| Purpose:Osteoporosis is a systemic bone disease which is featured by osteopenia and deterioration of bone tissue microstructure,thereby increasing bone brittleness and fracture susceptibility.The imbalance of bone metabolism caused by decreased bone formation and rapid bone resorption is the root cause of osteoporosis.Because of the changes of bone structure and hormone levels in osteoporosis patients,compared with normal people,the absorption of alveolar bone is more serious,and the probability of tooth loss is higher,which has become an intractable disease population for stomatologists in the process of clinical diagnosis and treatment.At present,drug therapy based on western medicine is the main treatment of osteoporosis,but these drugs have some adverse reactions more or less.Traditional Chinese medicine has a number of pharmacological effects and mild adverse reactions.Berberine is a kind of isoquinoline alkaloid isolated from Berberis and Coptis.Recent studies have shown that berberine is effective against many diseases,such as diabetes,hypercholesterolemia and inflammation,as well as osteoporosis.In recent years,the osteogenic properties of berberine have been consistently reported in previous studies.However,the studies about the application of berberine in bone regeneration have focused on the therapeutic potential,but the molecular mechanism of berberine in bone remodeling has not been entirely discussed.The purpose of this study is to analyze the molecular mechanism of berberine against osteoporosis as comprehensively as possible.Methods:First of all,network pharmacology was used to detect the hub targets and key pathways of berberine in the treatment of osteoporosis.The potential targets of berberine were acquired from TCMSP and STITCH,and the potential targets of osteoporosis were identified in four databases such as OMIM database and datasets from GEO database.After the intersection targets were selected,the protein and protein interaction network was constructed in STRING software,further gene function analysis,pathway analysis and module analysis were performed on the Metascape platform.Next,the molecular docking technique was utilized for verifing the affinity of berberine and key targets.The therapeutic effects of clinical drugs(raloxifene)and berberine were compared at the molecular level.Finally,the motion of berberine-core protein complexes was simulated by molecular dynamics at the microscopic level to verify the stability and flexibility of its binding.Results:Through network pharmacology study,39 berberine-related targets,1738osteoporosis-related targets and 23 intersection targets were found.The protein and protein interaction network found that ESR1,AKT1,MAPK1,AR,PTGS2 and TP53 play important roles in the process of berebrine against osteoporosis.GO functional analysis showed that berberine is mainly involved in "response to estrogen","binding to protein kinase" and "response to oxidative stress" to play a role in the treatment of osteoporosis.In the analysis of KEGG signal pathway,berberine interfered with the occurrence and development of osteoporosis mainly through "thyroid hormone signal pathway","estrogen signal pathway" and "the role of AGE-RAGE signal pathway in diabetic complications".Molecular docking experiments showed that berberine have good binding activities with ESR1,AKT1,MAPK1,AR,PTGS2 and TP53,further indicating that berberine acts on the core targets to make a difference.But compared with raloxifene,the curative effect of berberine was slightly worse,indicating that the clinical effect of berberine alone may not be obvious,so it’s necessary to be compatible with other traditional Chinese medicine to enhace the efficacy.Molecular dynamics experiments showed that berberine could maintain stability with ESR1,AKT1,MAPK1,AR,PTGS2 and TP53 in dynamic environment,which further verified the action sites of berberine.Conclusions:Network pharmacological studies have shown that berberine can treat osteoporosis by activating ESR1,AKT1,MAPK1,AR,PTGS2 and TP53 to stimulate the production of estrogen,the process of oxidative stress and the binding with protein kinase,further regulating thyroid hormone signal pathway and estrogen signal pathway.In addition,molecular docking and molecular dynamics experiments also proved that berberine has good binding activity to key targets(ESR1,AKT1,MAPK1,AR,PTGS2,TP53). |
