定量DCE-MRI和QCT评价兔糖尿病模型骨髓微血管渗透性和骨小梁改变的相关性
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摘要
目的采用动态对比增强磁共振成像(dynamic contrast enhanced MRI,DCE-MRI)与定量计算机断层扫描(quantitative computed tomography,QCT)定量评价四氧嘧啶诱导兔糖尿病模型骨髓微血管渗透性和骨小梁改变。材料与方法24只3.0 kg左右雄性日本大耳白兔随机分为糖尿病组(14只)和对照组(10只)。造模成功后各时间点(0、4、8、12、16周)对所有兔腰椎行矢状位FSE-T1WI、FSE-T2WI、DCE-MRI检查与CT成像。通过拟合药代动力学模型获得腰椎骨髓DCE-MRI定量渗透参数,包括容量转移常数(volume transfer constant,K~(trans))、速率常数(efflux rate constant,K_(ep))和容积分数(extracellular extravascular volume fraction,V_e)。同时用QCT软件测量腰椎骨密度(bone mineral density,BMD)。16周取腰椎体标本行苏木精-伊红染色法(hematoxylineosin staining,HE)计算骨小梁形态计量学参数,包括骨小梁数量(Tb.N)、骨小梁面积(Tb.Ar)。结果不同时间点渗透参数K_(ep)、V_e在对照组差异分别具有统计学意义(P均<0.001),而在糖尿病组差异均无统计学意义(P值均>0.05)。对照组腰椎K_(ep)在第4周到12周呈下降趋势,V_e在第4周到12周呈上升趋势,第16周下降。不同时间点BMD在对照组及糖尿病组差异均不具有统计学意义(P>0.05)。第16周糖尿病组腰椎HE染色显示骨小梁数量、面积减小。糖尿病组骨小梁面积、骨小梁数低于对照组(t=12.472;t=4.961;P<0.001)。Pearson相关分析结果显示Tb.N与K~(trans)、K_(ep)、V_e均无相关性(r值分别为0.135、0.093、-0.118;P>0.05),Tb.Ar与K~(trans)、K_(ep)、V_e均无相关性(r值分别为0.233、-0.008、-0.095;P>0.05)。BMD与K~(trans)、K_(ep)、V_e均无相关性(r值分别为0.497、0.513、-0.310;P>0.05)。结论四氧嘧啶兔糖尿病早期腰椎骨髓微血管渗透性参数变化与骨密度和骨小梁形态计量学参数无相关性,QCT测量的骨髓BMD变化晚于骨小梁形态计量学的变化。
Objective:To quantitatively evaluate the bone marrow microvascular permeability and trabecular changes induced by alloxan in diabetic rabbit model via dynamic contrast enhanced MRI(DCE-MRI)and quantitative CT(QCT).Materials and Methods:Eighteen rabbits were randomly divided into the diabetes group(n=14)and the control group(n=10).Fse-T1WI,Fse-T1WI,DCE-MRI examination and CT imaging were performed at each time point(0,4,8,12 and 16 weeks)after the model had been established successfully.DCE-MRI quantitative perfusion parameters of lumbar bone marrow were obtained by fitting the pharmacokinetic model,including volume transfer constant(K~(trans)),efflux rate constant(K_(ep))and extracellular extravascular volume fraction(V_e).QCT software was applied to measure Lumbar vertebral density(BMD).Lumbar vertebral specimens were collected at week 16for HE staining to calculate the morphometric parameters of bone trabeculae,including the number of bone trabeculae(Tb.N)and the area of bone trabeculae(Tb.Ar).Results:Osmotic parameters K_(ep )and V_e at different time points indicated statistically significant differences in the control group(P<0.001),which was not significant different in the diabetes group(P>0.05).In the control group,the K_(ep) of lumbar spine showed a descending trend from week 4 to week 12,while V_e displayed an rising trend from week 4 to week 12 and declined from week 16.There was no significant difference in BMD between the control group and the diabetes group at different time points(P>0.05).The results of HE staining exhibited that the number and area of bone trabeculae were decreased in the diabetic group at week 16.The trabecular bone area and trabecular bone count was lower than that of the control group(t=12.472,t=4.961,P<0.001).Pearson correlation analysis results showed that there was no correlation between Tb.N and K~(trans),K_(ep) and V_e(r values:0.135,0.093 and-0.118),as well as Tb.Ar and K~(trans),K_(ep) and V_e(r values:0.233,-0.008 and-0.0.095,P>0.05).No significant correlation was observed between BMD with K~(trans),K_(ep )and V_e(r values:0.497,0.513 and-0.310,P>0.05).Conclusions:The changes of bone marrow microvascular permeability parameters of the lumbar spine in diabetes mellitus rabbits induced by alloxan in the early stage of disease were not correlated with bone mineral density and trabecular morphometrics parameters,and the differences of bone marrow BMD measured by QCT were later than those of bone trabecular morphometrics.
Objective:To quantitatively evaluate the bone marrow microvascular permeability and trabecular changes induced by alloxan in diabetic rabbit model via dynamic contrast enhanced MRI(DCE-MRI)and quantitative CT(QCT).Materials and Methods:Eighteen rabbits were randomly divided into the diabetes group(n=14)and the control group(n=10).Fse-T1WI,Fse-T1WI,DCE-MRI examination and CT imaging were performed at each time point(0,4,8,12 and 16 weeks)after the model had been established successfully.DCE-MRI quantitative perfusion parameters of lumbar bone marrow were obtained by fitting the pharmacokinetic model,including volume transfer constant(K~(trans)),efflux rate constant(K_(ep))and extracellular extravascular volume fraction(V_e).QCT software was applied to measure Lumbar vertebral density(BMD).Lumbar vertebral specimens were collected at week 16for HE staining to calculate the morphometric parameters of bone trabeculae,including the number of bone trabeculae(Tb.N)and the area of bone trabeculae(Tb.Ar).Results:Osmotic parameters K_(ep )and V_e at different time points indicated statistically significant differences in the control group(P<0.001),which was not significant different in the diabetes group(P>0.05).In the control group,the K_(ep) of lumbar spine showed a descending trend from week 4 to week 12,while V_e displayed an rising trend from week 4 to week 12 and declined from week 16.There was no significant difference in BMD between the control group and the diabetes group at different time points(P>0.05).The results of HE staining exhibited that the number and area of bone trabeculae were decreased in the diabetic group at week 16.The trabecular bone area and trabecular bone count was lower than that of the control group(t=12.472,t=4.961,P<0.001).Pearson correlation analysis results showed that there was no correlation between Tb.N and K~(trans),K_(ep) and V_e(r values:0.135,0.093 and-0.118),as well as Tb.Ar and K~(trans),K_(ep) and V_e(r values:0.233,-0.008 and-0.0.095,P>0.05).No significant correlation was observed between BMD with K~(trans),K_(ep )and V_e(r values:0.497,0.513 and-0.310,P>0.05).Conclusions:The changes of bone marrow microvascular permeability parameters of the lumbar spine in diabetes mellitus rabbits induced by alloxan in the early stage of disease were not correlated with bone mineral density and trabecular morphometrics parameters,and the differences of bone marrow BMD measured by QCT were later than those of bone trabecular morphometrics.
引文
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[4]Fadini G.Is bone marrow another target of diabetic complications?Eur J Clin Invest,2011,41(4):457-463.
[5]Bhatwadekar A,Duan Y,Korah M,et al.Hematopoietic stem/progenitor involvement in retinal microvascular repair during diabetes:implications for bone marrow rejuvenation.Vision Res,2017,139:211-220.
[6]Fajardo R.Is diabetic skeletal fragility associated with microvascular complications in bone?Curr Osteoporos Rep,2017,15(1):1-8.
[7]Hu L,Zha Y,Wang L,et al.Quantitative evaluation of vertebral microvascular permeability and fat fraction in alloxan-induced diabetic rabbits.Radiology,2018,287(1):128-136.
[8]Cheng XG,Yu W.Progress and clinical application of quantitative CTbone density measurement technology.Chin J Med Imaging,2011,19(12):881-883.程晓光,余卫.定量CT骨密度测量技术的进展与临床应用.中国医学影像学杂志,2011,19(12):881-883.
[9]Sheu Y,Amati F,Schwartz AV,et al.Vertebral bone marrow fat,bone mineral density and diabetes:the osteoporotic fractures in men(MrOS)study.Bone,2017,97:299-305.
[10]Napoli N,Chandran M,Pierroz D,et al.Mechanisms of diabetes mellitus-induced bone fragility.Nat Rev Endocrinol,2017,13(4):208-219.
[11]Liu T,Zhao H,Li J,et al.Rosiglitazone attenuates atrial structural remodeling and atrial fibrillation promotion in alloxan-induced diabetic rabbits.Cardiovasc Ther,2014,32(4):178-183.
[12]Shanbhogue V,Hansen S,Frost M,et al.Bone disease in diabetes:another manifestation of microvascular disease?Lancet Diabetes Endocrinol,2017,5(10):827-838.
[13]Oikawa A,Siragusa M,Quaini F,et al.Diabetes mellitus induces bone marrow microangiopathy.Arterioscler Thromb Vasc Biol,2010,30(3):498-508.
[14]Fadini G.Is bone marrow another target of diabetic complications?Eur J Clin Invest,2011,41(4):457-463.
[15]Manavalan JS,Cremers S,Dempster DW,et al.Circulating osteogenic precursor cells in type 2 diabetes mellitus.J Clin Endocrinol Metab,2012,97(9):3240-3250.
[16]Burghardt AJ,Issever AS,Schwartz AV,et al.High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus.J Clin Endocrinol Metab,2010,95(11):5045-5055.
[17]Yu E W,P u t m a n M S,D e r r i c o N,e t a l.D e f e c t s i n c o r t i c a l microarchitecture among African-American women with type 2 diabetes.Osteoporos Int,2015,26(2):673-679.
[18]Shu A,Yin MT,Stein E,et al.Bone structure and turnover in type 2diabetes mellitus.Osteoporos Int,2012,23(2):635-641.
[19]Farr JN,Drake MT,Shreyasee A,et al.In vivo assessment of bone quality in postmenopausal women with type 2 diabetes.J Bone Miner Res,2014,29(4):787-795.
[20]Register TC,Lenchik L,Hsu FC,et al.Type 2 diabetes is not independently associated with spinal trabecular volumetric bone mineral density measured by QCT in the Diabetes Heart Study.Bone,2006,39(3):628-633.
[21]Rakic V,Davis WA,Chubb SA,et al.Bone mineral density and its determinants in diabetes:the Fremantle Diabetes Study.Diabetologia,2006,49(5):863-871.
[22]Vestergaard P.Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes:a meta-analysis.Osteoporos Int,2007,18(4):427-444.
[23]Ramiya VK,Maraist M,Arfors KE,et al.Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells.Nat Med,2000,6(3):278-282.
[24]Listed N.Hypoglycemia in the diabetes control and complications trial.The diabetes control and complications trial research group.Diabetes,1997,46(2):271-286.
[25]Mattila TK,Anthonius DB.Influence of intensive versus conventional glucose control on microvascular and macrovascular complications in type 1 and 2 diabetes mellitus.Drugs,2010,70(17):2229-2245.
[26]Rosenqvist U.The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus.The diabetes control and complications trial research group.New England J Med,1993,329(3):977-986.
[27]Burghardt AJ,Kazakia GJ,Sode M,et al.A longitudinal HR-pQCTstudy of alendronate treatment in postmenopausal women with low bone density:relations among density,cortical and trabecular microarchitecture,biomechanics,and bone turnover.J Bone Miner Res,2010,25(12):2558-2571.
[28]Nilsson AG,Sundh D,Johansson L,et al.Type 2 diabetes mellitus is associated with better bone microarchitecture but lower bone material strength and poorer physical function in elderly women:a populationbased study.J Bone Miner Res,2017,32(5):1062-1071.
[29]Patsch JM,Burghardt AJ,Yap SP,et al.Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures.J Bone Miner Res,2013,28(2):313-324.
[30]Tao B,Liu JM,Zhao HY,et al.Differences between measurements of bone mineral densities by quantitative ultrasound and dual-energy X-ray absorptiometry in type 2 diabetic postmenopausal women.J Clin Endocrinol Metab,2008,93(5):1670-1675.
[31]Heilmeier U,Cheng K,Pasco C,et al.Cortical bone laminar analysis reveals increased midcortical and periosteal porosity in type 2 diabetic postmenopausal women with history of fragility fractures compared to fracture-free diabetics.Osteoporos Int,2016,27(9):2791-2802.
[2]Shanbhogue V,Hansen S,Frost M,et al.Bone disease in diabetes:another manifestation of microvascular disease?Lancet Diabetes Endocrinol,2017,5(10):827-838.
[3]Hinton P.Role of reduced insulin-stimulated bone blood flow in the pathogenesis of metabolic insulin resistance and diabetic bone fragility.Med Hypotheses,2016,93:81-86.
[4]Fadini G.Is bone marrow another target of diabetic complications?Eur J Clin Invest,2011,41(4):457-463.
[5]Bhatwadekar A,Duan Y,Korah M,et al.Hematopoietic stem/progenitor involvement in retinal microvascular repair during diabetes:implications for bone marrow rejuvenation.Vision Res,2017,139:211-220.
[6]Fajardo R.Is diabetic skeletal fragility associated with microvascular complications in bone?Curr Osteoporos Rep,2017,15(1):1-8.
[7]Hu L,Zha Y,Wang L,et al.Quantitative evaluation of vertebral microvascular permeability and fat fraction in alloxan-induced diabetic rabbits.Radiology,2018,287(1):128-136.
[8]Cheng XG,Yu W.Progress and clinical application of quantitative CTbone density measurement technology.Chin J Med Imaging,2011,19(12):881-883.程晓光,余卫.定量CT骨密度测量技术的进展与临床应用.中国医学影像学杂志,2011,19(12):881-883.
[9]Sheu Y,Amati F,Schwartz AV,et al.Vertebral bone marrow fat,bone mineral density and diabetes:the osteoporotic fractures in men(MrOS)study.Bone,2017,97:299-305.
[10]Napoli N,Chandran M,Pierroz D,et al.Mechanisms of diabetes mellitus-induced bone fragility.Nat Rev Endocrinol,2017,13(4):208-219.
[11]Liu T,Zhao H,Li J,et al.Rosiglitazone attenuates atrial structural remodeling and atrial fibrillation promotion in alloxan-induced diabetic rabbits.Cardiovasc Ther,2014,32(4):178-183.
[12]Shanbhogue V,Hansen S,Frost M,et al.Bone disease in diabetes:another manifestation of microvascular disease?Lancet Diabetes Endocrinol,2017,5(10):827-838.
[13]Oikawa A,Siragusa M,Quaini F,et al.Diabetes mellitus induces bone marrow microangiopathy.Arterioscler Thromb Vasc Biol,2010,30(3):498-508.
[14]Fadini G.Is bone marrow another target of diabetic complications?Eur J Clin Invest,2011,41(4):457-463.
[15]Manavalan JS,Cremers S,Dempster DW,et al.Circulating osteogenic precursor cells in type 2 diabetes mellitus.J Clin Endocrinol Metab,2012,97(9):3240-3250.
[16]Burghardt AJ,Issever AS,Schwartz AV,et al.High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus.J Clin Endocrinol Metab,2010,95(11):5045-5055.
[17]Yu E W,P u t m a n M S,D e r r i c o N,e t a l.D e f e c t s i n c o r t i c a l microarchitecture among African-American women with type 2 diabetes.Osteoporos Int,2015,26(2):673-679.
[18]Shu A,Yin MT,Stein E,et al.Bone structure and turnover in type 2diabetes mellitus.Osteoporos Int,2012,23(2):635-641.
[19]Farr JN,Drake MT,Shreyasee A,et al.In vivo assessment of bone quality in postmenopausal women with type 2 diabetes.J Bone Miner Res,2014,29(4):787-795.
[20]Register TC,Lenchik L,Hsu FC,et al.Type 2 diabetes is not independently associated with spinal trabecular volumetric bone mineral density measured by QCT in the Diabetes Heart Study.Bone,2006,39(3):628-633.
[21]Rakic V,Davis WA,Chubb SA,et al.Bone mineral density and its determinants in diabetes:the Fremantle Diabetes Study.Diabetologia,2006,49(5):863-871.
[22]Vestergaard P.Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes:a meta-analysis.Osteoporos Int,2007,18(4):427-444.
[23]Ramiya VK,Maraist M,Arfors KE,et al.Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells.Nat Med,2000,6(3):278-282.
[24]Listed N.Hypoglycemia in the diabetes control and complications trial.The diabetes control and complications trial research group.Diabetes,1997,46(2):271-286.
[25]Mattila TK,Anthonius DB.Influence of intensive versus conventional glucose control on microvascular and macrovascular complications in type 1 and 2 diabetes mellitus.Drugs,2010,70(17):2229-2245.
[26]Rosenqvist U.The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus.The diabetes control and complications trial research group.New England J Med,1993,329(3):977-986.
[27]Burghardt AJ,Kazakia GJ,Sode M,et al.A longitudinal HR-pQCTstudy of alendronate treatment in postmenopausal women with low bone density:relations among density,cortical and trabecular microarchitecture,biomechanics,and bone turnover.J Bone Miner Res,2010,25(12):2558-2571.
[28]Nilsson AG,Sundh D,Johansson L,et al.Type 2 diabetes mellitus is associated with better bone microarchitecture but lower bone material strength and poorer physical function in elderly women:a populationbased study.J Bone Miner Res,2017,32(5):1062-1071.
[29]Patsch JM,Burghardt AJ,Yap SP,et al.Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures.J Bone Miner Res,2013,28(2):313-324.
[30]Tao B,Liu JM,Zhao HY,et al.Differences between measurements of bone mineral densities by quantitative ultrasound and dual-energy X-ray absorptiometry in type 2 diabetic postmenopausal women.J Clin Endocrinol Metab,2008,93(5):1670-1675.
[31]Heilmeier U,Cheng K,Pasco C,et al.Cortical bone laminar analysis reveals increased midcortical and periosteal porosity in type 2 diabetic postmenopausal women with history of fragility fractures compared to fracture-free diabetics.Osteoporos Int,2016,27(9):2791-2802.