运动通过调节骨自噬途径防治骨质疏松症的作用及可能机制

The Role and Possible Mechanisms of Exercise in Combating Osteoporosis by Modulating The Bone Autophagy Pathway

自噬(autophagy)是一种溶酶体降解途径,可调节多种骨细胞(包括成骨细胞、骨细胞和破骨细胞)的增殖、分化和凋亡功能,深度参与骨重塑过程。近年来,自噬在骨质疏松症及相关骨代谢疾病进程中所发挥的作用越来越受到重视,已成为该领域的研究热点。总结已有研究发现,衰老、氧化应激、雌激素缺乏和糖皮质激素治疗等因素会导致自噬活动异常,破坏骨重塑平衡,诱发骨质疏松。运动作为防治骨质疏松症的有效手段,可提高骨生物力学性能、增加骨密度,然而目前研究对于运动、骨自噬、骨质疏松之间的关系仍不清晰,运动通过骨自噬途径改善骨质疏松症可能成为一种新的分子调节机制。基于此,本文综述了运动防治骨质疏松症过程中骨细胞的自噬变化,以期揭示自噬在运动改善骨质疏松症中的作用及可能分子机制,为从自噬角度探寻防治骨质疏松症的临床干预手段提供参考。

Osteoporosis leads to an imbalance in bone remodelling,where bone resorption is greater than bone formation and osteoclast degradation increases,resulting in severe bone loss.Autophagy is a lysosomal degradation pathway that regulates the proliferation,differentiation,and apoptosis of various bone cells(including osteoblasts,osteoclasts,and osteoclasts),and is deeply involved in the bone remodelling process.In recent years,the role of autophagy in the progression of osteoporosis and related bone metabolic diseases has received more and more attention,and it has become a research hotspot in this field.Summarising the existing studies,it is found that senile osteoporosis is the result of a combination of factors.On the one hand,it is the imbalance of bone remodelling and the increase of bone resorption/bone formation ratio with ageing,which causes progressive bone loss.On the other hand,aging leads to a general decrease in the level of autophagy,a decrease in the activity of osteoblasts and osteoclasts,and an inhibition of osteogenic differentiation.The lack of oestrogen leads to the immune system being in a low activation state,and the antioxidant capacity is weakened and inflammatory response is increased,inducing autophagy-related proteins to participate in the transmission of inflammatory signals,excessive accumulation of reactive oxygen species(ROS)in the skeleton,and negatively regulating bone formation.In addition,with aging and the occurrence of related diseases,glucocorticoid treatments also mediate autophagy in bone tissue cells,contributing to the decline in bone strength.Exercise,as an effective means of combating osteoporosis,improves bone biomechanical properties and increases bone density.It has been found that exercise induces oxidative stress,energy imbalance,protein defolding and increased intracellular calcium ions in the organism,which in turn activates autophagy.In bone,exercise of different intensities activates messengers such as ROS,PI3K,and AMP.These messengers signal downstream cascades,which in turn induce autophagy to restore dynamic homeostasis in vivo.During exercise,increased production of AMP,PI3K,and ROS activate their downstream effectors,AMPK,Akt,and p38MAPK,respectively,and these molecules in turn lead to activation of the autophagy pathway.Activation of AMPK inhibits mTOR activity and phosphorylates ULK1 at different sites,inducing autophagy.AMPK and p38 up-regulate per-PGC-1αactivity and activate transcription factors in the nucleus,resulting in increased autophagy and lysosomal genes.Together,they activate FoxOs,whose transcriptional activity controls cellular processes including autophagy and can act on autophagy key proteins,while FoxOs proteins are expressed in osteoblasts.Exercise also regulates the expression of mTORC1,FoxO1,and PGC-1 through the PI3K/Akt signalling pathway,which ultimately plays a role in the differentiation and proliferation of osteoblasts and regulates bone metabolism.In addition,BMPs signaling pathway and long chain non-coding RNAs also play a role in the proliferation and differentiation of osteoblasts and autophagy process under exercise stimulation.Therefore,exercise may become a new molecular regulatory mechanism to improve osteoporosis through the bone autophagy pathway,but the specific mechanism needs to be further investigated.How exercise affects bone autophagy and thus prevents and treats bone-related diseases will become a future research hotspot in the fields of biology,sports medicine and sports science,and it is believed that future studies will further reveal its mechanism and provide new theoretical basis and ideas.