Abstract
Drynariae Rhizoma (DR) has been demonstrated to be effective in promoting fracture healing in clinical use. In the study, we tried to predicate potential signaling pathways and active ingredients of DR via network pharmacology, uncover its regulation mechanism to improve large bone defects by in vivo and in vitro experiment. We total discovered 18 potential active ingredients such as flavonoids and 81 corresponding targets, in which mitogen-activated protein kinase (MAPK) signaling pathway has the highest correlation with bone defects in pathway and functional enrichment analysis. Therefore, we hypothesized that flavonoids in DR improve large bone defects by activating MAPK signaling pathway. Animal experiments were carried out and all rats randomly divided into TFDR low, medium, and high dosage group, model group and control group. 12 weeks after treatment, according to X-ray and Micro-CT, TFDR medium dosage group significantly promote new bone mineralization compared with other groups. The results of HE and Masson staining and in vitro ALP level of BMSC also demonstrated the formation of bone matrix and mineralization in the TFDR groups. Also, angiographic imaging suggested that flavonoids in DR promoting angiogenesis in the defect area. Consistently, TFDR significantly enhanced the expression of BMP-2, RUNX-2, VEGF, HIF-1 in large bone defect rats based on ELISA and Real-Time PCR. Overall, we not only discover the active ingredients of DR in this study, but also explained how flavonoids in DR regulating MAPK signaling pathway to improve large bone defects.
Highlights
Large bone defects (LBDs) are commonly caused by factors such as high-energy traumas, infections, tumors or congenital malformations, which are important reasons for loss of limb function and seriously affecting quality of life (Mediouni and Volosnikov, 2012) It is reported that LBDs affect over two million people worldwide with an economic burden of $3 billion every year(Bone Grafts and Substitutes - Global Analysis and Market Forecasts, 2014; Bone Graft Substitutes Market Report - Global Forecast to 2027, 2019)
mitogen-activated protein kinase (MAPK), PI3K-Akt, vascular endothelial grow factor (VEGF) signaling pathway MAPK, PI3K-Akt, RANKL signaling pathway FoxO, NK-kappB signaling pathway TGF-beta, RANKL, BMP2 signaling pathway Notch signaling pathway RANKL, T cell receptor signaling pathway MAPK, CD31 signaling pathway MAPK, PI3K-Akt, RANKL signaling pathway Hypoxia-inducible factor 1 (HIF-1), PI3K-Akt signaling pathway level of ALogP, except for Stigmasterol, beta-sitosterol, 22Stigmasten-3-one, Cyclolaudenol acetate, cycloartenone and cyclolaudenol, which may suggest the major ingredients of Drynariae Rhizoma had a great water solubility
For the oral bioavailability (OB) portion, we noticed that the values of whole compositions were greater than 30, declaring that they were absorbed by the body
Summary
Large bone defects (LBDs) are commonly caused by factors such as high-energy traumas, infections, tumors or congenital malformations, which are important reasons for loss of limb function and seriously affecting quality of life (Mediouni and Volosnikov, 2012) It is reported that LBDs affect over two million people worldwide with an economic burden of $3 billion every year(Bone Grafts and Substitutes - Global Analysis and Market Forecasts, 2014; Bone Graft Substitutes Market Report - Global Forecast to 2027, 2019). Distraction osteogenesis (DO) was established by Dr Ilizarov (Gubin et al, 2016) and the basic principle of DO technique includes performing a transverse bone section (osteotomy) before gradually distracting the two bone segments. New bone tissue is generated in the gap between the two bone segments that are gradually and progressively distracted. Since the introduction of DO, its unique effectiveness on osteogenesis are significant compared with traditional techniques. The slow calcification and formation of new bone as well as long clinical course are the biggest problem. How to effectively promote the formation of new bone, improve the quality of calcification and shorten the fixation time are burning issues for DO (Spiegl et al, 2013). FDA have approved BMP-2, BMP-7, and parathyroid hormone (PTH) to promote the effect of DO. Due to the high cost, the inconvenience to carry, unstableness and other disadvantages, the results are not satisfying as expected in practical application
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
