Fig 5. Schematic representation of potential relationships between the 4 MRONJ-associated genes and the disease at the molecular level.

The 4 genes are indicated as yellow circles. Abbreviations: FPP: farnesyl diphosphate, HMBPP: (E)‐4‐hydroxy‐3‐methylbutyl‐2‐enyl pyrophosphate, IPP: isopentenyl diphosphate, NO: nitric oxide, and ROS: reactive oxygen species. Bisphosphonates and other drugs could trigger osteosclerosis or block angiogenesis. GcpE synthesizes HMBPP and is usually functionally inactivated by dioxygen. The gene could be activated under the condition of the lack of blood supply. HMBPP activates Vγ9Vδ2 T cells. The effect is 10⁴ greater than IPP that is accumulates when bisphosphonates are used. Vγ9Vδ2 T cells have strong cell lytic activity to induce osteocyte apoptosis and secretion of cytotoxic substances, which can lead to MRONJ. Activated cells also produce inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). This strong local inflammation can activate macrophages, which produce reactive oxygen species (ROS) and nitric oxide (NO). ROS and NO are capable of damaging DNA, proteins, and other cellular compartments, and can impose potentially lethal stress on bacteria. Actinomyces can survive and proliferate, whereas the other bacteria have no defenses and decrease in frequency.