Autophagy's Role in Bone Health: From Osteoblast Regulation to Oral Bone Regeneration

Autophagy-related proteins play a crucial role not only in osteoblast regulation but also in osteoclast activation. Several studies have demonstrated that autophagy is involved in osteoclast ruffled border formation, secretion, lysosomal trafficking, migration, and differentiation [95, 98]. Additionally, energy metabolism and osteoclast differentiation are regulated by multiple signaling pathways, including AMPK/mTOR/ULK1, AMPK/mTOR/p70S6K, PI3K/AKT/mTOR/p70S6K, and HIF-1α-miRNA-20a-Atg16L [95]. The inflammatory cytokine IL-17A also impacts osteoclastogenesis through Beclin-1 protein manipulation [99, 100]. Furthermore, autophagy is involved in glucocorticoid-induced osteoporosis [91].

Osteocytes, which reside in the mineralized matrix of bone with poor blood perfusion and nutrient supply, are highly vulnerable to hypoxia and oxidative stress. Higher levels of autophagy help osteocytes maintain intercellular homeostasis [95, 100]. Previous research has shown that autophagy levels correlate with osteocyte survival under hypoxic conditions, and autophagy activation reduces cell apoptosis [101]. Cyclic mechanical stretching also contributes to autophagy activation and osteocyte development [102]. Furthermore, autophagy level changes can alter osteocyte apoptosis rate [95],[103].

As shown in Figure 4, autophagy functions play a critical role in bone health. Regulating autophagy in bone is of great significance for treating tumors, trauma, and deformities caused by bone defects in the oral cavity. Many researchers have reviewed the effects of deficient autophagy on abnormal bone conditions [7, 90],[91]. Moreover, because autophagy has positive effects on stem cells, osteoblasts, osteoclasts, and osteocytes, regulating autophagy may have multi-targeted and multi-component synergistic effects on bone tissue regeneration in the oral cavity. However, systemic regulation should be approached with caution, as different cells and individuals may respond differently to autophagy regulation. Therefore, exploring precise autophagy regulating methods, especially those suitable for local drug delivery in the oral cavity, is of great importance for oral bone regeneration.