PERK activator CCT020312 prevents inflammation-mediated osteoporosis in the ovariectomized rats

Abstract

Objective

To investigate the therapeutic effects of PERK activator CCT020312 (CCT) on inflammation-mediated osteoporosis (IMO) in ovariectomized rats.

Methods

Rats were divided into Sham, IMO, IMO + 1 mg/kg CCT and IMO + 2 mg/kg CCT groups. IMO models were constructed by bilateral ovariectomy (OVX) on 1st day followed by injection with magnesium silicate (Talc) on the 59th day. Sham rats did not undergo OVX surgery and were injected with saline instead of Talc. From 60th to 79th day, rats were treated with DMSO (vehicle control) in the Sham and IMO groups, and 1 or 2 mg/kg CCT020312 in treatment groups. Osteopontin (OPN), osteocalcin (OCN), tartrate-resistant acid phosphatase (TRAP), C-terminal telopeptide of type I collagen (CTX-I), and pro-inflammatory factors were measured on the 80th day. ProdigyDEXA was used to evaluate bone mineral density and content (BMD/BMC). Bone volume/total volume (BV/TV), connectivity density (Conn.D), trabecular number (Tb.N), and trabecular separation (Tb.Sp) was assessed using 3D micro-CT scanner.

Results

CCT up-regulated Conn.D, BV/TV, and Tb.N, but down-regulated Tb.Sp in IMO rats. Besides, the declined femoral BMD and BMC in IMO rats were elevated after CCT treatment. Besides, IMO rats represented declined OPN and OCN, as well as increased TRAP, CTX-I, and pro-inflammatory factors, whereas those in the treatment groups were ameliorated regarding these indexes, with 2 mg/kg CCT showing better effect.

Conclusion

PERK activator CCT020312 can be served as a new therapeutic option for the protection against bone loss in the OVX rat model associated with inflammation probably by manipulating inflammatory factors.

摘要

目的:探讨PERK激活剂CCT020312对去卵巢大鼠炎症介导的骨质疏松症（IMO）的治疗效果。

方法：将大鼠分为4组：假手术组、IMO、IMO+1mg/kg CCT 和IMO+2mg/kg CCT。在第1天行双侧卵巢切除(OVX), 然后在第59天注射硅酸镁(滑石粉)来构建IMO模型。假手术组大鼠不接受OVX手术, 注射生理盐水代替滑石粉。第60天到第79天, 在假手术组和IMO组用二甲基亚砜(载体对照)处理大鼠, 在研究组中用1或2mg/kg CCT020312处理大鼠。在第80天测量骨桥蛋白(OPN)、骨钙素(OCN)、抗酒石酸酸性磷酸酶(TRAP)、I型版原蛋白C末端交联肽（CTX-I）和促炎因子。用ProdigyDEXA评估骨密度和骨含量（BMD/BMC）。采用3D微型计算机断层扫描仪评估骨体积/总体积（BV/TV）、连接密度（Conn.D）、小梁数（Tb.N）和小梁分离(Tb.Sp)。

结果：在IMO组大鼠中CCT 对Conn.D, BV/TV, and Tb.N起正调节作用, 但是对Tb.Sp起负调节作用, 另外在IMO组中, 经过CCT治疗后降低的股骨BMD和BMC得到了升高。另外, IMO组大鼠的特点是有较低的OPN和OCN, 以及升高的TRAP、CTX-1和促炎因子。而治疗组这些指标得到了改善, 2mg/kgCCT治疗的效果更好。

结论：PERK激活剂CCT020312通过调控炎症因子来预防OVX大鼠炎症性骨质疏松, 可作为一种新的治疗方法。

Keywords:

• Inflammation-mediated osteoporosis
• PERK
• CCT020312
• ovariectomy
• magnesium silicate

Disclosure statement

The authors have declared that no competing interests exist.

Data availability statement

The data used to support the findings of the present study are available from the corresponding author upon reasonable request.