BMP-2/β-TCP Local Delivery for Bone Regeneration in MRONJ-Like Mouse Model.

Akihiro Mikai,Kumiko Nawachi,Takuo Kuboki,Toshitaka Oohashi,Emilio Satoshi Hara,Ha Thi Thu Nguyen,Mitsuaki Ono,Aya Kimura-Ono,Ikue Tosa,Takeshi Takarada,Shuji Nosho

doi:10.3390/ijms21197028

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a severe pathological condition associated mainly with the long-term administration of bone resorption inhibitors, which are known to induce suppression of osteoclast activity and bone remodeling. Bone Morphogenetic Protein (BMP)-2 is known to be a strong inducer of bone remodeling, by directly regulating osteoblast differentiation and osteoclast activity. This study aimed to evaluate the effects of BMP-2 adsorbed onto beta-tricalcium phosphate (β-TCP), which is an osteoinductive bioceramic material and allows space retention, on the prevention and treatment of MRONJ in mice. Tooth extraction was performed after 3 weeks of zoledronate (ZA) and cyclophosphamide (CY) administration. For prevention studies, BMP-2/β-TCP was transplanted immediately after tooth extraction, and the mice were administered ZA and CY for an additional 4 weeks. The results showed that while the tooth extraction socket was mainly filled with a sparse tissue in the control group, bone formation was observed at the apex of the tooth extraction socket and was filled with a dense connective tissue rich in cellular components in the BMP-2/β-TCP transplanted group. For treatment studies, BMP-2/β-TCP was transplanted 2 weeks after tooth extraction, and bone formation was followed up for the subsequent 4 weeks under ZA and CY suspension. The results showed that although the tooth extraction socket was mainly filled with soft tissue in the control group, transplantation of BMP-2/β-TCP could significantly accelerate bone formation, as shown by immunohistochemical analysis for osteopontin, and reduce the bone necrosis in tooth extraction sockets. These data suggest that the combination of BMP-2/β-TCP could become a suitable therapy for the management of MRONJ.

Highlights

In a super-aging society, the increasing number of patients with bone-resorption diseases has become an important issue of societal concern
The results demonstrated that local administration of Bone Morphogenetic Protein (BMP)-2/β-TCP in the tooth extraction sockets significantly induced bone formation and reduced the bone necrosis in both medication-related osteonecrosis of the jaw (MRONJ)-like prevention and treatment models
The results showed that the area positive for OPN was markedly larger in the BMP-2/β-TCP transplantation group, compared with the control group (Figure 4A,B)

Summary

Introduction

In a super-aging society, the increasing number of patients with bone-resorption diseases (e.g., osteoporosis) has become an important issue of societal concern. Bone resorption inhibitors, such as bisphosphonates (BP), have been widely used for the treatment of osteoporosis and suppression of bone metastatic cancer [1,2,3,4]. It is known that bone resorption inhibitors cause an excessive suppression of osteoclast activities, resulting in the inactivation of bone remodeling and the increased susceptibility for oral bacterial infection [7,8,9]. Inhibition of angiogenesis is another major hypothesis in MRONJ pathophysiology since osteonecrosis itself is classically considered an interruption in vascular supply [7]

Objectives

Methods

Results