Elevated Expression of Macrophage Migration Inhibitory Factor Promotes Inflammatory Bone Resorption Induced in a Mouse Model of Periradicular Periodontitis

Abstract

Locally produced osteoclastogenic factor RANKL plays a critical role in the development of bone resorption in periradicular periodontitis. However, because RANKL is also required for healthy bone remodeling, it is plausible that a costimulatory molecule that upregulates RANKL production in inflammatory periradicular periodontitis may be involved in the pathogenic bone loss processes. We hypothesized that macrophage migration inhibitory factor (MIF) would play a role in upregulating the RANKL-mediated osteoclastogenesis in the periradicular lesion. In response to pulp exposure, the bone loss and level of MIF mRNA increased in the periradicular periodontitis, which peaked at 14 d, in conjunction with the upregulated expressions of mRNAs for RANKL, proinflammatory cytokines (TNF-a, IL-6, and IL-1b), chemokines (MCP-1 and SDF-1), and MIF's cognate receptors CXCR4 and CD74. Furthermore, expressions of those mRNAs were found significantly higher in wild-type mice compared with that of MIF 2/2 mice. In contrast, bacterial LPS elicited the production of MIF from ligament fibroblasts in vitro, which, in turn, enhanced their productions of RANKL and TNF-a. rMIF significantly upregulated the number of TRAP + osteoclasts in vitro. Finally, periapical bone loss induced in wild-type mice were significantly diminished in MIF 2/2 mice. Altogether, the current study demonstrated that MIF appeared to function as a key costimulatory molecule to upregulate RANKL-mediated osteoclastogenesis, leading to the pathogenically augmented bone resorption in periradicular lesions. These data also suggest that the approach to neutralize MIF activity may lead to the development of a therapeutic regimen for the prevention of pathogenic bone loss in periradicular periodontitis.

Effect of intercellular adhesion molecule 1 deficiency on the development of apical periodontitis

“…On the other hand, a cell culture study demonstrated that the RANK and RANKL factors are not sufficient for the firm and static union between osteoblasts and osteoclasts and that the ICAM-1/LFA molecules are necessary to the effective adhesion between these cells during the osteoclastogenesis (Okada et al 2002). However, those present in vivo findings confirm the requirement of RANKL expressed on osteoblasts for osteoclasts maturation and the crucial involvement of the RANK and RANKL in periapical lesion development, as previously described (Vernal et al 2006, Bezerra da Silva et al 2014, Braz-Silva et al 2018, Francisconi et al 2019, Howait et al 2019, Jakovljevic et al 2019. These osteoclastogenesis mediators were increased in the larger periapical lesions of the KO mice, even in the absence of an important adhesion molecule.…”

“…However, those present in vivo findings confirm the requirement of RANKL expressed on osteoblasts for osteoclasts maturation and the crucial involvement of the RANK and RANKL in periapical lesion development, as previously described (Vernal et al , Bezerra da Silva et al , Braz‐Silva et al , Francisconi et al . , Howait et al , Jakovljevic et al ). These osteoclastogenesis mediators were increased in the larger periapical lesions of the KO mice, even in the absence of an important adhesion molecule.…”

“…Routinely, TNF‐α levels have been positively correlated to increased bone destruction due its central role in activation of osteoclastic action during apical periodontitis development (Wang & Stashenko , Kawashima & Stashenko , Howait et al, ), although the TNF‐α level has not been different in the ICAM‐1 KO and WT animals. Similar results were found in humans, where TNF‐γ was identified by immunohistochemistry in only 8% of the periapical lesions at levels that do not correlate with the extent of bone resorption (Danin et al ).…”

“…Apical periodontitis results from polymicrobial infection of the dental pulp and root canal system leading to a progressive destruction of periodontal ligament, cementum, and alveolar bone. The destruction of apical and periapical tissues is mediated by a complex network of cellular and molecular mechanisms, which includes migration of inflammatory cells to the sites of infection and osteoclastogenesis (Wang & Stashenko , Stashenko et al , Nair , De Rossi et al , Fukada et al , da Silva et al , de Oliveira et al , De Rossi et al , Braz‐Silva et al , Jakovljevic et al , Howait et al ). The knowledge of regulatory mechanisms that control the host immune system response to infection is important for a better understanding of the aetiopathogenesis and treatment of immunoinflammatory diseases.…”

“…of infection and osteoclastogenesis (Wang & Stashenko 1993, Stashenko et al 1998, Nair 2000, De Rossi et al 2008, Fukada et al 2009, da Silva et al 2012, de Oliveira et al 2015, De Rossi et al 2016, Braz-Silva et al 2018, Jakovljevic et al 2019, Howait et al 2019. The knowledge of regulatory mechanisms that control the host immune system response to infection is important for a better understanding of the aetiopathogenesis and treatment of immunoinflammatory diseases.…”