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

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.

Suppression of Bone Necrosis around Tooth Extraction Socket in a MRONJ-like Mouse Model by E-rhBMP-2 Containing Artificial Bone Graft Administration

“…To investigate whether BMP-2/β-TCP transplantation affects the bone surrounding the tooth extraction socket in the MRONJ-like prevention model, the BMP-2/β-TCP complex was transplanted into the tooth extraction socket immediately after tooth extraction, and analyses were performed after four weeks post-transplantation. CY/ZA were administered continuously until seven weeks, according to a previously described protocol [ 34 ] ( Figure 3 A). The quality of the bone surrounding the tooth extraction socket in the MRONJ-like prevention model was evaluated by the number of empty lacunae and the bone mineral density (BMD) of furcation and mesial areas adjacent to the tooth extraction socket.…”

“…No significant difference in the number of empty lacunae was observed between the two groups at 200–300 µm (control: 115 ± 21.3 vs. BMP-2/β-TCP: 114 ± 22.1) ( Figure 3 F,G). Together, the results suggest that the transplantation of BMP-2/β-TCP enhances bone formation not only in the tooth extraction sockets [ 34 ], but also reduces bone necrosis around the tooth extraction sockets in the prevention of MRONJ symptoms in an MRONJ-like prevention models in mice.…”

“…Our data also demonstrated that the onset of MRONJ-associated symptoms was followed by tooth extraction in MRONJ model mice ( Figure 1 and Figure 2 ). Moreover, local delivery of BMP-2 promoted not only new bone formation in the tooth extraction sockets [ 34 ], but also reduced bone necrotic symptoms in the bone surrounding the tooth extraction sockets in both MRONJ-like prevention and treatment models in mice ( Figure 3 and Figure 4 ). On the other hand, it is still controversial whether BMP-2 could enhance BMD [ 39 , 40 ].…”

“…Ono et al [ 33 ] reported that E-rhBMP-2/β-TCP induced bone formation in a porcine maxillary sinus floor elevation model. Moreover, Mikai et al [ 34 ] also revealed the effectiveness of E-rhBMP-2/β-TCP in inducing bone formation in tooth extraction sockets. Therefore, in this study, we also focused on the combined effect of BMP-2/β-TCP in the bone quality of the surrounding alveolar bone in MRONJ-like mouse models.…”

“…is known to have osteoinductive, osteogenic abilities and cell-mediated resorption and has been used as a scaffold in the dental field for guided bone regeneration to prevent the ingrowth of soft tissues into bone defects [ 31 , 32 ]. Previously, Ono et al [ 33 ] and Mikai et al [ 34 ] demonstrated the advantages of hard biomaterial scaffolds (β-TCP) with BMP-2 for endogenous cell recruitment to induce bone formation around dental implants and in the tooth extraction socket in MRONJ-like mice models.…”