting acid and collagenase [4,5]. Osteoclastogenesis needs two factors, macrophage colony-stimulating factor (M-CSF) for proliferation and survival, and receptor activator of nuclear factor kappa-B ligand (RANKL) for differentiation and function [5]. M-CSF has a crucial role in sustaining the survival and proliferation of osteoclast precursor cells [6]. The binding of M-CSF to c-Fms on the osteoclast cell surface leads to the recruitment of c-Cbl and phosphatidylinositol

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