Dataset Information

IL-36 Induces Bisphosphonate-Related Osteonecrosis of the Jaw-Like Lesions in Mice by Inhibiting TGF-?-Mediated Collagen Expression.

ABSTRACT: Long-term administration of nitrogen-containing bisphosphonates can induce detrimental side effects such as bisphosphonate-related osteonecrosis of the jaw (BRONJ) in human. Although inflammation is known to be associated with BRONJ development, the detailed underlying mechanism remains unknown. Here, we report that the pro-inflammatory cytokine IL-36? is, in part, responsible for the BRONJ development. We found a notably higher level of IL-36? and lower level of collagen in the BRONJ lesions in mice. We also found that IL-36? remarkably suppressed TGF-?-mediated expression of Coll?1 and ?-Sma via the activation of Erk signaling pathway in mouse gingival mesenchymal stem cells. When IL-36 signaling was abrogated in vivo, development of BRONJ lesions was ameliorated in mice. Taken together, we showed the pathologic role of IL-36? in BRONJ development by inhibiting collagen expression and demonstrated that IL-36? could be a potential marker and a therapeutic target for the prevention and treatment of BRONJ. © 2016 American Society for Bone and Mineral Research.

SUBMITTER: Kim S

PROVIDER: S-EPMC5642919 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

IL-36 Induces Bisphosphonate-Related Osteonecrosis of the Jaw-Like Lesions in Mice by Inhibiting TGF-β-Mediated Collagen Expression.

Kim Sol S Williams Drake W DW Lee Cindy C Kim Terresa T Arai Atsushi A Shi Songtao S Li Xinmin X Shin Ki-Hyuk KH Kang Mo K MK Park No-Hee NH Kim Reuben H RH

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20161012 2

Long-term administration of nitrogen-containing bisphosphonates can induce detrimental side effects such as bisphosphonate-related osteonecrosis of the jaw (BRONJ) in human. Although inflammation is known to be associated with BRONJ development, the detailed underlying mechanism remains unknown. Here, we report that the pro-inflammatory cytokine IL-36α is, in part, responsible for the BRONJ development. We found a notably higher level of IL-36α and lower level of collagen in the BRONJ lesions in ...[more]

PMID: 27567012

Similar Datasets

Project description:Diabetes mellitus is an established risk factor associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ). Sustained activation of Nod-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome contributes to the persistent inflammation and impaired cutaneous wound healing in diabetic mice and human. We have recently demonstrated a compelling linkage between M1 macrophages and BRONJ conditions in both murine and human diseases. The aim of this study was to determine whether NLRP3 inflammasome activation is involved in BRONJ development in diabetic mice. We showed an increased incidence of delayed oral wound healing and bone necrosis of extraction sockets in db/db mice compared with those in nondiabetic db/+ controls, which correlated with an elevated expression of NLRP3, caspase-1, and IL-1? in macrophages residing at local wounds. Constitutively, bone marrow-derived macrophages from db/db mice (db/db BMDMs) secrete a relatively higher level of IL-1? than those from db/+ mice (db/+ BMDMs). Upon stimulation by NLRP3 activators, the secretion of IL-1? by db/db BMDMs was 1.77-fold higher than that by db/+ BMDMs (p?<?0.001). Systemic treatment of mice with zoledronate (Zol), a nitrogen-containing bisphosphonate, resulted in a 1.86- and 1.63-fold increase in NLRP3/caspase-1-dependent IL-1? secretion by db/+ and db/db BMDMs, respectively, compared with BMDMs derived from nontreated mice (p?<?0.001). Importantly, systemic administration of pharmacological inhibitors of NLRP3 activation improved oral wound healing and suppressed BRONJ formation in db/db mice. Mechanistically, we showed that supplementation with intermediate metabolites of the mevalonate pathway, inhibitors of caspase-1 and NLRP3 activation, an antagonist for P2X7 R, or a scavenger of reactive oxygen species (ROS), robustly abolished Zol-enhanced IL-1? release from macrophages in response to NLRP3 activation (p?<?0.001). Our findings suggest that diabetes-associated chronic inflammatory response may have contributed to impaired socket wound healing and rendered oral wound susceptible to the development of BRONJ via NLRP3 activation in macrophages.

Dataset Information

IL-36 Induces Bisphosphonate-Related Osteonecrosis of the Jaw-Like Lesions in Mice by Inhibiting TGF-?-Mediated Collagen Expression.

Publications

IL-36 Induces Bisphosphonate-Related Osteonecrosis of the Jaw-Like Lesions in Mice by Inhibiting TGF-β-Mediated Collagen Expression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure