Trehalose reduces bone loss in experimental biliary cirrhosis rats via ERK phosphorylation regulation by enhancing autophagosome formation

Abstract

Bone loss is a severe complication of primary biliary cirrhosis (PBC). Trehalose was intermittently administered in bile duct‐ligated (BDL) male rats, a PBC‐related osteoporosis model, for 4 weeks to reduce osteoporosis. Femoral bones were assessed ex vivo by micro computed tomography (CT) and histomorphometry. The potential mechanisms related to the reduction of osteoporosis were explored by evaluating the effect of trehalose on osteoblast autophagy, osteogenesis, osteoclastogenesis, and ERK phosphorylation. The results demonstrated that trehalose reduced osteoporosis of BDL rats and decreased osteoblast‐mediated osteoclast differentiation by enhancing osteoblast autophagy to regulate osteoprotegerin (OPG) secretion. Hydroxychloroquine (HCQ) increased the expression of OPG and OPG/receptor activator genes for nuclear factor‐κB ligand (RANKL) ratio, and reduced osteoblast‐mediated osteoclastogenesis by inhibiting autophagy flux and inducing autophagosome formation. Furthermore, trehalose increased the phosphorylation of ERK1/2 in MC3T3‐E1 cells, and the ERK inhibitor PD98059 reversed the upregulation of OPG gene and reduction of trehalose‐induced osteoclastogeneis. The treatment with HCQ markedly increased the ERK phosphorylation. The correlation between autophagosome formation and ERK phosphorylation was confirmed in autophagy proteins (ATG) 4B or ATG5‐deficient cells. Thus, trehalose could decrease osteoblast‐mediated osteoclastogenesis and reduce PBC‐related bone loss by regulating ERK phosphorylation via autophagosome formation.

Bone healing around titanium implants in a preclinical model of bile duct ligation‐induced liver injury

“…Based on these data, it might be assumed that early peri‐implant bone formation is not necessarily impaired in liver cirrhotic patients with their higher risk for osteoporotic fractures and periodontitis. Also, the BDL rat model shows no consistent changes in bone turnover markers (Doustimotlagh et al., 2017 , 2018 ; Veidal et al., 2010 ) and the impact of BDL on the bone structural parameters is moderate to low (Doustimotlagh et al., 2017 ; Moradi et al., 2019 ; Xu et al., 2020 ). Surprisingly, the implication of liver cirrhosis on aspects of bone regeneration, with osseointegration of dental implants being one indication, has not yet been studied.…”

“…Furthermore, BDL supported orthodontic tooth movement (Shirazi et al., 2008 ), but neither the cortical and trabecular thickness (Doustimotlagh et al., 2017 ) nor the femoral breaking strength was significantly affected one month following BDL (Moradi et al., 2019 ). MicroCT also revealed that six weeks post BDL, only minor changes in the trabecular structure become visible and the relative bone volume remains unchanged (Xu et al., 2020 ). Thus, a possible impact of BDL‐induced cirrhosis on peri‐implant bone formation cannot be predicted.…”

The Role of IL-35 in the Pathophysiological Processes of Liver Disease

“…The pathophysiology and treatment of LC were of high international standard and formed a qualified basis for rational clinical handling of LC patients. Primary biliary cirrhosis (PBC) was an autoimmune liver disease and LC, and mainly caused by the body's autoimmune disorders (Xu et al, 2020b).…”

“…Unconventionally, the transcription factor Foxp3 is not expressed or required by the newly identified iTr35 cells. Moreover, IL-35 and iTr35 cell develope a positive feedback loop to interact each other (Hamed et al, 2019;Xu et al, 2020b). It is found that HBV could also serve as a stimulus to the Treg to initiate IL-35.…”

Model Parameterization with Quantitative Proteomics: Case Study with Trehalose Metabolism in Saccharomyces cerevisiae

“…While in cosmetics, trehalose serves as liposome stabilizer and as stable sweetener for food. It has also recently been found to offer protection against bone loss in mice [7]. Its production in the industry relies on the use of enzymes from extremophiles expressed in other microbes [6].…”