title: IL-36 Induces Bisphosphonate-Related Osteonecrosis of the Jaw-Like Lesions in Mice by Inhibiting TGF-β-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-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 mice. We also found that IL-36α remarkably suppressed TGF-β-mediated expression of Collα1 and α-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-36α in BRONJ development by inhibiting collagen expression and demonstrated that IL-36α could be a potential marker and a therapeutic target for the prevention and treatment of BRONJ. © 2016 American Society for Bone and Mineral Research.
authors: The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
authors: Sol
authors: S
authors: Kim
authors: The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
authors: Drake W
authors: DW
authors: Williams
authors: The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
authors: Cindy
authors: C
authors: Lee
authors: The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
authors: Terresa
authors: T
authors: Kim
authors: The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
authors: Atsushi
authors: A
authors: Arai
authors: Department of Anatomy and Cell Biology, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA.
authors: Songtao
authors: S
authors: Shi
authors: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors: Xinmin
authors: X
authors: Li
authors: The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors: Ki-Hyuk
authors: KH
authors: Shin
authors: The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors: Mo K
authors: MK
authors: Kang
authors: The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.|Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors: No-Hee
authors: NH
authors: Park
authors: The Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.|UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
authors: Reuben H
authors: RH
authors: Kim
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology / Q000627:therapeutic use; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000188:drug therapy / Q000473:pathology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D007375:Interleukin-1 / Q000009:adverse effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D057134:Antibodies, Neutralizing; D007375:Interleukin-1; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: BISPHOSPHONATE; COLLAGEN; Erk; IL-36; OSTEONECROSIS OF THE JAW; TGF-β