: By binding to its chemokine receptor CXCR4 on osteoclast precursor cells (OCPs), it is well known that stromal cell-derived factor-1 (SDF-1) promotes the chemotactic recruitment of circulating OCPs to the homeostatic bone remodeling site. However, the engagement of circulating OCPs in pathogenic bone resorption remains to be elucidated. The present study investigated a possible chemoattractant role of macrophage migration inhibitory factor (MIF), another ligand for C-X-C chemokine receptor type 4 (CXCR4), in the recruitment of circulating OCPs to the bone lytic lesion. To accomplish this, we used Csf1r-eGFP-knock-in (KI) mice to establish an animal model of polymethylmethacrylate (PMMA) particle-induced calvarial osteolysis. In the circulating Csf1r-eGFP+ cells of healthy Csf1r-eGFP-KI mice, Csf1r+/CD11b+ cells showed a greater degree of RANKL-induced osteoclastogenesis compared to a subset of Csf1r+/RANK+ cells in vitro. Therefore, Csf1r-eGFP+/CD11b+ cells were targeted as functionally relevant OCPs in the present study. Although expression of the two cognate receptors for MIF, CXCR2 and CXCR4, was elevated on Csf1r+/CD11b+ cells, transmigration of OCPs toward recombinant MIF in vitro was facilitated by ligation with CXCR4, but not CXCR2. Meanwhile, the level of PMMA-induced bone resorption in calvaria was markedly greater in wild-type (WT) mice compared to that detected in MIF-knockout (KO) mice. Interestingly, in contrast to the elevated MIF, diminished SDF-1 was detected in a particle-induced bone lytic lesion of WT mice in conjunction with an increased number of infiltrating CXCR4+ OCPs. However, such diminished SDF-1 was not found in the PMMA-injected calvaria of MIF-KO mice. Furthermore, stimulation of osteoblasts with MIF in vitro suppressed their production of SDF-1, suggesting that MIF can downmodulate SDF-1 production in bone tissue. Systemically administered anti-MIF neutralizing monoclonal antibody (mAb) inhibited the homing of CXCR4+ OCPs, as well as bone resorption, in the PMMA-injected calvaria, while increasing locally produced SDF-1. Collectively, these data suggest that locally produced MIF in the inflammatory bone lytic site is engaged in the chemoattraction of circulating CXCR4+ OCPs. © 2016 American Society for Bone and Mineral Research.

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-α, IL-6, and IL-1β), 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^−/− 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-α. rMIF significantly upregulated the number of TRAP⁺ osteoclasts in vitro. Finally, periapical bone loss induced in wild-type mice were significantly diminished in MIF^−/− 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.

Aim: The aims of this study were to assess the prevalence and configuration of the second mesiobuccal (MB2) canal in the mesiobuccal MB root of permanent maxillary first molars at different root levels in a Saudi sub-population using cone‑beam computed tomography (CBCT) and to measure the inter-orifice distance between MB & MB2 at the pulpal floor level. Materials and Methods: This retrospective study was carried out on CBCT images of Saudi patients seen at King Abdul Aziz University. A total of 106 maxillary first molars were evaluated using a specialized software program (iCAT CBCT software). The prevalence of MB2, canal configuration and location of joining (apical-middle-coronal), if present was calculated. Also, the inter-orifice distance between both canals was measured at the level of the pulpal floor. Chi‑square and one-way analysis of variance (ANOVA) were used. Results: The MB2 canal was found in 92 (86.8%) maxillary first molar teeth. The MB and MB2 canals were joined in 61 (58%) cases, where the location of joining was 14 (23%), 17 (27%), and 31 (50%) in the coronal, middle, and apical third, respectively. The mean inter-orifice distance between both canals at the level of the pulpal floor was 2.52± 0.76 mm. Conclusion: The prevalence of MB2 canal in this Saudi sub-population was high. The prevalence decreased as the root canal approached the apical third. There was no correlation between the average distance and occurrence of canal joining. CBCT is useful in detecting and mapping the mesiobuccal root canal system, with a likelihood of enhancing the quality of root canal treatment.