内质网应激及其适应机制,未折叠的蛋白质反应(UPR),是由未折叠和错误折叠蛋白质的积累引发的。在破骨细胞生成过程中,合成了大量的活性蛋白。当蛋白质折叠过程发生失衡时,它导致破骨细胞触发UPR。这种紧密的联系导致UPR在破骨细胞生成中的作用日益被探索。近年来,一些研究报道了内质网应激和UPR在破骨细胞生成和骨吸收中的作用。这里,我们回顾了相关文献,讨论了UPR信号级联反应,破骨细胞生成相关信号通路,以及UPR在破骨细胞生成和骨吸收中的作用。发现UPR信号(PERK,CHOP,和IRE1-XBP1)促进成骨细胞中核因子κB配体(RANKL)的受体激活剂的表达,并间接增强破骨细胞的形成。IRE1通过促进NF-κB促进破骨细胞生成,MAPK信号,或促炎因子的释放(IL-6,IL-1β,和TNFα)。CREBH通过促进NFATc1表达促进破骨细胞分化。PERK信号通路还通过NF-κB和MAPK信号通路促进破骨细胞生成,自噬,和RANKL从成骨细胞分泌。然而,salubrinal(eIF2α去磷酸化的抑制剂,可上调p-eIF2α表达)通过抑制NFATc1表达直接抑制破骨细胞生成,并通过促进成骨细胞分泌RANKL间接促进破骨细胞生成。因此,p-PERK及其下游信号在破骨细胞生成中的具体作用和机制仍需进一步实验证实。此外,ATF6和BiP在破骨细胞形成中的确切作用还需要进一步探索.总之,我们详细而系统的综述为下一步全面阐明UPR与破骨细胞之间的关系提供了一些参考,旨在为破骨细胞过度分化引起的疾病的治疗提供新的见解,比如骨质疏松症。
Endoplasmic reticulum (ER) stress and its adaptive mechanism, the unfolded protein response (UPR), are triggered by the accumulation of unfolded and misfolded proteins. During
osteoclastogenesis, a large number of active proteins are synthesized. When an imbalance in the protein folding process occurs, it causes osteoclasts to trigger the UPR. This close association has led to the role of the UPR in
osteoclastogenesis being increasingly explored. In recent years, several studies have reported the role of ER stress and UPR in
osteoclastogenesis and bone resorption. Here, we reviewed the relevant literature and discussed the UPR signaling cascade response, osteoclastogenesis-related signaling pathways, and the role of UPR in
osteoclastogenesis and bone resorption in detail. It was found that the UPR signal (PERK, CHOP, and IRE1-XBP1) promoted the expression of the receptor activator of the nuclear factor-kappa B ligand (RANKL) in osteoblasts and indirectly enhanced osteoclastogenesis. IRE1 promoted osteoclastogenesis via promoting NF-κB, MAPK signaling, or the release of pro-inflammatory factors (IL-6, IL-1β, and TNFα). CREBH promoted osteoclast differentiation by promoting NFATc1 expression. The PERK signaling pathway also promoted osteoclastogenesis through NF-κB and MAPK signaling pathways, autophagy, and RANKL secretion from osteoblasts. However, salubrinal (an inhibitor of eIF2α dephosphorylation that upregulated p-eIF2α expression) directly inhibited osteoclastogenesis by suppressing NFATc1 expression and indirectly promoted osteoclastogenesis by promoting RANKL secretion from osteoblasts. Therefore, the specific effects and mechanisms of p-PERK and its downstream signaling on osteoclastogenesis still need further experiments to confirm. In addition, the exact role of ATF6 and BiP in osteoclastogenesis also required further exploration. In conclusion, our detailed and systematic
review provides some references for the next step to fully elucidate the relationship between UPR and osteoclastogenesis, intending to provide new insights for the treatment of diseases caused by osteoclast over-differentiation, such as osteoporosis.