奥美拉唑对去势大鼠骨密度和骨代谢的影响
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摘要
目的:观察质子泵抑制剂奥美拉唑对去势雌性大鼠骨密度和骨代谢的影响,为临床合理应用质子泵抑制剂提供依据。方法:8月龄SD雌性大鼠,分成假手术组(Sham+NS组)、假手术给药组(Sham+OMZ组)、去势组(OV+NS组)、去势给药组(OV+OMZ组)。去势组大鼠行去卵巢手术建模,假手术组同等部位切除部分脂肪。给药组大鼠按体质量30 mg·kg~(-1)·d~(-1)灌胃奥美拉唑,非给药组按2 mL·d~(-1)生理盐水灌胃。以双能X线吸收法(DXA)检测骨密度;酶联免疫吸附法检测血清中骨代谢标志物TRAP、CTX-1、PINP、BALP、OC浓度;qRT-PCR法检测股骨骨髓细胞OPG、RANKL、c-FOS、NFATc1的mRNA表达水平以及R/O值。结果:去势组较假手术组骨密度降低、TRAP、CTX-1、PINP、OC浓度升高、R/O值升高,去势给药组较去势组骨密度降低、TRAP、CTX-1、PINP、OC浓度升高、R/O值升高。结论:质子泵抑制剂奥美拉唑可能诱导去势雌性大鼠体内的RANKL表达量相对增加,R/O值升高,进而通过OPG/RANK/RANKL信号通路使得破骨细胞活动相对增强,骨吸收代谢加快,加速骨质疏松进程。
OBJECTIVE To observe the effect of omeprazole, a proton pump inhibitor, on bone mineral density and bone metabolism in ovariectomized female rats, and to provide evidence for rational use of proton pump inhibitors in clinic. METHODS Female SD rats of 8 months old were divided as follows: Sham+NS group, Sham+OMZ group, OV+NS group, OV+OMZ group. Modeling: Ovariectomy was performed in OV group rats, and part of the fat was removed at the same site in the Sham group. Drug administration: Rats in the administration group were orally administered at a body weight of 30 mg·kg~(-1)·d~(-1), 2 mL normal saline(NS) was administered to the non-administration group. Index: Bone mineral density(BMD) was measured by dual energy X-ray absorptiometry(DXA); serum levels of bone metabolic markers TRAP, CTX-1, PINP, BALP and OC were detected by enzyme-linked immunosorbent assay(ELISA); and the expression levels of OPG, RANKL, c-FOS, NFATc 1 and R/O in femoral bone marrow cells were detected by qRT-PCR. RESULTS Compared with Sham+NS group, OV+NS group had lower BMD, higher TRAP, CTX-1, PINP, OC concentration and R/O value, while OV+OMZ group had lower BMD, higher TRAP, CTX-1, PINP, OC concentration and R/O value than OV+NS group. CONCLUSION Omeprazole may induce a relative increase in the expression level of RANKL and an increase in the R/O value in the ovariectomized rats, thereby enhancing the osteoclast activity through the OPG/RANK/RANKL signaling pathway, speed up bone resorption metabolism, and finially accelerate the osteoporosis process.
OBJECTIVE To observe the effect of omeprazole, a proton pump inhibitor, on bone mineral density and bone metabolism in ovariectomized female rats, and to provide evidence for rational use of proton pump inhibitors in clinic. METHODS Female SD rats of 8 months old were divided as follows: Sham+NS group, Sham+OMZ group, OV+NS group, OV+OMZ group. Modeling: Ovariectomy was performed in OV group rats, and part of the fat was removed at the same site in the Sham group. Drug administration: Rats in the administration group were orally administered at a body weight of 30 mg·kg~(-1)·d~(-1), 2 mL normal saline(NS) was administered to the non-administration group. Index: Bone mineral density(BMD) was measured by dual energy X-ray absorptiometry(DXA); serum levels of bone metabolic markers TRAP, CTX-1, PINP, BALP and OC were detected by enzyme-linked immunosorbent assay(ELISA); and the expression levels of OPG, RANKL, c-FOS, NFATc 1 and R/O in femoral bone marrow cells were detected by qRT-PCR. RESULTS Compared with Sham+NS group, OV+NS group had lower BMD, higher TRAP, CTX-1, PINP, OC concentration and R/O value, while OV+OMZ group had lower BMD, higher TRAP, CTX-1, PINP, OC concentration and R/O value than OV+NS group. CONCLUSION Omeprazole may induce a relative increase in the expression level of RANKL and an increase in the R/O value in the ovariectomized rats, thereby enhancing the osteoclast activity through the OPG/RANK/RANKL signaling pathway, speed up bone resorption metabolism, and finially accelerate the osteoporosis process.
引文
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[14] Walsh MC.Biology of the RANKL-RANK-OPG System in Immunity,Bone,and Beyond[J].Front Immunol,2014,5:511.
[15] Knevel R,de Rooy DP,Saxne T,et al.A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis[J].Arthritis Res Ther,2014,16(3):R108.
[16] Delgado-Calle J,Anderson J,Cregor MD,et al.Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma[J].Cancer Res,2016,76(5):1089-1100.
[17] Tudpor K,van der Eerden BC,Jongwattanapisan P,et al.Thrombin receptor deficiency leads to a high bone mass phenotype by decreasing the RANKL/OPG ratio[J].Bone,2015,72:14-22.
[2] vander Hoorn MM,Tett SE,de Vries OJ,et al.The effect of dose and type of proton pump inhibitor use on risk of fractures and osteoporosis treatment in older Australian women:A prospective cohort study[J].Bone,2015,81:675-682.
[3] Khalili H,Huang ES,Jacobson BC,et al.Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors:a prospective cohort study[J].BMJ (Clinical research ed.),2012,344:e372.
[4] Fraser LA,Leslie WD,Targownik LE,et al.The effect of proton pump inhibitors on fracture risk:report from the Canadian Multicenter Osteoporosis Study[J].Osteoporos Int,2013,24(4):1161-1168.
[5] Gray SL,LaCroix AZ,Larson J,et al.Proton pump inhibitor use,hip fracture,and change in bone mineral density in postmenopausal women:results from the Women’s Health Initiative[J].Arch Intern Med,2010,170(9):765-771.
[6] Roux C,Briot K,Gossec L,et al.Increase in vertebral fracture risk in postmenopausal women using omeprazole[J].Calcif Tissue Int,2009,84(1):13-19.
[7] Yu EW,Blackwell T,Ensrud KE,et al.Acid-suppressive medications and risk of bone loss and fracture in older adults[J].Calcif Tissue Int,2008,83(4):251-259.
[8] Lewis JR,Barre D,Zhu K,et al.Long-term proton pump inhibitor therapy and falls and fractures in elderly women:a prospective cohort study[J].J Bone Miner Res,2014,29(11):2489-2497.
[9] Black DM.Clinical Practice Postmenopausal Osteoporosis[J].N Engl J Med,2016,374(3):254-262.
[10] Eastell R.Use of bone turnover markers in postmenopausal osteoporosis[J].Lancet Diabetes Endocrinol,2017,5(11):908-923.
[11] Obermayer-Pietsch B.Biochemical markers of bone metabolism and their importance[J].Z Rheumatol,2016,75(5):451-458.
[12] Bart Clarke.Normal bone anatomy and physiology[J].Clin J Am Soc Nephrol,2008,3 Suppl 3:S131-9.
[13] Trouvin AP.Receptor activator of nuclear factor-κB ligand and osteoprotegerin:maintaining the balance to prevent bone loss[J].Clin Interv Aging,2010,5:345-354.
[14] Walsh MC.Biology of the RANKL-RANK-OPG System in Immunity,Bone,and Beyond[J].Front Immunol,2014,5:511.
[15] Knevel R,de Rooy DP,Saxne T,et al.A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis[J].Arthritis Res Ther,2014,16(3):R108.
[16] Delgado-Calle J,Anderson J,Cregor MD,et al.Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma[J].Cancer Res,2016,76(5):1089-1100.
[17] Tudpor K,van der Eerden BC,Jongwattanapisan P,et al.Thrombin receptor deficiency leads to a high bone mass phenotype by decreasing the RANKL/OPG ratio[J].Bone,2015,72:14-22.