Indigenous Microbiota Protects against Inflammation-Induced Osteonecrosis

D. W. Williams; H. E. Vuong; S. Kim; A. Lenon; K. Ho; E. Y. Hsiao; E. C. Sung; R. H. Kim

doi:10.1177/0022034520908594

Indigenous Microbiota Protects against Inflammation-Induced Osteonecrosis

D. W. Williams, H. E. Vuong, S. Kim, A. Lenon, K. Ho, E. Y. Hsiao, E. C. Sung, R. H. Kim

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a rare intraoral lesion that occurs in patients undergoing long-term and/or high-dose therapy with nitrogen-containing bisphosphonates, a RANKL inhibitor, antiangiogenic agents, or mTOR inhibitors. The presence of pathogenic bacteria is highly associated with advanced stages of MRONJ lesions; however, the exact role of indigenous microbes in MRONJ development is unknown. Here, we report that the normal oral flora in mice protects against inflammation-induced osteonecrosis. In mice that developed osteonecrosis following tooth extraction, there was increased bacterial infiltration when compared with healed controls. Antibiotic-mediated oral dysbiosis led to a local inhibition of bone resorption in the presence of ligature-induced periodontitis (LIP). There was no significant difference in empty lacunae, necrotic bone formation, osteoclast number, and surface area in antibiotic-treated as compared with conventionally colonized mice following extraction of healthy teeth after zoledronic acid infusions. However, extraction of LIP teeth led to increased empty lacunae, necrotic bone, and osteoclast surface area in antibiotic- and zoledronic acid–treated mice as compared with conventionally colonized mice. Our findings suggest that the presence of the indigenous microbiota protects against LIP-induced osteonecrosis.

Original language	English (US)
Pages (from-to)	676-684
Number of pages	9
Journal	Journal of dental research
Volume	99
Issue number	6
DOIs	https://doi.org/10.1177/0022034520908594
State	Published - Jun 1 2020

Bibliographical note

Funding Information:
Medication-related osteonecrosis of the jaw (MRONJ) is a rare intraoral lesion that occurs in patients undergoing long-term and/or high-dose therapy with nitrogen-containing bisphosphonates, a RANKL inhibitor, antiangiogenic agents, or mTOR inhibitors. The presence of pathogenic bacteria is highly associated with advanced stages of MRONJ lesions; however, the exact role of indigenous microbes in MRONJ development is unknown. Here, we report that the normal oral flora in mice protects against inflammation-induced osteonecrosis. In mice that developed osteonecrosis following tooth extraction, there was increased bacterial infiltration when compared with healed controls. Antibiotic-mediated oral dysbiosis led to a local inhibition of bone resorption in the presence of ligature-induced periodontitis (LIP). There was no significant difference in empty lacunae, necrotic bone formation, osteoclast number, and surface area in antibiotic-treated as compared with conventionally colonized mice following extraction of healthy teeth after zoledronic acid infusions. However, extraction of LIP teeth led to increased empty lacunae, necrotic bone, and osteoclast surface area in antibiotic- and zoledronic acid–treated mice as compared with conventionally colonized mice. Our findings suggest that the presence of the indigenous microbiota protects against LIP-induced osteonecrosis. osteoclast(s) medication-related osteonecrosis of the jaw/MRONJ ligature-induced periodontitis/periodontal disease wound healing bone antibiotic(s) SCADA Henry M. Thornton Fellowship New York Stem Cell Foundation https://doi.org/10.13039/100003194 Robertson Investigator National Institute of Dental and Craniofacial Research https://doi.org/10.13039/100000072 DE023348 National Institute of Dental and Craniofacial Research https://doi.org/10.13039/100000072 DE025172 National Institute of General Medical Sciences https://doi.org/10.13039/100000057 GM106996 university of california, los angeles https://doi.org/10.13039/100007185 Dean's Faculty Research Seed grant ADA Foundation https://doi.org/10.13039/100001440 Dentsply Sirona Research Award for Dual Degree edited-state corrected-proof typesetter ts1

Funding Information:
We thank the University of California, Los Angeles (UCLA), Translational Procurement Core Laboratory for expedited and cooperative services. Additionally, we thank the UCLA Technology Center for Genomics and Bioinformatics for expedited sequencing service. We thank Teresa Wild and Niki Moutsopoulos for providing P. gingivalis and the microbiome quantification protocol.

Funding Information:
This study was supported in part by the National Institutes of Health / National Institute of Dental and Craniofacial Research (grant DE025172 to D.W.W.; grant DE023348 to R.H.K.) and National Institutes of Health / National Institute of General Medical Sciences (grant GM106996 to H.E.V.), the ADA Foundation Dentsply Sirona Research Award (to D.W.W.), the Henry M. Thornton Fellowship (to D.W.W.), and UCLA School of Dentistry Dean’s Faculty Research Seed Grant (to R.H.K.). E.Y.H. is a New York Stem Cell Foundation–Robertson Investigator.

Publisher Copyright:
© International & American Associations for Dental Research 2020.

Keywords

antibiotic(s)
bone
ligature-induced periodontitis/periodontal disease
medication-related osteonecrosis of the jaw/MRONJ
osteoclast(s)
wound healing

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title = "Indigenous Microbiota Protects against Inflammation-Induced Osteonecrosis",

abstract = "Medication-related osteonecrosis of the jaw (MRONJ) is a rare intraoral lesion that occurs in patients undergoing long-term and/or high-dose therapy with nitrogen-containing bisphosphonates, a RANKL inhibitor, antiangiogenic agents, or mTOR inhibitors. The presence of pathogenic bacteria is highly associated with advanced stages of MRONJ lesions; however, the exact role of indigenous microbes in MRONJ development is unknown. Here, we report that the normal oral flora in mice protects against inflammation-induced osteonecrosis. In mice that developed osteonecrosis following tooth extraction, there was increased bacterial infiltration when compared with healed controls. Antibiotic-mediated oral dysbiosis led to a local inhibition of bone resorption in the presence of ligature-induced periodontitis (LIP). There was no significant difference in empty lacunae, necrotic bone formation, osteoclast number, and surface area in antibiotic-treated as compared with conventionally colonized mice following extraction of healthy teeth after zoledronic acid infusions. However, extraction of LIP teeth led to increased empty lacunae, necrotic bone, and osteoclast surface area in antibiotic- and zoledronic acid–treated mice as compared with conventionally colonized mice. Our findings suggest that the presence of the indigenous microbiota protects against LIP-induced osteonecrosis.",

keywords = "antibiotic(s), bone, ligature-induced periodontitis/periodontal disease, medication-related osteonecrosis of the jaw/MRONJ, osteoclast(s), wound healing",

author = "Williams, {D. W.} and Vuong, {H. E.} and S. Kim and A. Lenon and K. Ho and Hsiao, {E. Y.} and Sung, {E. C.} and Kim, {R. H.}",

note = "Funding Information: Medication-related osteonecrosis of the jaw (MRONJ) is a rare intraoral lesion that occurs in patients undergoing long-term and/or high-dose therapy with nitrogen-containing bisphosphonates, a RANKL inhibitor, antiangiogenic agents, or mTOR inhibitors. The presence of pathogenic bacteria is highly associated with advanced stages of MRONJ lesions; however, the exact role of indigenous microbes in MRONJ development is unknown. Here, we report that the normal oral flora in mice protects against inflammation-induced osteonecrosis. In mice that developed osteonecrosis following tooth extraction, there was increased bacterial infiltration when compared with healed controls. Antibiotic-mediated oral dysbiosis led to a local inhibition of bone resorption in the presence of ligature-induced periodontitis (LIP). There was no significant difference in empty lacunae, necrotic bone formation, osteoclast number, and surface area in antibiotic-treated as compared with conventionally colonized mice following extraction of healthy teeth after zoledronic acid infusions. However, extraction of LIP teeth led to increased empty lacunae, necrotic bone, and osteoclast surface area in antibiotic- and zoledronic acid–treated mice as compared with conventionally colonized mice. Our findings suggest that the presence of the indigenous microbiota protects against LIP-induced osteonecrosis. osteoclast(s) medication-related osteonecrosis of the jaw/MRONJ ligature-induced periodontitis/periodontal disease wound healing bone antibiotic(s) SCADA Henry M. Thornton Fellowship New York Stem Cell Foundation https://doi.org/10.13039/100003194 Robertson Investigator National Institute of Dental and Craniofacial Research https://doi.org/10.13039/100000072 DE023348 National Institute of Dental and Craniofacial Research https://doi.org/10.13039/100000072 DE025172 National Institute of General Medical Sciences https://doi.org/10.13039/100000057 GM106996 university of california, los angeles https://doi.org/10.13039/100007185 Dean's Faculty Research Seed grant ADA Foundation https://doi.org/10.13039/100001440 Dentsply Sirona Research Award for Dual Degree edited-state corrected-proof typesetter ts1 Funding Information: We thank the University of California, Los Angeles (UCLA), Translational Procurement Core Laboratory for expedited and cooperative services. Additionally, we thank the UCLA Technology Center for Genomics and Bioinformatics for expedited sequencing service. We thank Teresa Wild and Niki Moutsopoulos for providing P. gingivalis and the microbiome quantification protocol. Funding Information: This study was supported in part by the National Institutes of Health / National Institute of Dental and Craniofacial Research (grant DE025172 to D.W.W.; grant DE023348 to R.H.K.) and National Institutes of Health / National Institute of General Medical Sciences (grant GM106996 to H.E.V.), the ADA Foundation Dentsply Sirona Research Award (to D.W.W.), the Henry M. Thornton Fellowship (to D.W.W.), and UCLA School of Dentistry Dean{\textquoteright}s Faculty Research Seed Grant (to R.H.K.). E.Y.H. is a New York Stem Cell Foundation–Robertson Investigator. Publisher Copyright: {\textcopyright} International & American Associations for Dental Research 2020.",

year = "2020",

month = jun,

day = "1",

doi = "10.1177/0022034520908594",

language = "English (US)",

volume = "99",

pages = "676--684",

journal = "Journal of dental research",

issn = "0022-0345",

publisher = "SAGE Publications Inc.",

number = "6",

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TY - JOUR

T1 - Indigenous Microbiota Protects against Inflammation-Induced Osteonecrosis

AU - Williams, D. W.

AU - Vuong, H. E.

AU - Kim, S.

AU - Lenon, A.

AU - Ho, K.

AU - Hsiao, E. Y.

AU - Sung, E. C.

AU - Kim, R. H.

N1 - Funding Information: Medication-related osteonecrosis of the jaw (MRONJ) is a rare intraoral lesion that occurs in patients undergoing long-term and/or high-dose therapy with nitrogen-containing bisphosphonates, a RANKL inhibitor, antiangiogenic agents, or mTOR inhibitors. The presence of pathogenic bacteria is highly associated with advanced stages of MRONJ lesions; however, the exact role of indigenous microbes in MRONJ development is unknown. Here, we report that the normal oral flora in mice protects against inflammation-induced osteonecrosis. In mice that developed osteonecrosis following tooth extraction, there was increased bacterial infiltration when compared with healed controls. Antibiotic-mediated oral dysbiosis led to a local inhibition of bone resorption in the presence of ligature-induced periodontitis (LIP). There was no significant difference in empty lacunae, necrotic bone formation, osteoclast number, and surface area in antibiotic-treated as compared with conventionally colonized mice following extraction of healthy teeth after zoledronic acid infusions. However, extraction of LIP teeth led to increased empty lacunae, necrotic bone, and osteoclast surface area in antibiotic- and zoledronic acid–treated mice as compared with conventionally colonized mice. Our findings suggest that the presence of the indigenous microbiota protects against LIP-induced osteonecrosis. osteoclast(s) medication-related osteonecrosis of the jaw/MRONJ ligature-induced periodontitis/periodontal disease wound healing bone antibiotic(s) SCADA Henry M. Thornton Fellowship New York Stem Cell Foundation https://doi.org/10.13039/100003194 Robertson Investigator National Institute of Dental and Craniofacial Research https://doi.org/10.13039/100000072 DE023348 National Institute of Dental and Craniofacial Research https://doi.org/10.13039/100000072 DE025172 National Institute of General Medical Sciences https://doi.org/10.13039/100000057 GM106996 university of california, los angeles https://doi.org/10.13039/100007185 Dean's Faculty Research Seed grant ADA Foundation https://doi.org/10.13039/100001440 Dentsply Sirona Research Award for Dual Degree edited-state corrected-proof typesetter ts1 Funding Information: We thank the University of California, Los Angeles (UCLA), Translational Procurement Core Laboratory for expedited and cooperative services. Additionally, we thank the UCLA Technology Center for Genomics and Bioinformatics for expedited sequencing service. We thank Teresa Wild and Niki Moutsopoulos for providing P. gingivalis and the microbiome quantification protocol. Funding Information: This study was supported in part by the National Institutes of Health / National Institute of Dental and Craniofacial Research (grant DE025172 to D.W.W.; grant DE023348 to R.H.K.) and National Institutes of Health / National Institute of General Medical Sciences (grant GM106996 to H.E.V.), the ADA Foundation Dentsply Sirona Research Award (to D.W.W.), the Henry M. Thornton Fellowship (to D.W.W.), and UCLA School of Dentistry Dean’s Faculty Research Seed Grant (to R.H.K.). E.Y.H. is a New York Stem Cell Foundation–Robertson Investigator. Publisher Copyright: © International & American Associations for Dental Research 2020.

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Y1 - 2020/6/1

N2 - Medication-related osteonecrosis of the jaw (MRONJ) is a rare intraoral lesion that occurs in patients undergoing long-term and/or high-dose therapy with nitrogen-containing bisphosphonates, a RANKL inhibitor, antiangiogenic agents, or mTOR inhibitors. The presence of pathogenic bacteria is highly associated with advanced stages of MRONJ lesions; however, the exact role of indigenous microbes in MRONJ development is unknown. Here, we report that the normal oral flora in mice protects against inflammation-induced osteonecrosis. In mice that developed osteonecrosis following tooth extraction, there was increased bacterial infiltration when compared with healed controls. Antibiotic-mediated oral dysbiosis led to a local inhibition of bone resorption in the presence of ligature-induced periodontitis (LIP). There was no significant difference in empty lacunae, necrotic bone formation, osteoclast number, and surface area in antibiotic-treated as compared with conventionally colonized mice following extraction of healthy teeth after zoledronic acid infusions. However, extraction of LIP teeth led to increased empty lacunae, necrotic bone, and osteoclast surface area in antibiotic- and zoledronic acid–treated mice as compared with conventionally colonized mice. Our findings suggest that the presence of the indigenous microbiota protects against LIP-induced osteonecrosis.

AB - Medication-related osteonecrosis of the jaw (MRONJ) is a rare intraoral lesion that occurs in patients undergoing long-term and/or high-dose therapy with nitrogen-containing bisphosphonates, a RANKL inhibitor, antiangiogenic agents, or mTOR inhibitors. The presence of pathogenic bacteria is highly associated with advanced stages of MRONJ lesions; however, the exact role of indigenous microbes in MRONJ development is unknown. Here, we report that the normal oral flora in mice protects against inflammation-induced osteonecrosis. In mice that developed osteonecrosis following tooth extraction, there was increased bacterial infiltration when compared with healed controls. Antibiotic-mediated oral dysbiosis led to a local inhibition of bone resorption in the presence of ligature-induced periodontitis (LIP). There was no significant difference in empty lacunae, necrotic bone formation, osteoclast number, and surface area in antibiotic-treated as compared with conventionally colonized mice following extraction of healthy teeth after zoledronic acid infusions. However, extraction of LIP teeth led to increased empty lacunae, necrotic bone, and osteoclast surface area in antibiotic- and zoledronic acid–treated mice as compared with conventionally colonized mice. Our findings suggest that the presence of the indigenous microbiota protects against LIP-induced osteonecrosis.

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KW - ligature-induced periodontitis/periodontal disease

KW - medication-related osteonecrosis of the jaw/MRONJ

KW - osteoclast(s)

KW - wound healing

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Indigenous Microbiota Protects against Inflammation-Induced Osteonecrosis

Abstract

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