Inhibition of tanshinone IIA on renin activity protected against osteoporosis in diabetic mice

Abstract

Context: Salvia miltiorrhiza Bge. (Labiatae) (SMB) is applied clinically for management of diabetic osteoporosis in China, and research results has suggested its potential action on renin-angiotensin system (RAS). Objective: This study screens and explores naturally occurring bioactive constituents from the root of SMB acting on renin activity and evaluates its osteoprotective efficacy in diabetic mice. Materials and methods: Human embryonic kidney (HEK) 293 cells, engineered to express human renin, were used as an in vitro model to identify bioactive compound, tanshinone IIA, inhibiting renin activity. The C57BL/6 mice (n ¼ 10 in each group) with diabetes induced by streptozotocin (STZ) were intraperitoneally injected with tanshinone IIA (10 and 30 mg/kg). The mice without STZ treatment and the diabetic mice treated with aliskiren were used as non-diabetic control and positive control, respectively. Results: Tanshinone IIA was found to display inhibitory effects on renin activity of HEK-293 cells; moreover, it down-regulated protein expression of ANG II in human renin-expressed HEK-293 cells. Treatment of diabetic mice with tanshinone IIA with both doses could significantly decrease ANG II level in serum (from 16.56 ± 1.70 to 10.86 ± 0.68 and 9.14 ± 1.31 pg/mL) and reduce ANG II expression in bone, consequently improving trabecular bone mineral density and micro-structure of proximal tibial end and increasing trabecular bone area of distal femoral end in diabetic mice. Conclusions: This study revealed beneficial effects of tanshinone IIA on bone of diabetic mice, and potentially suggested the application of Salvia miltiorrhiza in the treatment of osteoporosis and drug development of tanshinone IIA as a renin inhibitor.

The Skeletal Effects of Tanshinones: A Review

“…Twelve in vivo studies using Sprague Dawley rats, Wnt1 sw/sw mice and C57BL/6J mice were included. Kunming (KM) mice and ICR mice [ 30 , 32 , 36 , 37 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. No human studies on this topic were reported.…”

“…For animal studies, the doses of tanshinone used were between 0.36 and 200 mg/kg [ 30 , 32 , 36 , 37 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. The disease model used in these studies included retinoic acid, ovariectomy (OVX)/oestrogen deficiency, streptozocin/diabetes, lipopolysaccharide/inflammation and collagen/rheumatoid arthritis-induced bone loss, as well as polyethylene (PE) particle-induced calvarial osteolysis mimicking osteolysis in arthroplasty.…”

“…Diabetes has a major impact on bone stability, since both type 1 and type 2 diabetes elevate fracture risk, making skeletal fragility a complication of diabetes [ 56 , 57 ]. In 8-week-old C57BL/J6 mice with streptozotocin-induced diabetic osteoporosis, T-IIA treatment (10 and 30 mg/kg; 3 times a week for 8 weeks) increased the bone mineral density (BMD) of trabecular bone compared to the negative control [ 42 ]. Improvement in the bone structural properties was marked by increased volumetric BMD, BV/TV, bone area fraction, connectivity density and a decrease in the structural model index (SMI) [ 42 ].…”

“…In 8-week-old C57BL/J6 mice with streptozotocin-induced diabetic osteoporosis, T-IIA treatment (10 and 30 mg/kg; 3 times a week for 8 weeks) increased the bone mineral density (BMD) of trabecular bone compared to the negative control [ 42 ]. Improvement in the bone structural properties was marked by increased volumetric BMD, BV/TV, bone area fraction, connectivity density and a decrease in the structural model index (SMI) [ 42 ]. Inflammation also directly affects bone remodelling because proinflammatory cytokines have been implicated in the regulation of osteoblasts and osteoclasts [ 58 ].…”

“…T-IIA restored retinoic acid-induced decrease of cortical bone thickness and Tb.N by increasing serum oestradiol levels and preventing high bone remodelling in Wistar rats [ 44 ]. T-IIA also improved bone structural properties in mice with STZ-induced diabetic osteoporosis [ 42 ]. Additionally, T-IIA [ 39 , 40 ], T06 [ 30 ] and total tanshinones (T-IIA + C-T) [ 43 ] prevented OVX-induced bone loss in rats and mice by improving bone microstructures.…”