Immune cellular profile of bisphosphonate‐related osteonecrosis of the jaw

Silva, PG de Barros; Oliveira, CC de; Brizeno, Lac; Wong, D. V. T.; Júnior, Rcp Lima; Gonçalves, RP; Sousa, FB; Mota, Mário Rogério Lima; Ribeiro, Ronaldo de Albuquerque; Alves, Apnn

doi:10.1111/odi.12513

Cited by 31 publications

(20 citation statements)

References 57 publications

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“…Indeed, it is well documented that age represents one of the major risk factors associated to BRONJ onset 38. Our data agree with previous in vitro 39 and ex vivo 40, 41 studies that described a correlation between inflammation and nitrogen containing BPs. Here we are the first to show a direct pro-inflammatory action on pre-osteoblasts, since previously it was investigated on immune cells, mainly macrophages 39, 42, 43.…”

Section: Discussionsupporting

confidence: 93%

Nitrogen Containing Bisphosphonates Impair the Release of Bone Homeostasis Mediators and Matrix Production by Human Primary Pre-Osteoblasts

et al. 2019

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Bisphosphonates (BPs) represent the first-line treatment for a wide array of bone disorders. Despite their well-known action on osteoclasts, the effects they induce on osteoblasts are still unclear. In order to shed light on this aspect we evaluated the impact of two nitrogen containing bisphosphonates, Alendronate (ALN) and Zoledronate (ZOL), on human primary pre-osteoblasts. At first, we showed an inhibitory effect on cell viability and alkaline phosphatase activity starting from µM concentrations of both drugs. In addition, an inhibitory trend on mineralized nodules deposition was observed. Then low doses of both ALN and ZOL rapidly increased the release of the pro-inflammatory mediators TNFα and IL-1β, while increased DKK-1 and Sclerostin, both inhibitors of osteoblastogenesis. Finally, ALN and 10-7M ZOL decreased the expression of type I Collagen and Osteopontin, while both drugs slightly stimulated SPARC production. With these results, we would like to suggest a direct inhibitory action on bone-forming cells by nitrogen containing bisphosphonates.

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Section: Discussionsupporting

confidence: 93%

Nitrogen Containing Bisphosphonates Impair the Release of Bone Homeostasis Mediators and Matrix Production by Human Primary Pre-Osteoblasts

et al. 2019

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“…Macrophages may inhibit osteocyte viability through the effect of TNF-α and IL-6 in the model of monosodium urate crystal-induced inflammation [87]. During the stage of bone repair, expression of IL-18 from macrophages may serve an important role by increasing expression during bone formation or decreasing expression in the model of bisphosphonate-related osteonecrosis of the jaw [88,89]. Osteocytes may be regulated by macrophage secreting inflammatory cytokines (TNF-α, IL-6) to influence bone turnover.…”

Section: The Effect Of Macrophages In Osteocytesmentioning

confidence: 99%

The Role of Macrophage in the Pathogenesis of Osteoporosis

Yang

2019

IJMS

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Osteoporosis is a systemic disease with progressive bone loss. The bone loss is associated with an imbalance between bone resorption via osteoclasts and bone formation via osteoblasts. Other cells including T cells, B cells, macrophages, and osteocytes are also involved in the pathogenesis of osteoporosis. Different cytokines from activated macrophages can regulate or stimulate the development of osteoclastogenesis-associated bone loss. The fusion of macrophages can form multinucleated osteoclasts and, thus, cause bone resorption via the expression of IL-4 and IL-13. Different cytokines, endocrines, and chemokines are also expressed that may affect the presentation of macrophages in osteoporosis. Macrophages have an effect on bone formation during fracture-associated bone repair. However, activated macrophages may secrete proinflammatory cytokines that induce bone loss by osteoclastogenesis, and are associated with the activation of bone resorption. Targeting activated macrophages at an appropriate stage may help inhibit or slow the progression of bone loss in patients with osteoporosis.

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“…Previous studies have explored MRONJ animal models to provide explanations for the disease process. Hypotheses examined in these studies include oversuppression of osteoclasts bone resorption in the jaws, more than in endochondral bones [14], angiogenesis inhibition [15,16] and more recently, alterations of innate and adaptive immune responses [17,18].…”

Section: Introductionmentioning

confidence: 99%

Medication-related osteonecrosis of the jaws after tooth extraction in senescent female mice treated with zoledronic acid: microtomographic, histological and immunohistochemical characterization

Biguetti

Oliva

Healy

et al. 2019

Preprint

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Treatment with cumulative dosages of zoledronic acid (ZA) in elderly patients is a risk factor for the development of medication-related osteonecrosis of the jaws (MRONJ), mainly related to surgical triggers such as tooth extraction. However, animal models for the investigation and understanding of MRONJ pathophysiology in senescent and postmenopausal stages remains to be developed and characterized. The aim of this study was to analyze MRONJ development in senescent female mice treated with cumulative dosages of ZA. For this purpose, twenty 129/Sv female mice, 64 weeks old, were treated with 0.9% saline solution as Control group (n=10), and with ZA at 250µg/Kg (n=10), once a week, starting 4 weeks before the upper right incisor extraction and until the end of the experimental time points (7 days and 21 days).At 7 and 21 days, specimens were harvested for microCT, histological, birefringence and immunohistochemical analysis. Clinically, an incomplete epithelialization was observed in ZA group at 7 days and a delayed bone matrix mineralization and collagen maturation at 7 and 21 days compared to the controls. Controls revealed sockets filled with mature bone at 21 days as observed by microCT and birefringence, while ZA group presented delayed bone deposition at 7 and 21 days, as well increased leukocyte infiltration and blood clot at 7 days, and increased bone sequestrum and empty osteocyte lacunae at 21 days (p<0.05). Also, ZA group presented decreased quantity TGFb+ and Runx-2+ cells at 7 days, and decreased quantity of TRAP+ osteoclasts compared to the control at 21 days (p<0.05). Togheter, these data demonstrate the usefulness of this model to understanding the pathophysiology of MRONJ.

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Immune cellular profile of bisphosphonate‐related osteonecrosis of the jaw

Abstract: BRONJ is characterized by increases in immunostaining for proinflammatory markers and NF-kB and inversely associated with cells exhibiting IL-18 bp.

Cited by 31 publications

References 57 publications

Nitrogen Containing Bisphosphonates Impair the Release of Bone Homeostasis Mediators and Matrix Production by Human Primary Pre-Osteoblasts

Nitrogen Containing Bisphosphonates Impair the Release of Bone Homeostasis Mediators and Matrix Production by Human Primary Pre-Osteoblasts

The Role of Macrophage in the Pathogenesis of Osteoporosis

Medication-related osteonecrosis of the jaws after tooth extraction in senescent female mice treated with zoledronic acid: microtomographic, histological and immunohistochemical characterization

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