Restriction of nidogen containing bisphosphonates- related osteonecrosis (BRONJ) to the jaw bone - Immunohistochemistry and molecular biology assessment of the animal BRONJ- model in the the Wistar- rat

• Applicant: Privatdozent Falk Wehrhan, Ph.D.
• Subject Area: Dentistry, Oral Surgery
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 232352343

No accepted etiology of the Bisphosphonate related osteonecrosis of the jaw (BRONJ) is available at present. BRONJ is characterized by intraoral exposed bone, osteopetrotic changes of the bone, impaired intraoral hard- and soft tissue healing and inflammation. Aminobisphosphonate (BP)- related toxicity to tissues or BP-related local inflammation as underlying mechanisms have been proposed in the past. This is not likely, however, since the identical clinical picture of BRONJ is presented following therapy with Denosumab, a monoclonal anti-Rank(L) antibody. The unique biologic feature of jaw bone is represented by its developmental biology related origin from the cranial neural crest cells (CNC), which implies CNC-related signal transduction of osseous remodelling within jaw bones. Msx-1 is exclusively expressed in CNC-derived osseous structures and pivotal to CNC-derived tissue remodeling. Own results showed suppression of Msx-1 and Rank(L) in BP-altered jaw bone at protein- and mRNA-level. Furthermore BP were shown to induce polarization of macrophages towards the inflammation-related M1 type. Rank(L) is essentially involved in signal transduction of jaw bone osseous remodelling and macrophage differentiation. Thus, impaired Msx-1/ Rank(L)-signalling could explain BP- and Denosumab specific osteonecrosis of the jaw.This experimental project (model wistar rat) shall clarify if BP treatment leads to differential impairment of bone remodelling and macrophage differentiation in jaw bone compared with extracranial mesenchymal determined tibia bone. The aim of this study is to quantitatively compare the expression patterns of Msx-1, Msx-2, Bmp-2/4, Dlx-5, Runx-2, Rank(L) during healing of an extraction socket and a tibia fracture following application of zoledronic acid. Furthermore, it shall be clarified if BP preferentially interact with Connexin-43 expressing osseous neural crest derived structures as described in literature. The results of the project will provide information describing the formal pathology of BRONJ. Moreover, the data of the project will elucidate the site specific signal transduction of osseous remodelling in jaw bones and the possible specific osteoimmunologic microenvironment. The results of the study might help to enable the evidence based therapeutic use of BP and Denosumab treating jaw bone specific osteoproliferative and inflammatory diseases like cherubism, ossifying fibroma and primary chronic osteomyelitis.

• DFG Programme: Research Grants
• Participating Persons: Professorin Dr. Kerstin Amann; Professor Dr. Karl Andreas Schlegel; Dr. Philipp Stockmann