Tanshinone I Mitigates Steroid-Induced Osteonecrosis of the Femoral Head and Activates the Nrf2 Signaling Pathway in Rats

Abstract

Steroid-induced osteonecrosis of the femoral head (SIONFH) is a frequent orthopedic disease caused by long-term or high-dose administration of corticosteroids. Tanshinone I (TsI), a flavonoid compound isolated from Salvia miltiorrhiza Bunge, has been reported to inhibit osteoclastic differentiation in vitro. This study aimed to investigate whether TsI can ameliorate SIONFH. Herein, SIONFH was induced by intraperitoneal injection of 20 μg/kg lipopolysaccharide every 24 h for 2 days, followed by an intramuscular injection of 40 mg/kg methylprednisolone every 24 h for 3 days. Four weeks after the final injection of methylprednisolone, the rats were intraperitoneally administrated with low-dose (5 mg/kg) and high-dose (10 mg/kg) TsI once daily for 4 weeks. Results showed that TsI significantly alleviated osteonecrotic lesions of the femoral heads as determined by micro-CT analysis. Furthermore, TsI increased alkaline phosphatase activity and expressions of osteoblastic markers including osteocalcin, type I collagen, osteopontin, and Runt-related transcription factor 2 and decreased tartrate-resistant acid phosphatase activity and expressions of osteoclastic markers including cathepsin K and acid phosphatase 5. TsI also reduced inflammatory response and oxidative stress and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in the femoral heads. Taken together, our findings show that TsI can relieve SIONFH, indicating that it may be a candidate for preventing SIONFH.

Taxifolin‐mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of glucocorticoid‐induced osteonecrosis of the femoral head

“…Based on network pharmacology and molecular docking techniques, we first identified the potential effects of TAX on regulating oxidative stress and bone regeneration in GIONFH. The Keap‐Nrf2 pathway is considered to be a key pathway for regulating oxidative stress and apoptosis, and exerts a therapeutic role in GIONFH(Chen et al, 2021, Xu et al, 2021, Zhang et al, 2021). We hypothesized that TAX could directly interact with Keap1, the primary repressor of Nrf2.…”

“…In the state of oxidative stress, Nrf2 could be transferred to the nucleus, so a series of protective phase II detoxification enzyme and antioxidant enzyme genes and proteins can be expressed, mainly including NQO1 and HO1 (Li et al, 2009; Loboda et al, 2016). The Nrf2 signaling pathway holds a crucial role in managing oxidative stress and apoptosis, making it a key element in the therapeutic approach toward GIONFH (Chen et al, 2021, Xu et al, 2021, Zhang, Wang, et al, 2021). Additionally, TAX has been previously reported to regulate anti‐oxidation activity via the Nrf2 pathway.…”

Expanding the therapeutic potential of Salvia miltiorrhiza: a review of its pharmacological applications in musculoskeletal diseases

“…Salvianolic acid B also inhibited the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and AP2 protein, while increasing the content of osteocalcin and alkaline phosphatase in steroid-induced ON-FH rats, suggesting that Salvianolic acid B prevented steroid-induced femoral head necrosis by inhibiting the expression of PPARγ. Subsequent studies by Xu et al (2021) established a steroid-induced femoral head necrosis model (SIONFH) by intramuscular injection of methyl prednisone. Osteonecrosis of the femoral head was significantly alleviated after intraperitoneal injection of tanshinone I.…”

“…Effects and mechanism of Salvia miltiorrhiza and its active ingredients on osteoarthritis.ON-FH rats, suggesting that Salvianolic acid B prevented steroidinduced femoral head necrosis by inhibiting the expression of PPARγ. Subsequent studies byXu et al (2021) established a steroid-induced femoral head necrosis model (SIONFH) by intramuscular injection of methyl prednisone. Osteonecrosis of the femoral head was significantly alleviated after intraperitoneal…”

Cycloastragenol prevents bone loss via inhibiting osteoclast activity in glucocorticoid-induced osteonecrosis of the femoral head: An in vivo study

“…What's more, enhanced osteoclast activity was proved to be positively correlated with the early progression of GIONFH, with evidence that the increased protein expression of RANKL in necrotic bone is correlated with the progression stage of GIONFH [ 13 ]. Recently, the efficacy of natural osteoclast inhibitors in the prophylaxis and treatment of GIONFH has been evaluated [ [14] , [15] , [16] ], indicative of their positive therapeutic potential.…”