The Role of RANK/RANKL/OPG Signalling Pathways in Osteoclastogenesis in Odontogenic Keratocysts, Radicular Cysts, and Ameloblastomas

Abstract

The aim of this study was to evaluate the immunohistochemical expression of molecules involved in osteoclastogenesis, including the receptor activator of nuclear factor kappa B (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) in odontogenic keratocysts (OKCs), which has been named as a keratocystic odontogenic tumour by the WHO, and compare their expression with radicular cysts and ameloblastomas. RANK is a member of tumour necrosis factor receptor family and it is activated by RANK ligand. OPG binds to RANKL and inactivates it. The imbalance of these factors could cause the differential bone resorption activity in some diseases and tumours. The expression of these molecules was evaluated in ameloblastomas (n = 20), OKCs (n = 20), and radicular cysts (n = 20) by immunohistochemistry. Immunohistochemical reactivity for RANK, RANKL, and OPG was detected in neoplastic and nonneoplastic epithelium and connective tissue cells. RANK showed the greatest expression in OKCs followed by ameloblastomas, with the lowest expression seen in radicular cysts. Expression of RANKL was detected in all lesions and no significant differences were observed between groups. OPG was expressed very low in all groups. In the stroma, the number of RANK positive cells was higher in OKCs when compared with ameloblastomas and radicular cysts but radicular cyst had higher numbers of RANKL positive cells in the stroma than ameloblastomas. The molecular system of RANK/RANKL/OPG is variably expressed in OKCs, radicular cysts, and ameloblastomas and this system may be involved in the osteoclastogenic mechanisms in OKCs and ameloblastomas. Advanced studies could further clarify the role of RANK, RANKL, and OPG in mediating tumour associated bone osteolysis.

The extra domain A of fibronectin facilitates osteoclastogenesis in radicular cysts through vascular endothelial growth factor

“…During the interaction between EDA + FN and fibroblasts, expression of osteoclastogenesis‐related genes is altered (Khan et al , Gondokaryono et al , Xiang et al , Liu et al ). As illustrated in this study, when the autocrine effects of EDA + FN on fibroblasts were blocked by IST‐9, the genes facilitating osteoclastogenesis were concomitantly decreased, including COX‐2, TNF‐α, VEGF and RANKL/OPG (Tekkesin et al , Wang & Li , Wang et al 2015a, Wang et al 2015b; P < 0.05).…”

“…According to previous studies, fibroblasts isolated from the fibrous capsule of odontogenic cysts induce more osteoclasts than do normal controls (Wang & Li , Wang et al 2015a, Wang et al 2015b), possibly attributed to the differentiation of myofibroblasts, which are activated during chronic inflammation (Kouhsoltani et al ) or inappropriate wound healing (Lemanska‐Perek et al ). Chronic inflammation may initiate radicular cysts that can also activate fibroblasts in capsules, generating extracellular matrix (ECM; Jiang et al ), cellular factors and metabolic products (de Moraes et al , Tekkesin et al , Bernardi et al ), leading to osteoclastogenesis and bone destruction, as illustrated by radiolucent periapical areas.…”

TNF‐α (−308G>A) and TNF‐R1 (36A>G) single nucleotide polymorphisms are strong risk factors for odontogenic keratocystic tumor development

“…Pro‐ and anti‐apoptotic paths in KCOT development have also been described, with altered expression of p53, bcl‐2, Bax, and survivin, among others . Finally, some authors pointed to a potential role of inflammatory mechanisms in the pathogenesis of the jaw cysts/tumors, via their influence on the bone‐remodeling system, represented by the triad RANK/RANKL/OPG (receptor activator of nuclear factor‐κB/RANK ligand/osteoprotegerin) . It must be emphasized that TNF‐α is one of the most potent osteoclastogenic cytokines, acting on the modulation of local bone destruction.…”

Current Concepts and Occurrence of Epithelial Odontogenic Tumors: I. Ameloblastoma and Adenomatoid Odontogenic Tumor

“…The facts that receptor activator of nuclear factor κB ligand (RANKL) and MMP-9 are expressed in ameloblastomas may suggest that ameloblastoma cells have the potential to induce osteoclastogenesis, resulting in the rapid destruction of bone marrow 22,23. The higher expression rates of interleukin (IL)-1α and IL-6 are associated with tumor size in ameloblastomas.…”