重组人甲状旁腺素对1型糖尿病小鼠早期骨关节炎的保护作用
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摘要
目的观察重组人甲状旁腺素(parathyroid hormone,PTH1-34)对1型糖尿病(type 1diabetes mellitus,T1DM)小鼠手术诱导的关节炎模型早期骨关节炎(osteoarthritis,OA)的影响。方法分别取12周龄的C57BL/6J雄性小鼠,采用完全随机分组法分为野生小鼠组(WT组)、T1DM小鼠组(T1DM组)和T1DM小鼠PTH1-34干预组(T1DM+PTH组),利用链脲佐菌素(streptozotocin,STZ;45 mg/kg)腹腔注射建立T1DM小鼠模型,3组右下肢内侧半月板切除手术诱导OA小鼠模型;以野生小鼠未建模的左下肢作为对照组。标本获得后分别采用CT扫描重建、HE染色、番红O-固绿染色、OA软骨组织病理学评分观察小鼠膝关节软骨下骨骨量的变化及OA样改变,并进行统计学分析。结果 CT扫描分析显示WT组OA关节软骨下骨骨体积占组织总体积百分比(BV/TV)较对照组关节下降(0. 329vs 0. 351,P <0. 05),软骨下骨骨小梁数量(Tb. N)及厚度(Tb. Th)分别下降9. 9%和8. 2%(P <0. 05);T1DM组OA关节软骨下骨BV/TV较WT组OA关节下降明显(0. 241 vs 0. 329,P <0. 05),软骨下骨Tb. N及Tb. Th分别下降20. 2%和11. 2%(P <0. 05); T1DM+PTH组OA关节较T1DM组OA关节软骨下骨BV/TV改善明显(0. 301 vs 0. 241,P <0. 05),软骨下骨Tb. N及Tb. Th分别上升14. 9%和9. 9%(P <0. 05)。组织病理学评分显示建模组均形成OA样改变,评分结果提示:T1DM组OA关节关节炎评分明显高于WT组OA关节(P <0. 05);应用PTH1-34干预,T1DM+PTH组小鼠OA关节关节炎评分低于T1DM组OA关节(P <0. 05)。结论 OA早期伴有软骨下骨骨量降低,T1DM可加速骨量的丢失并促进OA早期进展,使用PTH1-34后可逆转T1DM小鼠OA早期软骨下骨骨量丢失,在T1DM OA发生早期起到保护作用。
Objective To investigate the protective effect of exogenous parathyroid hormone( PTH1-34) against early osteoarthritis induced by surgery in a mouse model of type 1 diabetes mellitus( T1 DM).Methods Twelve-week-old male C57 BL/6 J mice were randomly divided into control group( Con group)wild-type group( WT group),type 1 diabetes group( T1 DM group) and type 1 diabetes with PTH1-34 intervention group( T1 DM + PTH group). A mouse model of T1 DM was established by intraperitoneal injection of streptozotocin( STZ,45 mg/kg),and osteoarthritis( OA) was induced by medial meniscectomy;for PTH1-34 intervention,the mice received daily intraperitoneal injection of 10 μL/g of 0. 001% PTH1-34 for 3 consecutive weeks. CT scan reconstruction,HE staining,safranin O-fast green staining,osteoarthritis cartilage histopathology scores were used to assess the changes of subchondral bone volume and osteoarthritislike changes in the knee joints of the mice. Results In WT group,CT scan showed a significantly lowered percentage of subchondral bone volume in the total tissue volume( BV/TV) in the knee with surgically induced OA compared with the con group( 0. 329 vs 0. 351,P < 0. 05),and the number and thickness of the trabecular bone( Tb. N and Tb. Th,respectively) in the subchondral bone were decreased by 9. 9% and8. 2% in the knee with OA,respectively( P < 0. 05). In T1 DM group,BV/TV of the subchondral bone in the knee with OA was significantly lower than that in WT group( 0. 241 vs 0. 329,P < 0. 05),and Tb. N and Tb. Th in the subchondral bone were decreased by 20. 2% and 11. 2%,respectively( P < 0. 05). PTH1-34 treatment significantly improved the BV/TV in the diabetic mice( 0. 301 vs 0. 241,P < 0. 05) and increased subchondral bone Tb. N and Tb. Th by 14. 9% and 9. 9%,respectively( P < 0. 05). Assessment based on the arthritis scores showed the occurrence of osteoarthritis-like changes in all the 3 groups; the score was significantly higher in T1 DM group than in WT group( P < 0. 05),and was significantly lower in T1 DM +PTH group than in T1 DM group( P < 0. 05). Conclusion Early-stage OA is associated with subchondral bone loss,and type 1 diabetes can accelerate the bone loss and exacerbate early progression of OA. PTH1-34 treatment can reverse subchondral bone loss and thus offers protection in diabetic mice with early OA.
Objective To investigate the protective effect of exogenous parathyroid hormone( PTH1-34) against early osteoarthritis induced by surgery in a mouse model of type 1 diabetes mellitus( T1 DM).Methods Twelve-week-old male C57 BL/6 J mice were randomly divided into control group( Con group)wild-type group( WT group),type 1 diabetes group( T1 DM group) and type 1 diabetes with PTH1-34 intervention group( T1 DM + PTH group). A mouse model of T1 DM was established by intraperitoneal injection of streptozotocin( STZ,45 mg/kg),and osteoarthritis( OA) was induced by medial meniscectomy;for PTH1-34 intervention,the mice received daily intraperitoneal injection of 10 μL/g of 0. 001% PTH1-34 for 3 consecutive weeks. CT scan reconstruction,HE staining,safranin O-fast green staining,osteoarthritis cartilage histopathology scores were used to assess the changes of subchondral bone volume and osteoarthritislike changes in the knee joints of the mice. Results In WT group,CT scan showed a significantly lowered percentage of subchondral bone volume in the total tissue volume( BV/TV) in the knee with surgically induced OA compared with the con group( 0. 329 vs 0. 351,P < 0. 05),and the number and thickness of the trabecular bone( Tb. N and Tb. Th,respectively) in the subchondral bone were decreased by 9. 9% and8. 2% in the knee with OA,respectively( P < 0. 05). In T1 DM group,BV/TV of the subchondral bone in the knee with OA was significantly lower than that in WT group( 0. 241 vs 0. 329,P < 0. 05),and Tb. N and Tb. Th in the subchondral bone were decreased by 20. 2% and 11. 2%,respectively( P < 0. 05). PTH1-34 treatment significantly improved the BV/TV in the diabetic mice( 0. 301 vs 0. 241,P < 0. 05) and increased subchondral bone Tb. N and Tb. Th by 14. 9% and 9. 9%,respectively( P < 0. 05). Assessment based on the arthritis scores showed the occurrence of osteoarthritis-like changes in all the 3 groups; the score was significantly higher in T1 DM group than in WT group( P < 0. 05),and was significantly lower in T1 DM +PTH group than in T1 DM group( P < 0. 05). Conclusion Early-stage OA is associated with subchondral bone loss,and type 1 diabetes can accelerate the bone loss and exacerbate early progression of OA. PTH1-34 treatment can reverse subchondral bone loss and thus offers protection in diabetic mice with early OA.
引文
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[2] PALAZZO C,NGUYEN C,LEFEVRE-COLAU M M,et al.Risk factors and burden of osteoarthritis[J]. Ann Phys Rehabil Med,2016,59(3):134-138. DOI:10. 1016/j. rehab.2016. 01. 006.
[3] SCHWARZ S,MROSEWSKI I,SILAWAL S,et al. The interrelation of osteoarthritis and diabetes mellitus:considering the potential role of interleukin-10 and in vitro models for further analysis[J]. Inflamm Res,2018,67(4):285-300.DOI:10. 1007/s00011-017-1121-8.
[4]王飞,薛庆云.代谢综合征与骨关节炎发生、发展相关性的研究进展[J].中华骨科杂志,2016,36(4):248-256.WANG F,XUE Q Y. Research progress on the relationship between metabolic syndrome and the occurrence and development of osteoarthritis[J]. Chin J Orthop,2016,36(4):248-256.
[5]王华军,查振刚.糖尿病对骨关节炎影响的研究进展[J].暨南大学学报(自然科学与医学版),2016,37(1):1-6.WANG H J,ZHA Z G. The research progress in the adverse effects of diabetes on osteoarthritis[J]. J Jinan Univ(Nat Sci Med Ed),2016,37(1):1-6.
[6] LOUATI K,VIDAL C,BERENBAUM F,et al. Association between diabetes mellitus and osteoarthritis:systematic literature review and meta-analysis[J]. RMD Open,2015,1(1):e000077. DOI:10. 1136/rmdopen-2015-000077.
[7]王华军,陈均源,罗斯敏,等.糖尿病与骨关节炎相关性的Meta分析[J].中国矫形外科杂志,2017,25(11):994-998.WANG H J,CHEN J Y,LUO S M,et al. Correlation between diabetes and osteoarthritis:a meta-analysis[J]. Orthopedic J China,2017,25(11):994-998.
[8] NIEVES-PLAZA M,CASTRO-SANTANA L E,FONT Y M,et al. Association of hand or knee osteoarthritis with diabetes mellitus in a population of Hispanics from Puerto Rico[J]. J Clin Rheumatol,2013,19(1):1-6. DOI:10. 1097/RHU.0b013e31827cd578.
[9]邵李涛,戴慕巍,刘光源,等.甲状旁腺激素1-34对骨关节炎患者关节软骨及软骨下骨的作用研究进展[J].临床合理用药杂志,2017,10(18):175-176.SHAO L T,DAI M W,LIU G Y,et al. Research progress on effects of parathyroid hormone 1-34 on articular cartilage and subchondral bone in osteoarthritis patients[J]. Chin J Clin Ration Drug Use,2017,10(18):175-176.
[10] CHEN C H,HO M L,CHANG L H,et al. Parathyroid hormone-(1-34)ameliorated knee osteoarthritis in rats via autophagy[J]. J Appl Physiol,2018,124(5):1177-1185.DOI:10. 1152/japplphysiol. 00871. 2017.
[11] MORITA Y,ITO H,ISHIKAWA M,et al. Subchondral bone fragility with meniscal tear accelerates and parathyroid hormone decelerates articular cartilage degeneration in rat osteoarthritis model[J]. J Orthop Res,2018,36(7):1959-1968. DOI:10. 1002/jor. 23840.
[12] ABDELRAZEK H,KILANY O E,MUHAMMAD M,et al.Black seed thymoquinone improved insulin secretion,hepatic glycogen storage,and oxidative stress in streptozotocin-induced diabetic male wistar rats[J]. Oxid Med Cell Longev,2018,2018:8104165. DOI:10. 1155/2018/8104165.
[13] NOVIKOVA L,SMIRNOVA I V,RAWAL S,et al. Variations in rodent models of type 1 diabetes:islet morphology[J]. J Diabetes Res,2013,2013:965832. DOI:10.1155/2013/965832.
[14]唐浚洲,苏楠,周思儒,等.手术诱导的小鼠骨关节炎模型中关节软骨MMP-13表达上调[J].第三军医大学学报,2014,36(9):919-922.TANG J Z,SU N,ZHOU S R,et al. Increased expression of MMP-13 in articular cartilage in surgically induced osteoarthritis mice[J]. J Third Mil Med Univ,2014,36(9):919-922.
[15]谢靖,杨冠.一种新的半月板切断导致小鼠骨关节炎方法的建立[J].军事医学,2013,37(9):708-711.XIE J,YANG G. A novel model of osteoarthritis in mice induced by transection of medial meniscus[J]. Mil Med Sci,2013,37(9):708-711.
[16] GLASSON S,LITTLE C. The recent paper“Multimodal imaging demonstrates concomitant changes in bone and cartilage after destabilization of the medial meniscus and increased joint laxity”[J]. Osteoarthr Cartil,2011,19(8):1076-1077. DOI:10. 1016/j. joca. 2011. 04. 018.
[17] GLASSON S S,CHAMBERS M G,VAN DEN BERG W B,et al. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the mouse[J]. Osteoarthr Cartil,2010,18:S17-S23. DOI:10. 1016/j. joca. 2010. 05. 025.
[18]吉喆,党晓谦,王坤正,等.小鼠骨关节炎模型中胫骨软骨下骨微结构的Micro-CT分析[J].西安交通大学学报(医学版),2015,36(5):623-627.JI Z,DANG X Q,WANG K Z,et al. Micro-CT analysis on subchondral-bone microstructure of tibia in a mouse model of osteoarthritis[J]. J Xi’an Jiaotong Univ(Med Sci),2015,36(5):623-627.
[19] SAVI F M,BRIERLY G I,BALDWIN J,et al. Comparison of different decalcification methods using rat mandibles as a model[J]. J Histochem Cytochem,2017,65(12):705-722. DOI:10. 1369/0022155417733708.
[20] BELLIDO M,LUGO L,ROMAN-BLAS J A,et al. Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis[J]. Arthritis Res Ther,2010,12(4):R152. DOI:10. 1186/ar3103.
[21] LAIGUILLON M C,COURTIES A,HOUARD X,et al.Characterization of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte activation:toward pathophysiological delineation of diabetes mellitus-related osteoarthritis[J]. Osteoarthr Cartil,2015,23(9):1513-1522. DOI:10. 1016/j. joca. 2015. 04. 026.
[22] MOONEY R A,SAMPSON E R,LEREA J,et al. High-fat diet accelerates progression of osteoarthritis after meniscal/ligamentous injury[J]. Arthritis Res Ther,2011,13(6):R198. DOI:10. 1186/ar3529.
[23] ORTH P,CUCCHIARINI M,WAGENPFEIL S,et al. PTH[1-34]-induced alterations of the subchondral bone provoke early osteoarthritis[J]. Osteoarthr Cartil,2014,22(6):813-821. DOI:10. 1016/j. joca. 2014. 03. 010.
[2] PALAZZO C,NGUYEN C,LEFEVRE-COLAU M M,et al.Risk factors and burden of osteoarthritis[J]. Ann Phys Rehabil Med,2016,59(3):134-138. DOI:10. 1016/j. rehab.2016. 01. 006.
[3] SCHWARZ S,MROSEWSKI I,SILAWAL S,et al. The interrelation of osteoarthritis and diabetes mellitus:considering the potential role of interleukin-10 and in vitro models for further analysis[J]. Inflamm Res,2018,67(4):285-300.DOI:10. 1007/s00011-017-1121-8.
[4]王飞,薛庆云.代谢综合征与骨关节炎发生、发展相关性的研究进展[J].中华骨科杂志,2016,36(4):248-256.WANG F,XUE Q Y. Research progress on the relationship between metabolic syndrome and the occurrence and development of osteoarthritis[J]. Chin J Orthop,2016,36(4):248-256.
[5]王华军,查振刚.糖尿病对骨关节炎影响的研究进展[J].暨南大学学报(自然科学与医学版),2016,37(1):1-6.WANG H J,ZHA Z G. The research progress in the adverse effects of diabetes on osteoarthritis[J]. J Jinan Univ(Nat Sci Med Ed),2016,37(1):1-6.
[6] LOUATI K,VIDAL C,BERENBAUM F,et al. Association between diabetes mellitus and osteoarthritis:systematic literature review and meta-analysis[J]. RMD Open,2015,1(1):e000077. DOI:10. 1136/rmdopen-2015-000077.
[7]王华军,陈均源,罗斯敏,等.糖尿病与骨关节炎相关性的Meta分析[J].中国矫形外科杂志,2017,25(11):994-998.WANG H J,CHEN J Y,LUO S M,et al. Correlation between diabetes and osteoarthritis:a meta-analysis[J]. Orthopedic J China,2017,25(11):994-998.
[8] NIEVES-PLAZA M,CASTRO-SANTANA L E,FONT Y M,et al. Association of hand or knee osteoarthritis with diabetes mellitus in a population of Hispanics from Puerto Rico[J]. J Clin Rheumatol,2013,19(1):1-6. DOI:10. 1097/RHU.0b013e31827cd578.
[9]邵李涛,戴慕巍,刘光源,等.甲状旁腺激素1-34对骨关节炎患者关节软骨及软骨下骨的作用研究进展[J].临床合理用药杂志,2017,10(18):175-176.SHAO L T,DAI M W,LIU G Y,et al. Research progress on effects of parathyroid hormone 1-34 on articular cartilage and subchondral bone in osteoarthritis patients[J]. Chin J Clin Ration Drug Use,2017,10(18):175-176.
[10] CHEN C H,HO M L,CHANG L H,et al. Parathyroid hormone-(1-34)ameliorated knee osteoarthritis in rats via autophagy[J]. J Appl Physiol,2018,124(5):1177-1185.DOI:10. 1152/japplphysiol. 00871. 2017.
[11] MORITA Y,ITO H,ISHIKAWA M,et al. Subchondral bone fragility with meniscal tear accelerates and parathyroid hormone decelerates articular cartilage degeneration in rat osteoarthritis model[J]. J Orthop Res,2018,36(7):1959-1968. DOI:10. 1002/jor. 23840.
[12] ABDELRAZEK H,KILANY O E,MUHAMMAD M,et al.Black seed thymoquinone improved insulin secretion,hepatic glycogen storage,and oxidative stress in streptozotocin-induced diabetic male wistar rats[J]. Oxid Med Cell Longev,2018,2018:8104165. DOI:10. 1155/2018/8104165.
[13] NOVIKOVA L,SMIRNOVA I V,RAWAL S,et al. Variations in rodent models of type 1 diabetes:islet morphology[J]. J Diabetes Res,2013,2013:965832. DOI:10.1155/2013/965832.
[14]唐浚洲,苏楠,周思儒,等.手术诱导的小鼠骨关节炎模型中关节软骨MMP-13表达上调[J].第三军医大学学报,2014,36(9):919-922.TANG J Z,SU N,ZHOU S R,et al. Increased expression of MMP-13 in articular cartilage in surgically induced osteoarthritis mice[J]. J Third Mil Med Univ,2014,36(9):919-922.
[15]谢靖,杨冠.一种新的半月板切断导致小鼠骨关节炎方法的建立[J].军事医学,2013,37(9):708-711.XIE J,YANG G. A novel model of osteoarthritis in mice induced by transection of medial meniscus[J]. Mil Med Sci,2013,37(9):708-711.
[16] GLASSON S,LITTLE C. The recent paper“Multimodal imaging demonstrates concomitant changes in bone and cartilage after destabilization of the medial meniscus and increased joint laxity”[J]. Osteoarthr Cartil,2011,19(8):1076-1077. DOI:10. 1016/j. joca. 2011. 04. 018.
[17] GLASSON S S,CHAMBERS M G,VAN DEN BERG W B,et al. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the mouse[J]. Osteoarthr Cartil,2010,18:S17-S23. DOI:10. 1016/j. joca. 2010. 05. 025.
[18]吉喆,党晓谦,王坤正,等.小鼠骨关节炎模型中胫骨软骨下骨微结构的Micro-CT分析[J].西安交通大学学报(医学版),2015,36(5):623-627.JI Z,DANG X Q,WANG K Z,et al. Micro-CT analysis on subchondral-bone microstructure of tibia in a mouse model of osteoarthritis[J]. J Xi’an Jiaotong Univ(Med Sci),2015,36(5):623-627.
[19] SAVI F M,BRIERLY G I,BALDWIN J,et al. Comparison of different decalcification methods using rat mandibles as a model[J]. J Histochem Cytochem,2017,65(12):705-722. DOI:10. 1369/0022155417733708.
[20] BELLIDO M,LUGO L,ROMAN-BLAS J A,et al. Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis[J]. Arthritis Res Ther,2010,12(4):R152. DOI:10. 1186/ar3103.
[21] LAIGUILLON M C,COURTIES A,HOUARD X,et al.Characterization of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte activation:toward pathophysiological delineation of diabetes mellitus-related osteoarthritis[J]. Osteoarthr Cartil,2015,23(9):1513-1522. DOI:10. 1016/j. joca. 2015. 04. 026.
[22] MOONEY R A,SAMPSON E R,LEREA J,et al. High-fat diet accelerates progression of osteoarthritis after meniscal/ligamentous injury[J]. Arthritis Res Ther,2011,13(6):R198. DOI:10. 1186/ar3529.
[23] ORTH P,CUCCHIARINI M,WAGENPFEIL S,et al. PTH[1-34]-induced alterations of the subchondral bone provoke early osteoarthritis[J]. Osteoarthr Cartil,2014,22(6):813-821. DOI:10. 1016/j. joca. 2014. 03. 010.