Inhibition of Gremlin1 reduces osteoclast activation and alleviates inflammation-induced bone loss by disrupting the NF-κB signaling pathway

Objectives: Gremlin1 plays a crucial role in the development of various inflammatory diseases that cause bone loss, including periodontitis and apical periodontitis (AP). The impact of Gremlin1 on osteoclast activation and its mechanisms in the progression of inflammation-induced bone loss remains unclear. This study aimed to investigate the role of Gremlin1 in the activation of osteoclasts within the inflamed peri-apical region and its possible mechanism. Methods: A local Gremlin1 knock-down AP animal model was established. Micro-computed tomography and hematoxylin and eosin staining were used to assess the volume of bone defects and the extent of inflammatory infiltration. Tartrate-resistant acid phosphatase staining was used to quantify osteoclast numbers and immunohistochemical staining was used to assess the expression of osteoclast differentiation-related proteins in inflamed peri-apical tissues. Subsequently, THP-1 cells with differential expression of Gremlin1 were stimulated to develop into osteoclasts and the activation of osteoclasts and variables associated with osteoclastogenesis were re-evaluated. The activation level of the NF-κB signaling pathway was examined using in vivo and in vitro models. Results: Local administration of adeno-associated virus-silenced Gremlin1 to peri-apical tissues significantly inhibited alveolar bone loss. The number of osteoclasts and the expression of genes associated with osteoclastogenesis were markedly decreased. The in vivo and in vitro experimental findings were consistent and revealed that the silencing of Gremlin1 effectively suppresses activation of the NF-κB signaling pathway. Conversely, over-expression of Gremlin1 may facilitate activation of this pathway. Conclusion: Gremlin1 regulates osteoclasts differentiation through the NF-κB signaling pathway, thereby attenuating the development of inflammation-induced bone loss.