Possible pathogenic engagement of soluble Semaphorin 4D produced by γδT cells in medication-related osteonecrosis of the jaw (MRONJ)

Movila, Alexandru; Mawardi, Hani; Nishimura, Kazuaki; Kiyama, Tomomi; Egashira, Kenji; Kim, Jae Young; Villa, Alessandro; Sasaki, Hajime; Woo, Sook Bin; Kawai, Toshihisa

doi:10.1016/j.bbrc.2016.10.012

Cited by 34 publications

(39 citation statements)

References 28 publications

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“…They are increased in the synovial fluid and membrane of OA patients and triggered the inflammatory cascade [28]. The increased content of IL-6 in serum and synovial fluid was reported to be associated with the severity of lesions in X-ray imaging and knee cartilage loss in OA patients [29], while Sema4D was reported to be upregulated in medication-related osteonecrosis of the jaw and associated with the increased secretion of TNF-α, IFN-γ, and IL-1β [30]. And Sema4D promoted the production of TNF-α in macrophages [30].…”

Section: Discussionmentioning

confidence: 99%

“…The increased content of IL-6 in serum and synovial fluid was reported to be associated with the severity of lesions in X-ray imaging and knee cartilage loss in OA patients [29], while Sema4D was reported to be upregulated in medication-related osteonecrosis of the jaw and associated with the increased secretion of TNF-α, IFN-γ, and IL-1β [30]. And Sema4D promoted the production of TNF-α in macrophages [30]. Sema4D KO mice developed attenuated hypersensitivity responses and lower expression of IL-1β and IL-6 [5].…”

Section: Discussionmentioning

confidence: 99%

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Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

Lei

Zhuang

et al. 2020

BioMed Research International

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Osteoarthritis (OA) is the most common chronic degenerative joint disease, and it remains the main cause of chronic disability in elderly individuals. Sema4D (semaphorin 4D) is involved in the immune system and related to bone injury, osteoporosis, osteoblast differentiation, and rheumatoid arthritis. However, the role of Sema4D in OA remains unclear. Hence, the LPS-stimulated chondrocyte cell injury model was constructed in this study to investigate the role of Sema4D in OA development. The results showed that Sema4D was increased in LPS-treated ATDC5 cells, and the knockdown of Sema4D suppressed the decline of cell viability, the increase of cell apoptosis, and the increase of IL-6, IL-1β, and TNF-α secretion in ATDC5 cells induced by LPS. Meanwhile, Sema4D overexpression aggravated the cell injury triggered by LPS, and inhibiting Plexin B1 partly abolished the effect of Sema4D overexpression on LPS-induced chondrocyte injury. Furthermore, silencing of Sema4D blocked the activation of the MAPK pathway in LPS-stimulated ATDC5 cells. Enhanced Sema4D promoted the activation of the MAPK pathway in LPS-stimulated ATDC5 cells. What is more, inhibiting the MAPK signaling pathway abolished the promoting effect of Sema4D overexpression on LPS-induced chondrocyte injury. Therefore, our study suggested that the knockdown of Sema4D protects ATDC5 cells against LPS-induced injury through inactivation of the MAPK signaling pathway via interacting with Plexin B1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

Lei

Zhuang

et al. 2020

BioMed Research International

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“…Namely, the small size of the animal requires reduced amount of the drug, rapid cumulative effects due to rapid mice metabolism, and the possibility of using genetically-manipulated animals to determine a cause-and-effect relationship between the target disruption of a gene and its function [21][22][23]. Several MRONJ models have been developed using mainly C57BL/6 and other mice strains (S1 Table), [15,17,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. The C57BL/6 is the most widely used inbred strain and with a large source of genetically modified lines [40].…”

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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“…In contrast, ONJ is not seen in C57/BL6 wild-type mice undergoing tooth extraction and zoledronate treatment, although mice exhibit delayed wound healing30. The activity of regulatory T cells (Tregs)27 or γδ T cells31 reportedly promotes ARONJ development, although it is unclear how these activities promote osteonecrosis development.…”

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confidence: 99%

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

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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.

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Possible pathogenic engagement of soluble Semaphorin 4D produced by γδT cells in medication-related osteonecrosis of the jaw (MRONJ)

Cited by 34 publications

References 28 publications

Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

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

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

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