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

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.