Bone-Forming Peptide-4 Induces Osteogenic Differentiation and VEGF Expression on Multipotent Bone Marrow Stromal Cells.

Mi Eun Kim,Taek Rim Yoon,Ju Yeon Kang,Hyung Keun Kim,Jun Sik Lee,Jong Keun Seon

doi:10.3389/fbioe.2021.734483

Abstract

Bone morphogenetic proteins (BMPs) have been widely used as treatment for bone repair. However, clinical trials on fracture repair have challenged the effectiveness of BMPs and suggested that delivery of multipotent bone marrow stromal cells (BMSCs) might be beneficial. During bone remodeling and bone fracture repair, multipotent BMSCs differentiate into osteoblasts or chondrocytes to stimulate bone formation and regeneration. Stem cell-based therapies provide a promising approach for bone formation. Extensive research has attempted to develop adjuvants as specific stimulators of bone formation for therapeutic use in patients with bone resorption. We previously reported for the first time bone-forming peptides (BFPs) that induce osteogenesis and bone formation. BFPs are also a promising osteogenic factor for prompting bone regeneration and formation. Thus, the aim of the present study was to investigate the underlying mechanism of a new BFP-4 (FFKATEVHFRSIRST) in osteogenic differentiation and bone formation. This study reports that BFP-4 induces stronger osteogenic differentiation of BMSCs than BMP-7. BFP-4 also induces ALP activity, calcium concentration, and osteogenic factors (Runx2 and osteocalcin) in a dose dependent manner in BMSCs. Therefore, these results indicate that BFP-4 can induce osteogenic differentiation and bone formation. Thus, treatment of multipotent BMSCs with BFP-4 enhanced osteoblastic differentiation and displayed greater bone-forming ability than BMP-7 treatment. These results suggest that BFP-4-stimulated cell therapy may be an efficient and cost-effective complement to BMP-7-based clinical therapy for bone regeneration and formation.

Highlights

Bone is a constantly renewing tissue by a process that is exquisitely balanced by bone-forming cells, bone-resorbing cells, osteoblasts, and osteoclasts (Douglas et al, 2018; Hamamura et al, 2019; Vesela et al, 2019)
We previously reported that the bone-forming peptides (BFPs) series, which is derived from the immature region of bone morphogenetic proteins (BMPs)-7, is capable of osteogenic differentiation and bone-regeneration activity
We identified a new peptide with the sequence FFKATEVHFRSIRST (Figure 1A), which we called BFP-4

Summary

Introduction

Bone is a constantly renewing tissue by a process that is exquisitely balanced by bone-forming cells, bone-resorbing cells, osteoblasts, and osteoclasts (Douglas et al, 2018; Hamamura et al, 2019; Vesela et al, 2019). Bone remodeling is strongly regulated by interactions among cytokines, hormones, and other molecules that affect communication between osteoclasts and osteoblasts. Any disruption in this network may result in abnormal bone mass, including osteoporosis (Florencio-Silva et al, 2015; Han et al, 2018; Owen and Reilly, 2018; Kumar and Roger, 2019). Various materials for osteogenesis and bone formation have been studied for a long time, and bone morphogenetic proteins (BMPs) is a representative factor with good efficacy in bone formation. BMPs are the key proteins mediating the differentiation, recruitment, and maturation of mesenchymal stromal cells (MSCs) into osteoblasts via osteogenesis (Sangadala et al, 2019). It is still required to find a more stable and economical inducer than BMP-7 as a factor inducing bone formation

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