The Role of Wnt Signaling in Age-Related Alveolar Bone Loss and Regeneration.

Abstract

The periodontium is a uniquely dynamic tissue system requiring precise signaling for lifelong adaptation. The canonical Wnt/β-catenin pathway is a master regulator of bone homeostasis; however, its role in the specialized environment of the alveolar bone-marked by rapid turnover, complex mechanical forces, and exposure to the oral microbiome-remains incompletely understood, particularly in the context of aging. This review critically synthesizes evidence on Wnt signaling in alveolar bone remodeling, with a focus on age-related dysregulation, contrasting established paradigms from long bone biology with emerging oral-tissue-specific data. Wnt/β-catenin signaling is essential for periodontal homeostasis, orchestrating osteoblastogenesis and mechanotransduction. Its activity is compartment-specific within the periodontium and is potently suppressed in pathology. Key mechanisms of age-related decline include the upregulation of Wnt antagonists (e.g., sclerostin, DKK1), cellular senescence, altered FoxO-Wnt crosstalk under oxidative stress, and impaired mechanosensing. These changes converge to disrupt regenerative capacity, tipping the balance toward net alveolar bone loss. Therapeutically, sclerostin inhibition demonstrates robust preclinical efficacy in rescuing bone loss in models of periodontitis and estrogen deficiency. However, the potential cardiovascular risks of systemic Wnt activation suggest that redirecting efforts toward localized delivery strategies could be a promising alternative. Aging induces a multifaceted suppression of regenerative Wnt signaling in the periodontium. Modulating the Wnt pathway shows great potential for oral bone regeneration. However, significant challenges exist, especially in designing local delivery systems that are both safe and effective. Overcoming these hurdles is crucial for successful clinical applications. Future research must bridge the gap between skeletal biology and direct oral-specific investigations to enable targeted therapies that preserve periodontal health in an aging population.