New research reveals the underlying mechanisms of alveolar bone resorption (ABR) associated with apical periodontitis (AP), the leading cause of tooth loss among adults. A study conducted on male rats highlights the role of fat mass and obesity-associated protein (FTO) and hexokinase 1 (HK1) in promoting osteoclastogenesis—the process through which bone-destroying cells (osteoclasts) are formed—thereby exacerbates ABR. The findings suggest potential therapeutic targets for managing AP-related bone loss.
Alveolar bone resorption occurs predominantly as part of the inflammatory response following infection of the root canal system, leading to the destruction of the supporting bone around teeth. This pathologic process, primarily mediated by increased osteoclast activities, significantly increases the risk of tooth loss. Despite existing knowledge surrounding AP and its consequences, the precise mechanisms driving osteoclastogenesis remain poorly understood. Researchers aimed to delineate the roles of specific proteins and metabolic pathways contributing to this condition.
Using rat models of apical periodontitis, the team observed reduced levels of N6-methyladenosine (m6A) modifications—a prevalent internal modification of RNA associated with gene regulation—in conjunction with elevated FTO expression. FTO is known as an m6A demethylase, which acts to promote changes in gene expression by modulating mRNA stability. The upregulation of FTO correlated with increased HK1 levels, indicating enhanced glycolytic activity. This study elucidates the pathway where FTO reduces m6A modifications of HK1 mRNA, leading to increased HK1 expression. Subsequently, HK1 enhances glycolysis, which is necessary for osteoclast differentiation and function.
Indeed, glycolysis plays a pivotal role during residual cellular processes, including the proliferation and differentiation of osteoclasts. Elevated HK1 levels support this metabolic process and stabilize receptor activator of NF-κB (RANK) protein expression—a key precursor for osteoclast formation. The research found the stabilization of RANK relies on the deubiquitination activities of ubiquitin-specific protease 14 (USP14), which is also enhanced by the FTO/HK1 signaling axis. Notably, targeted inhibition of either FTO or HK1 using specific inhibitors, namely Dac51 for FTO and 2-DG for HK1, significantly inhibited osteoclastogenesis, indicating the therapeutic potential of these approaches.
The research team integrated several methodologies, including proteomics, molecular biology techniques, and histological assessments, to evaluate the stages of osteoclast development and the associated metabolic changes. The team successfully established both the rat AP model and bone marrow-derived macrophages (BMDMs) cultures, which effectively mimicked osteoclastogenesis. After verifying this model, the impact of HK1 and RANK levels was assessed using quantitative imaging techniques.
High rates of glycolysis were found to correlate with the abundance of osteoclast-specific markers, such as NFATc1 and MMP9, both of which are known to facilitate osteoclast differentiation. Documentation of these findings sheds light on the metabolic demands of osteoclastogenesis, proposing glycolytic pathways as valid therapeutic targets for disease states presenting with excessive bone resorption.
Importantly, interventions targeting FTO and HK1 not only diminished the osteoclast counts but also reduced the extent of bone resorption visible via micro-CT imaging. Treatment groups displayed significant reductions in the size of periapical lesions and the expression of osteoclast markers. This emphasizes the feasibility of these strategies as clinical interventions for managing ABR associated with apical periodontitis.
The current findings not only clarify the molecular mechanisms underpinning bone resorption during apical periodontitis but also pave the way for novel treatment paradigms targeting metabolic pathways involved. The interplay between FTO, HK1, and USP14 presents insights for future studies aiming to implement strategic therapies for effectively mitigating bone loss arising from inflammatory dental diseases.