AdipoAI suppresses osteoclastogenesis by activating AdipoR1/APPL1: An in vivo experimental study in diabetes-associated peri-implantitis

Aim: Diabetics experience severe peri--implant inflammatory bone damage. We aimed to provide powerful evidence supporting the novel adiponectin receptor agonist AdipoAI in treating diabetes--associated peri--implantitis. Materials and Methods: Twenty--four ZDF--Leprfa/Crl rats were randomly allocated to three groups (N = 8). After feeding with a high--fat diet to establish diabetic rats, experimental peri--implantitis was induced by implanting titanium rods (1.5 mm diameter and 20 mm length) contaminated with Staphylococcus aureus into the femurs. Radiographic evaluation, microCT, histological analyses and qRT--PCR were used to detect inflammatory infiltration and bone destruction. In vitro, the inhibition by AdipoAI of osteoclastogenesis, including the number and function of osteoclasts, was investigated by TRAP staining, immunofluorescence, qRT--PCR and Western blotting. Immunofluorescence, qRT--PCR and Western blotting were also utilized to explore AdipoR1, APPL1, NF-kB and Wnt5a--Ror2 signalling molecules in this process. One-way ANOVA with Tukey's post hoc test was used to compare the data. Results: AdipoAI reduced inflammation and bone destruction caused by peri-implantitis in diabetic rats, which were manifested by a reduction in F4/80--positive macrophage infiltration by 72%, the number of osteoclasts by 58% and the levels of cytokines (p <.05) in disease group. In vitro, 1 mu M AdipoAI decreased the number of osteoclasts to 51%, inhibited F--actin ring formation and reduced the levels of related markers (p <.05). Mechanistically, AdipoAI activated AdipoR1/APPL1 and conversely suppressed the phosphorylation of IkB--alpha, nuclear translocation of P65 and the Wnt5a--Ror2 signalling pathway ( p <.05). Conclusions: AdipoAI suppressed osteoclastogenesis in diabetes--associated peri-implantitisby inhibiting the NF--k.B and Wnt5a--Ror2 pathways via the AdipoR1/APPL1 axis.