Osteonecrosis of the Jaw Developed in Mice

Park, Sil; Kanayama, Keiichi; Kaur, Kawaljit; Tseng, Han-Ching; Banankhah, Sina; Quje, Davood Talebi; Sayre, James W.; Jewett, Anahid; Nishimura, Ichiro

doi:10.1074/jbc.m115.652305

Cited by 50 publications

(28 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These methods are considered more straightforward techniques to investigate ARONJ development compared with our models and thus represent a limitation of our study. Meanwhile, over 5–15 weeks of observation, osteonecrosis development in these models occurred in 0–40% of osteocytes274041424344 in approximately 10% of wild-type mice26; however, our model promotes osteonecrosis development in three weeks in 100% of wild-type mice, and 60–80% of lacunae observed in the model were empty. This enabled us to analyze effects of inflammatory cytokines on osteonecrosis development.…”

Section: Discussionmentioning

confidence: 75%

See 1 more Smart Citation

Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis

Morita

Iwasaki

Sato

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Various conditions, including bacterial infection, can promote osteonecrosis. For example, following invasive dental therapy with anti-bone resorptive agents, some patients develop osteonecrosis in the jaw; however, pathological mechanisms underlying these outcomes remain unknown. Here, we show that administration of anti-resorptive agents such as the bisphosphonate alendronate accelerates osteonecrosis promoted by infectious osteomyelitis. Potent suppression of bone turnover by these types of agents is considered critical for osteonecrosis development; however, using mouse models we found that acceleration of bone turnover by teriparatide injection did not prevent osteonecrosis but rather converted osteoclast progenitors to macrophages expressing inflammatory cytokines, which were required for osteonecrosis development. In fact, we demonstrate that TNFα-, IL-1α/β- or IL-6-deficient mice as well as wild-type mice administered a TNFα-inhibitor were significantly resistant to development of osteonecrosis accompanying infectious myelitis, even under bisphosphonate treatment. Our data provide new insight into mechanisms underlying osteonecrosis and suggest new ways to prevent it.

show abstract

Section: Discussionmentioning

confidence: 75%

“…Osteonecrosis was reportedly seen following administration of the bisphosphonate zoledronate, following tooth extraction in wild-type mice274041424344. These methods are considered more straightforward techniques to investigate ARONJ development compared with our models and thus represent a limitation of our study.…”

Section: Discussionmentioning

confidence: 97%

Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis

Morita

Iwasaki

Sato

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Our results here point to an additional factor contributing to the variability of ONJ incidence and severity in animal model studies that lack a concomitant systemic risk factor [9, 11, 40–46]. In our experience, occurrence of spontaneous periradicular lesions around maxillary teeth in C57Bl/6J or DBA1/J male mice ranges from 35–50% [24], varies among vendor shipment of animals, and is unavoidable.…”

Section: Discussionmentioning

confidence: 78%

Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease

Soundia

Hadaya

Esfandi

et al. 2016

Bone

View full text Add to dashboard Cite

Osteonecrosis of the jaws (ONJ) is a complication of antiresorptive medications, such as denosumab or bisphosphonates, prescribed to patients with bone malignancy or osteoporosis. The most common instigating local factor in ONJ pathogenesis is tooth extraction. However, in adults the great majority of teeth are extracted due to dental disease. Here, we have investigated alveolar bone healing after extraction of healthy teeth or teeth with naturally occurring periradicular disease in mice treated with high dose zoledronic acid (ZA), a potent bisphosphonate, or OPG-Fc, a RANKL inhibitor. C57BL/6 mice were treated for eight weeks and in vivo micro-CT was performed to identify spontaneously occurring periradicular lesions around the roots of maxillary molars. Then, extractions of molars with and without dental disease were performed in all groups. Four weeks later, animals were euthanized and maxillae were dissected and analyzed. Clinically, all vehicle animals with extraction of healthy or diseased teeth, and most OPG-Fc or ZA animals with extraction of healthy teeth showed normal mucosal healing. On the contrary, most animals with OPG-Fc or ZA treatment and extraction of diseased teeth demonstrated impaired healing with visible mucosal defects. Radiographically, bone socket healing was significantly compromised in OPG-Fc and ZA-treated mice with periradicular disease in comparison to other groups. Histologically, all vehicle animals showed normal mucosal healing and socket remodeling. OPG-Fc and ZA animals with extraction of healthy teeth showed normal mucosal healing, woven bone formation in the socket, and decreased remodeling of the original socket confines. OPG-Fc and ZA animals with extraction of diseased teeth showed mucosal defects, persistent prominent inflammatory infiltrate, bone exposure and areas of osteonecrosis. These findings support that dental disease is critical in the pathogenesis of ONJ, not only as the instigating cause for tooth extraction, but also as a compounding factor in ONJ development and pathophysiology.

show abstract

“…After ligature placement for 2 weeks, the maxillary second molar was extracted using forceps in Ext and PD-Ext mice under anesthesia. We analyzed the closure of the extraction socket and bacterial colony formation in liver and spleen after 4 weeks of tooth extraction because it was reported that the extraction socket was completely covered by the epithelial tissue in 4 weeks after tooth loss 60 . The healing of oral mucosa and bacterial dissemination after tooth extraction normally finished in l17a −/− Il17f −/− mice as well as Il6ra flox/flox Foxp3 -Cre mice.…”

Section: Methodsmentioning

confidence: 99%

Host defense against oral microbiota by bone-damaging T cells

et al. 2018

View full text Add to dashboard Cite

The immune system evolved to efficiently eradicate invading bacteria and terminate inflammation through balancing inflammatory and regulatory T-cell responses. In autoimmune arthritis, pathogenic TH17 cells induce bone destruction and autoimmune inflammation. However, whether a beneficial function of T-cell-induced bone damage exists is unclear. Here, we show that bone-damaging T cells have a critical function in the eradication of bacteria in a mouse model of periodontitis, which is the most common infectious disease. Bacterial invasion leads to the generation of specialized TH17 cells that protect against bacteria by evoking mucosal immune responses as well as inducing bone damage, the latter of which also inhibits infection by removing the tooth. Thus, bone-damaging T cells, which may have developed to stop local infection by inducing tooth loss, function as a double-edged sword by protecting against pathogens while also inducing skeletal tissue degradation.

show abstract

Osteonecrosis of the Jaw Developed in Mice

Cited by 50 publications

References 52 publications

Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis

Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis

Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease

Host defense against oral microbiota by bone-damaging T cells

Contact Info

Product

Resources

About