Abstract
Traditional herb pair Salvia miltiorrhiza Bunge-Radix Puerariae (DG) owns various biological activities including anti-inflammatory and anti-oxidative stress. Oxidative stress is one high-risk factor for osteoporosis, then effect of DG on osteoporosis and underlying mechanisms was explored both in vivo and in vitro. Firstly, the predication from network pharmacology hinted that DG has the potential for ameliorating osteoporosis. Consistent with predication, DG significantly restored bone loss and deficiency of type II collagen, decreased TRAP and Cathepsin K positive areas in femur. Meanwhile it improved important characteristics of microarchitectural deterioration of tissue, reduced the numbers of NFATc1-positive osteoclast in the vertebra as well as decreased the serum osteoclast-specific cytokine RANKL and OPG release in OVX rats exhibiting its protective effect against osteoporosis. In vitro, DG noticeably decreased osteoclastic-special marker protein expressions of RANK, c-Fos and NFATc1. Furthermore, autophagy pathway p62/LC3B, ROS production and NF-κB were all activated by RANKL stimulation and blocked by DG pretreatment. Moreover, autophagy inhibitors, ROS scavenger, Ca2+ chelator and NF-κB inhibitor remarkably suppressed c-Fos and NFATc1 expressions. Taken together, DG may ameliorate osteoporosis by regulating osteoclast differentiation mediated by autophagy and oxidative stress. This study provided a mechanistic basis for DG treating osteoporosis and offered a safe dose for DG in preventing and improving bone diseases.
Highlights
Osteoporosis is a progressive skeletal disorder characterized by increased bone resorption and reduced bone mineral density (Mirza and Canalis, 2015)
Accumulated studies showed that autophagy and oxidative stress are involved in the process of osteoporosis (Schröder, 2015; Shen et al, 2018; Wang et al, 2019)
Autophagy is activated in response to several pro-inflammatory cytokines such as IL-1β and TNF-α accompanied by a robust increase in osteoclast differentiation and bone resorption (Wehmeyer et al, 2016; Jiang et al, 2019)
Summary
Osteoporosis is a progressive skeletal disorder characterized by increased bone resorption and reduced bone mineral density (Mirza and Canalis, 2015). RANKL binding to its receptor activates a series of downstream signal pathways including AKT-PLCγ (Ma et al, 2018), MAPKs (Li et al, 2018; Du et al, 2020) and NF-κB (Thummuri et al, 2015; Tu et al, 2020). Autophagy is activated in response to several pro-inflammatory cytokines such as IL-1β and TNF-α accompanied by a robust increase in osteoclast differentiation and bone resorption (Wehmeyer et al, 2016; Jiang et al, 2019). Autophagy-related proteins including atg, atg, atg4β, and LC3B are identified involved in the formation of ruffled border and facilitation of osteoclast polarization, results in bone resorption (Hu et al, 2020). ROS is a critical intracellular signal mediator which induces osteoblast apoptosis through multiple cellular signaling pathways and identifies the osteogenesis deterioration (Atashi et al, 2015)
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