Chronic intermittent hypobaric hypoxia attenuates root resorption following delayed tooth replantation by upregulating OPG/RANKL signaling pathway

Abstract Background Tooth avulsion, a severe dental trauma prevalent among adolescents, is commonly treated with delayed replantation. However, this procedure is frequently complicated by root resorption, which can ultimately lead to tooth loss. Given that adolescent patients are not candidates for implant therapy, strategies to mitigate root resorption and prolong the survival of replanted teeth are critically needed. This study aimed to investigate the effect of chronic intermittent hypobaric hypoxia (CIHH) on root resorption following delayed tooth replantation and to elucidate its potential mechanisms. Methods Human clinical specimens from non-replanted and replanted teeth were compared using X-ray and computed tomography (CT) for root resorption. In a rat model, animals were allocated to four groups: Non-replantation or Replantation, each under normobaric normoxic (NN) or chronic intermittent hypobaric hypoxia (CIHH, simulating 4,000 m altitude, 5 h/day) conditions. After one month, root resorption was assessed by micro-CT, and periodontal healing and osteoclast distribution were evaluated via histology. OPG and RANKL protein levels were quantified by IHC and Western blot. Furthermore, bone marrow-derived macrophages (BMMs) and bone mesenchymal stem cells (BMSCs) were isolated and induced to differentiate into osteoclasts and osteoblasts, with differentiation assessed by TRAP and ALP staining, respectively. Results Clinical specimens revealed that delayed replantation resulted in significant root resorption. In the rat model, delayed replanted tooth also exhibits obvious root absorption. However, CIHH treatment significantly attenuated root resorption, reduced the number of osteoclasts on the root surface. Importantly, CIHH significantly downregulated RANKL expression without significantly affecting OPG levels. Consistent with the in vivo findings, in vitro experiments demonstrated that CIHH markedly suppressed osteoclast differentiation from BMMs, but did not significantly affect the osteogenic differentiation capacity of BMSCs. Conclusions CIHH mitigates root resorption after delayed tooth replantation, which is associated with reduced RANKL expression and decreased osteoclast presence.