Actinomyces and MRONJ: A retrospective study and a literature review

Cerrato, Alessia; Zanette, Gastone; Boccuto, Mariagrazia; Angelini, Annalisa; Valente, Marialuisa; Bacci, Christian

doi:10.1016/j.jormas.2020.07.012

Cited by 23 publications

(24 citation statements)

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“…Actinomyces was increased by an average of 10.1% in MRONJ patients when compared to healthy controls. The result was consistent with a previous study [14] indicating that Actinomyces is dominant in oral microbiome of MRONJ patients. The present approach was more quantitative due to the shotgun metagenomic sequencing.…”

Section: Discussionsupporting

confidence: 93%

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Shotgun metagenome sequencing identification of a set of genes encoded by Actinomyces associated with medication-related osteonecrosis of the jaw

et al. 2020

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Medication-related osteonecrosis of the jaw (MRONJ) is intractable and severely affects a patient’s quality of life. Although many cases of MRONJ have been reported in the past decade, the disease pathophysiology is unclear and there are no evidence-based therapeutic strategies. MRONJ usually features bone inflammation and infection. Prior studies that explored the association between MRONJ and microbial infection used the culture-based approach, which is not applicable to hundreds of unculturable taxa in the human oral microbiome, or 16S ribosomal RNA gene sequencing, which does not provide quantitative information of the abundance of specific taxa, and information of the presence, abundance, and function of specific genes in the microbiome. Here, deep shotgun metagenome sequencing (>10 Gb per sample) of bulk DNA extracted from saliva of MRONJ patients and healthy controls was performed to overcome these limitations. Comparative quantitative analyses of taxonomic and functional composition of these deep metagenomes (initially of 5 patients and 5 healthy controls) revealed an average 10.1% increase of genus Actinomyces and a 33.2% decrease in genus Streptococcus normally predominant in the human oral microbiota. Pan-genome analysis identified genes present exclusively in the MRONJ samples. Further analysis of the reads mapping to the genes in the extended dataset comprising five additional MRONJ samples and publicly available dataset of nine healthy controls resulted in the identification of 31 genes significantly associated with MRONJ. All these genes were encoded by Actinomyces genomic regions. Of these, the top two abundant genes were almost exclusively encoded by Actinomyces among usual taxa in the human oral microbiota. The potential relationships of these key genes with the disease are discussed at molecular level based on the literature. Although the sample size was small, this study will aid future studies to verify the data and characterize these genes in vitro and in vivo to understand the disease mechanisms, develop molecular targeted drugs, and for early stage screening and prognosis prediction.

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Section: Discussionsupporting

confidence: 93%

“…MRONJ lesions are characterized by scattered areas of necrotic bone, as evidenced by empty osteocyte lacunae [13]. Secondly, bone inflammation and infection are usually associated with MRONJ, and bone invasion by Actinomyces was observed in 82.18% of patients [14].…”

Section: Introductionmentioning

confidence: 99%

Shotgun metagenome sequencing identification of a set of genes encoded by Actinomyces associated with medication-related osteonecrosis of the jaw

et al. 2020

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“…According to De Ceulaer et al, MRONJ could be considered as a bisphosphonate-induced Actinomyces infection [16]. Most specimens (83/101) from oncological patients who had the histological confirmation of MRONJ revealed the presence of Actinomyces infection [17]. In this study, we found different bacteria distribution in MRONJ lesions and normal oral mucosa.…”

Section: Discussionsupporting

confidence: 54%

Porphyromonas, Treponema, and Mogibacterium promote IL8/IFNγ/TNFα-based pro-inflammation in patients with medication-related osteonecrosis of the jaw

et al. 2020

Journal of Oral Microbiology

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Objective: Refractory infection is an important factor affecting the progression of medicationrelated osteonecrosis of the jaw (MRONJ) from clinical stage I to stage II/III. The aim of this study was to explore the distribution of bacteria and their association with the inflammatory pathway of stage II/III MRONJ. Materials and Methods: Nine specimens of fresh inflammation tissue, located next to the necrotic bone or sequestrum, were collected from MRONJ patients. Nine specimens from normal oral mucosa were collected from healthy patients. The 16S rRNA gene sequencing method was used to determine the distribution characteristics of the bacterial colony. The protein microarray analysis was used to detect the expression of inflammatory cytokines. Results: The average relative abundance of Bacteroidetes, Spirochaetes, Synergistetes, and Tenericutes was higher, while Proteobacteria and Actinobacteria were lower in the MRONJ group. Most pro-inflammatory cytokines were up-regulated in the MRONJ group; yet, only IFNγ, TNFα, and IL8 showed statistical differences (P < 0.05). Porphyromonas and Treponema were positively correlated with IL8, and Mogibacterium was positively correlated with IFNγ and TNFα. Conclusions: IL8/IFNγ/TNFα pro-inflammatory effect caused by Porphyromonas, Treponema, and Mogibacterium may be the leading cause of advancing MRONJ and thus may be used as a new target for infection control.

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“…Although it is well established that MRONJ is a complication of the above-mentioned therapies, the exact pathogenesis is unknown and seems to be multifactorial 6 . The altered remodelling and reduced blood supply impair the immune defense of the bone 7 – 10 . This mechanism is suggested to facilitate the development of osteomyelitis as a result of mechanical trauma and infection 11 – 14 , which may progress to osteonecrosis due to the poor regenerative potential caused by these factors 15 .…”

Section: Introductionmentioning

confidence: 99%

Targeted histological evaluation shows high incidence of actinomyces infection in medication-related osteonecrosis of the jaws

Brody

Scheich

Dobó‐Nagy

2022

Sci Rep

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Medication-Related Osteonecrosis of the Jaws (MRONJ) is a difficult-to-treat complication of the therapy of osteoporosis and some malignancies cured with bisphosphonates and antiresorptive drugs. The pathomechanism is unclear, but there is increasing observation that Actinomyces infection may play a role in its development and progression. The aim of our study was to demonstrate that histological examination using a validated triple staining procedure for Actinomyces bacteria strains can detect a high rate of Actinomyces infection in patient's samples with MRONJ. 112 previously hematoxylin-eosin (HE) stained samples submitted with the clinical diagnosis of MRONJ were re-evaluated histologically using an appropriate triple special staining validated for the identification of Actinomyces infection. During the first evaluation, when pathologists did not specifically look for Actinomyces, only 8.93% of the samples were reported as positive. In contrast, re-evaluation with triple staining provided a yield of 93.7% positive samples, therefore, we suggest the triple special staining to be standard in MRONJ histology evaluation. These results show that if the clinician suspects Actinomyces infection and brings this to the attention of the pathologist, it could significantly increase the number of correct diagnoses. It serves as an aid for clinicians in therapeutic success of MRONJ by selecting a long-term adequate antibiotic medication which is suitable for the elimination of actinomyces infection.

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Actinomyces and MRONJ: A retrospective study and a literature review

Cited by 23 publications

References 50 publications

Shotgun metagenome sequencing identification of a set of genes encoded by Actinomyces associated with medication-related osteonecrosis of the jaw

Shotgun metagenome sequencing identification of a set of genes encoded by Actinomyces associated with medication-related osteonecrosis of the jaw

Porphyromonas, Treponema, and Mogibacterium promote IL8/IFNγ/TNFα-based pro-inflammation in patients with medication-related osteonecrosis of the jaw

Targeted histological evaluation shows high incidence of actinomyces infection in medication-related osteonecrosis of the jaws

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