RANK/RANKL/OPG signaling pathways in necrotic jaw bone from bisphosphonate-treated subjects

Abstract

Osteonecrosis of the jaw (ONJ) is a chronic complication affecting long-term bisphosphonate-treated subjects, recognized by non-healing exposed bone in the maxillofacial region. The pathophysiological mechanism underlying ONJ has not been fully elucidated. The aim of the present study was to investigate the role of RANK/RANKL/OPG signaling pathway and, in parallel, to evaluate angiogenic and matrix mineralization processes in jaw bone necrotic samples obtained from bisphosphonate-treated subjects with established ONJ. Necrotic bone samples and native bone samples were processed for Light and Field Emission in Lens Scanning Electron Microscope (FEISEM) analyses, for Real-Time RT-PCR to evaluate the gene expression of TNFRSF11A (RANK), TNFSF11 (RANKL), and TNFSF11B (OPG) and for immunohistochemical analyses of VEGF and BSP expression. Morphological analyses performed by Light microscope and FEISEM show empty osteocytic lacunae and alteration of lamellar organization with degradation of the mineralized bone matrix in necrotic bone samples. A significant increase in TNFRSF11A, TNFSF11, TRAF6 and NFAT2 gene expression, and a reduction of TNFSF11B gene transcription level compared is also showed in necrotic bone compared to control samples. No significant difference of VEGF expression is evidenced, while lower BSP expression in necrotic bone compared to healthy samples is found. Even if the pathogenesis of bisphosphonate-associated ONJ remains unknown, a link between oral pathogens and its development seems to exist. We suppose lipopolysaccharide produced by bacteria colonizing and infecting necrotic bone and the surrounding viable area could trigger RANK/RANKL/OPG signaling pathway and, in this context, osteoclasts activation could be considered as a protective strategy carried out by the host bone tissue to delimitate the necrotic area and to counteract infection.

Diminished Progression of Periapical Lesions with Zoledronic Acid in Ovariectomized Rats

“…The micro-CT analysis showed that the OVX-veh group had greater bone loss, and this loss was diminished with ZOL treatment at both time points according to previous studies (11). In the sagittal section, the SHAM-ZOL 30 d group had less bone loss in comparison with all of the other groups, most likely as a result of the beneficial effect of estrogen and ZOL in decreasing bone resorption (17).…”

Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis

“…Histopathologic Analysis of bone tissue from patients who developed ONJ on DMab for bone metastases revealed a decrease number of osteoclasts with few nuclei. This morpohology is strikingly different from ONJ linked to bisphosphonates where osteoclast numbers are increased with giant, hypernucleated and detached and undergoing apoptosis (16, 45-47). Thus, a careful screening of RA patients for hypocalcemia and ONJ is recommended before DMab administration.…”

Serum levels of RANKL and OPG, and the RANKL/OPG ratio in bisphosphonate-related osteonecrosis of the jaw: Are they useful biomarkers for the advanced stages of osteonecrosis?

“…Di Nisio et al ( 34 ) proposed that bacteria in the necrotic area could trigger the RANK/RANKL/OPG signaling pathway. We explored whether serum levels of RANKL and OPG, or the RANKL/OPG ratio had any relationship with the different stages of MRONJ.…”