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Comparative Study
. 2017 Jun 6;15(1):128.
doi: 10.1186/s12967-017-1230-8.

Osteoclast profile of medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis

Christian Gross  1 , Manuel Weber  2 , Kay Creutzburg  3 , Patrick Möbius  3 , Raimund Preidl  2 , Kerstin Amann  4 , Falk Wehrhan  2
Affiliations
Comparative Study

Osteoclast profile of medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis

Christian Gross et al. J Transl Med. .

Abstract

Background: The medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy [MRONJ (BP)] is characterized by non-healing exposed bone in the maxillofacial region. The pathogenesis of MRONJ (BP) is not fully understood. Giant, hypernucleated, inactive osteoclasts were found in MRONJ (BP) tissues, which indicated that accelerated cell-cell fusion might play a role. Dendritic cell-specific transmembrane protein (DC-STAMP) is associated with the cell-cell fusion of osteoclasts and precursor cells. Tartrate-resistant acid phosphatase (TRAP) is essential for osteoclastic bone resorption. The cell-cell fusion, as part of the osteoclastogenesis, and the resorptive activity can determine the morphology of osteoclasts. This study analyzed jaw bone from patients with MRONJ (BP), osteomyelitis (OM) and osteoradionecrosis (ORN) because a comparison with the osteoclast profiles of OM and ORN is essential for characterizing the osteoclast profile of MRONJ (BP).

Methods: Formalin-fixed routine jaw bone specimens from 70 patients [MRONJ (BP) n = 30; OM: n = 15, ORN: n = 15, control: n = 10] were analyzed retrospectively for osteoclast quantity, morphology and the expression of TRAP and DC-STAMP. The specimens were processed for hematoxylin and eosin staining (H&E), histochemistry (TRAP) and immunohistochemistry (anti-DC-STAMP) and were analyzed via virtual microscopy.

Results: The quantity, diameter and nuclearity of osteoclasts were significantly higher in MRONJ (BP) specimens than in OM, ORN and control specimens. Giant, hypernucleated osteoclasts were detected in MRONJ (BP) specimens only. Osteoclastic TRAP expression was lower in MRONJ (BP) and ORN specimens than in OM and control specimens. The DC-STAMP expression of osteoclasts and mononuclear cells was significantly higher in MRONJ (BP) and ORN specimens than in OM and control specimens.

Conclusions: This study indicates that the osteoclast profile of MRONJ (BP) is characterized by osteoclast inactivation and a high cell-cell fusion rate; however, the presence of giant, hypernucleated osteoclasts cannot be attributed to increased DC-STAMP-triggered cell-cell fusion alone. The incidental characterization of the osteoclast profiles of OM and ORN revealed differences that might facilitate the histopathological differentiation of these diseases from MRONJ (BP), which is essential because their therapies are somewhat different.

Keywords: BRONJ; Bisphosphonate; DC-STAMP; MRONJ; Osteoclasts; Osteomyelitis; Osteonecrosis; Osteoradionecrosis; TRAP.

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Figures

Fig. 1
Fig. 1
Whole slide imaging. The figure depicts an H&E stained MRONJ (BP) section consisting of mainly vital jaw bone. The histological section was scanned using a Pannoramic 250 Flash II Scanner (3DHISTECH Kft., Budapest, Hungary). Sections were analyzed via virtual microscopy using Pannoramic Viewer (3DHISTECH Kft., Budapest, Hungary). Within a scanned section, two visual fields were defined (a, rectangles). b Depicts a visual field. c Illustrates a caption within a visual field. Regions of interest (ROI) were marked, and their areas were calculated. Osteoclasts are tagged with “OC”
Fig. 2
Fig. 2
Quantitative and morphological analysis of osteoclasts (H&E): MRONJ (BP) vs. OM vs. ORN vs. control. a Depicts a giant hypernucleated osteoclast (arrowhead) within a MRONJ (BP) histological section. Note the pyknotic nuclei, the round shape, the detachment from the bone surface and the lack of ruffled borders. b Illustrates the number of osteoclasts per ROI. c, d Illustrate morphological differences in osteoclasts. * and ° mark statistical outliers. For detailed data see Table 2. MRONJ (BP) medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy, OC osteoclasts, OM osteomyelitis, ORN osteoradionecrosis, DC-STAMP dendritic cell-specific transmembrane protein, TRAP tartrate-resistant acid phosphatase
Fig. 3
Fig. 3
Analysis of TRAP staining: MRONJ (BP) vs. OM vs. ORN vs. control. a Shows 2 TRAP+ osteoclasts (arrowheads) within an OM histological section. b Depicts a TRAP+ osteoclast (arrowhead) within a control histological section. Note the direct contact with the bone surface. c Illustrates the number of TRAP+ osteoclasts per ROI. d Depicts the respective osteoclast labeling indices. * marks statistical outliers. For detailed data see Table 2. MRONJ (BP) medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy, OC osteoclasts, OM osteomyelitis, ORN osteoradionecrosis, DC-STAMP dendritic cell-specific transmembrane protein, TRAP tartrate-resistant acid phosphatase
Fig. 4
Fig. 4
Analysis of (anti-)DC-STAMP staining: MRONJ (BP) vs. OM vs. ORN vs. control. a Shows a DC-STAMP+ osteoclast (arrowhead) and DC-STAMP+ mononuclear cells (arrows) within a MRONJ (BP) histological section. b Illustrates the number of DC-STAMP+ cells per ROI. c Depicts the number of DC-STAMP+ osteoclasts per ROI. d Illustrates the respective osteoclast labeling indices. * and ° mark statistical outliers. For detailed data, see Table 2. MRONJ (BP) medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy, OC osteoclasts, OM osteomyelitis, ORN osteoradionecrosis, DC-STAMP dendritic cell-specific transmembrane protein, TRAP tartrate-resistant acid phosphatase
Fig. 5
Fig. 5
Analysis of OCs within MRONJ (BP) specimens. a Shows three different visual fields of the same MRONJ (BP) histological section [(anti-)DC-STAMP staining]. Nuclear counterstaining was performed. Arrowheads mark a bundle of potential osteoclastic precursors with a high expression of DC-STAMP. The arrow marks an osteoclast with intermediate DC-STAMP expression. Double arrows tag giant hypernucleated osteoclasts with no DC-STAMP expression. Below the visual fields, an illustration model depicts the gradual loss of DC-STAMP receptors during osteoclastogenesis. b, c Show the comparison between DC-STAMP+ osteoclasts and average osteoclasts (H&E). b Illustrates differences in osteoclast diameter. b Visualizes differences in number of nuclei per osteoclast
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