Valproic acid prevents glucocorticoid‑induced osteonecrosis of the femoral head of rats

Abstract

Abstract. Glucocorticoids (Gcs) are the most common cause of atraumatic osteonecrosis of the femoral head (ONFH) because their effect compromises the osteogenic capability of bone marrow-derived mesenchymal stem cells (BMScs). Valproic acid (VPA) is a widely used anti-epileptic and anti-convulsant drug. Previous studies have reported that VPA promotes osteogenic differentiation of MScs in vitro and osteogenesis in vivo as a histone deacetylase (HdAc) inhibitor. The purpose of the present study was to investigate the efficacy of VPA as a precautionary treatment of ONFH after Gc treatment in rats. In vitro, the effect of VPA, dexamethasone or a combination treatment of the two on the proliferation and osteogenic differentiation of human BMScs was assessed using a cell counting Kit-8 and apoptosis assays, and by measuring the expression of proteins associated with osteogenesis. In vivo, a Gc-induced ONFH model was established in rats and VPA was added during Gc treatment to investigate the preventive effect of VPA against ONFH. Rat BMScs were also extracted to investigate the osteogenic capacity. The results of micro-computed tomography scanning, angiography of the femoral head and histological and immunohistochemical analyses indicated that 11 of 15 rats induced with methylprednisolone (MP) presented with ONFH, while only 2 of 15 rats treated with a combination of MP and VPA developed ONFH. VPA produced beneficial effects on subchondral bone trabeculae in the femoral head with significant preservation of bone volume and blood supply, as well as improved osteogenic capability of BMScs compared with those in rats treated with Gc alone. In conclusion, VPA attenuated the inhibitory effect of Gc on BMSc proliferation and osteogenesis by inhibiting apoptosis and elevating the expression of proteins associated with osteogenesis, which may contribute to the prevention of Gc-induced ONFH in rats.

Calycosin modulates inflammation via suppressing TLR4/NF‐κB pathway and promotes bone formation to ameliorate glucocorticoid‐induced osteonecrosis of the femoral head in rat

“…Injection of high‐dose MPS has been demonstrated to successfully establish ONFH in rats (D. Zhou et al, 2018). In this study, 30 mg/kg MPS was injected for three consecutive days to induce ONFH.…”

Intermittent administration sodium valproate has a protective effect on bone health in ovariectomized rats

“…Animals in the IVPA group receive gavage treatment with three-day consecutive treatment of VPA(300 mg/kg) followed by four-day saline treatment each week, and rats in the EVPA group receive gavage treatment with VPA(300 mg/kg)once a day until 12 weeks. The dosage and mode of VPA used in this experiment refer to the previous studies [12,15,17].Two intraperitoneal injections of calcein(20 mg/kg) were injected at the 3rd and 10th day before the rats were sacri ced. Body weight changes of all rats were examined before and after experiment.…”

“…Besides, VPA could cause tubular renal dysfunction and subsequent abnormal metabolism and loss of calcium and phosphorus [10]. Interestingly, clinical and animal experiments have shown the decreased bone mineral density(BMD) with VPA treatment [11,12], but some studies have failed to show such harmful effects on BMD [13,14], and even several cellular, and animal experiments have shown VPA's bene cial effects on bone health [15][16][17].…”

“…However, the effect of VPA on bone health is still controversial and con icting, especially for the bone lose in osteoporosis. At present, the results of animal studies are based on different modes of administration [12,15,17]. Therefore, we hypothesized that different administration modes of VPA have different effects on bone remodeling, resulting in different results in bone mass, bone mineral density and bone strength.…”

Pharmacological modulation of cell functional activity with valproic acid and erythropoietin

“…VA decreases the inhibiting effect of glucocorticoids on BM-MSC proliferation and osteogenesis through inhibiting apoptosis and increasing expression of proteins associated with osteogenesis, which can promote prevention of glucocorticoid-induced necrosis of femoral head in rats (Zhou et al 2018).…”