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Normal bone remodelling requires the coordinated regulation of the genesis and activity of osteoblast and osteoclast lineages. Any interference with these integrated cellular systems can result in dysregulation of remodelling with the consequent loss of bone matrix. Bacteria are important causes of bone pathology in common conditions such as periodontitis, dental cysts, bacterial arthritis, and osteomyelitis. It is now established that many of the bacteria implicated in bone diseases contain or produce molecules with potent effects on bone cells. Some of these molecules, such as components of the gram-positive cell walls (lipoteichoic acids), are weak stimulators of bone resorption in vitro, while others (PMT, cpn60) are as active as the most active mammalian osteolytic factors such as cytokines like IL-1 and TNF. The complexity of the integration of bone cell lineage development means that there are still question marks over the mechanism of action of many well-known bone-modulatory molecules such as parathyroid hormone. The key questions which must be asked of the now-recognized bacterial bone-modulatory molecules are as follows: (i) what cell population do they bind to, (ii) what is the nature of the receptor and postreceptor events, and (iii) is their action direct or dependent on the induction of secondary extracellular bone-modulating factors such as cytokines, eicosanoids, etc. In the case of LPS, this ubiquitous gram-negative polymer probably binds to osteoblasts or other cells in bone through the CD14 receptor and stimulates them to release cytokines and eicosanoids which then induce the recruitment and activation of osteoclasts. This explains the inhibitor effects of nonsteroidal and anticytokine agents on LPS-induced bone resorption. However, other bacterial factors such as the potent toxin PMT may act by blocking the normal maturation pathway of the osteoblast lineage, thus inducing dysregulation in the tightly regulated process of resorption and replacement of bone matrix. At the present time, it is not possible to define a general mechanism by which bacteria promote loss of bone matrix. Many bacteria are capable of stimulating bone matrix loss, and the information available would suggest that each organism possesses different factors which interact with bone in different ways. With the rapid increase in antibiotic resistance, particularly with Staphylococcus aureus and M. tuberculosis, organisms responsible for much bone pathology in developed countries only two generations ago, we would urge that much greater attention should be focused on the problem of bacterially induced bone remodelling in order to define pathogenetic mechanisms which could be therapeutic targets for the development of new treatment modalities.
Objective: To contrast the pattern of bony reversal linesin bisphosphonate osteonecrosis of the jaw with infected osteomyelitis derived acute osteonecrosis of the jaw. Study design: This study investigated the histochemical characteristics of reversal lines in 50 cases of BP-related osteonecrosis of the jaw (BRONJ) compared with non-BP-involved bones in 20 cases of chronic osteomyelitis of the jaws. Necrotic bones were stained by using the toluidine blue, Safranin O, Giemsa, van Gieson, and Masson's trichrome staining methods. Results: All BP-involved bones in BRONJ were distinguishable from non-BP-involved bones in chronic osteomyelitis of the jaws by multiple thick, irregular, reversal lines, which were strongly stained with toluidine blue, Safranin O, and Giemsa solution. The reversal lines of BP-involved bones (average 31.2 ± 10.85 μm) were thicker than those of osteomyelitic bones (average 11.1 ± 3.76 μm), and they were closely associated with immature bony matrices containing collagenous materials positive for van Gieson and Masson's trichrome staining with statistical significance (P = .0212 in t test statistics). The immature reversal lines of BP-involved bones continuously appeared as thick non-birefringence lines between lamellate structures as observed under a polarizing microscope, whereas the reversal lines of non-BP-involved bones were gradually thinned as their mineralization advanced. Conclusions: BP-involved bones had immature bony matrices outlined by thick reversal lines, which might be crucial to rapid osteonecrosis of BRONJ and also could be hallmarks for the differential diagnosis of BRONJ from chronic osteomyelitis of the jaws.
Five surgically treated patients with osteoradionecrosis of the jaws are presented. The clinical history of the disease varied from 3 to 17 years. In three cases the progression of the disease was enhanced by surgical procedures performed in the irradiated area causing exfoliation of the premaxillary area in one case and spontaneous mandibular fracture in two cases. Actinomyces israelii was demonstrated in tissue sections of all five cases by using FITC-labeled specific antiserum and additionally with peroxidase-antiperoxidase method in one case. Candida was found in histologic sections of three cases. Radiation damage in the oral soft tissues and jawbones makes the atmosphere favorable for anaerobic microorganisms. The present results indicate that the role of A. israelii in the pathogenesis of osteoradionecrosis of the jaws has not been fully appreciated.
The skeleton is the largest mammalian organ system, containing a myriad of blood vessels, tissue surfaces and bone cells for bacterial colonization. Although rock-like, the skeleton is a dynamic structure that is undergoing constant remodelling. This is the result of the opposing actions of two key cells: the osteoblast, which produces bone, and the osteoclast, a multinucleate cell that 'eats' bone. It is not generally realized that the most prevalent chronic bacterial diseases of Homo sapiens afflict the skeleton. Several pathogens, and members of the normal microbiota, have evolved specific cellular and molecular mechanisms for invading bone, including its cellular constituents. The host cellular pathways that are activated and lead to destruction or loss of the bone matrix will be described.
Actinomycosis of the jaws is a rare disease, which has been recently described in patients with infected osteoradionecrosis (IORN) and bisphosphonate-associated osteonecrosis (BON). We investigated our archive material for Actinomycosis of the jaws with special regard to underlying disease. Out of a total number of 45 patients with Actinomycosis, 43 (93.5%) suffered from BON (58.7%) or IORN (35.6%), while there were only 3 patients (6.7%) without anti-tumor treatment. In all cases, we found direct association of Actinomyces colonies with bone; in the surrounding medullary space, mixed inflammatory infiltrates with variable amounts of osteoclasts were a typical finding. Pseudoepitheliomatous hyperplasia occurred in 60.9% of patients. Cell-rich vessel obliteration was seen in less than 25.9% of BON patients, while hyalinized vessel obliteration was obtained in 37.5% of IORN patients. Additionally performed polymerase chain reaction (PCR) on paraffin-embedded and ethylene diamine tetracetic acid (EDTA)-decalcified tissue specimens confirmed the presence of Actinomyces israelii in seven of seven cases analyzed. We conclude that Actinomycosis of the jaws is a particular complication in patients with BON and/or IORN. Patients with Actinomycosis of the jaws during or after these forms of anti-cancer therapy are suggested to represent a distinct patient cohort with a relevant impairment of their general condition.
The roles of the 'classical'Actinomyces spp. as colonizers of oral cavities of man and animals, in development of intra-oral infections and as agents of actinomycosis have been well documented. This mini-review focuses on perceptions of human colonization and infection that have emerged in the past decade, largely as a result of advances in classification, identification and direct detection from clinical material. Arguably, of the greatest importance is the recognition of actinomycosis as a major factor and indicator of poor prognosis in both infected osteoradionecrosis and bisphosphonate-associated osteonecrosis of the jaws. Among recently described species, Actinomyces graevenitzii has been isolated almost exclusively from oral and respiratory sites and may be a causative agent of actinomycosis. Conversely, several other Actinomyces spp. are isolated commonly from superficial soft tissue infections. Members of the genus Actinobaculum, which is closely related to Actinomyces, are strongly associated with urosepsis. Isolation and identification of Actinomyces and related genera by conventional methods remain difficult. Diagnosis is commonly belated and based solely upon histological findings. Development of direct detection methods may aid patient management and further elucidate clinical associations.
Histochemical observation of bony reversal lines in bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol
Histochemical observation of bony reversal lines in bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Oct 13. pii: S2212-4403(16)30612-5. doi: 10.1016/j.oooo.2016.09.225. [Epub ahead of print]