Zhao Zhenhui,Xiong Zhu,Zeng Shuaidan,et al.Research progress on the genetics and molecular regulatory mechanisms of developmental hip dysplasia[J].Journal of Clinical Pediatric Surgery,2023,22(11):1095-1100.[doi:10.3760/cma.j.cn101785-202210022-019]
发育性髋关节发育不良遗传学及分子调控机制的研究进展
- Title:
- Research progress on the genetics and molecular regulatory mechanisms of developmental hip dysplasia
- 关键词:
- 发育性髋关节发育不良; 遗传学; 发病机制
- Keywords:
- Developmental Dysplasia of the Hip; Genetics; Pathogenesis
- 摘要:
- 发育性髋关节发育不良(developmental dysplasia of the hip,DDH)是儿童骨科常见的骨骼肌肉畸形,主要临床表现包括髋关节不稳定、半脱位甚至完全脱位。部分轻度的DDH可自行缓解;但其他未经早期正确诊治的DDH会出现进行性加重,导致髋部疼痛、活动受限、步态异常,最终可致成年期退行性关节炎。DDH可能为先天因素与后天环境因素共同作用所致,但DDH确切的遗传学模式、发病机理以及DDH发生、发展过程中的具体分子调控机制尚不清楚。本文对近年来DDH遗传学研究及其发病相关的分子调控机制研究进行简要归纳与总结。
- Abstract:
- Developmental dysplasia of the hip (DDH) is one of the common musculoskeletal malformations in pediatric orthopedics.Its abnormalities mainly include instability,subluxation and even a complete dislocation of hip joint.Mild dysplasia may disappear by itself.However,other hip deformities misdiagnosed and improperly treated during an early stage worsen progressively,leading to hip pain,limited movement,abnormal gait and ultimately adult degenerative arthritis.DDH may be caused by congenital predisposing and acquired environmental factors.However,its exact genetic model,pathogenesis and specific molecular regulation mechanism in the occurrence and development of DDH have remained elusive.Only through clarifying the specific pathogenesis of DDH disease,clinicians gain a deeper understanding of the disease to achieve its early diagnosis and timely treatment for better outcomes.This review summarized the latest genetic researches of DDH and the molecular regulatory mechanism related to its pathogenesis.
参考文献/References:
[1] Wang CL,Zuo B,Li D,et al.The long noncoding RNA H19 attenuates force-driven cartilage degeneration via miR-483-5p/Dusp5[J].Biochem Biophys Res Commun,2020,529(2):210-217.DOI:10.1016/j.bbrc.2020.05.180.
[2] O’Beirne JG,Chlapoutakis K,Alshryda S,et al.International interdisciplinary consensus meeting on the evaluation of developmental dysplasia of the hip[J].Ultraschall Med,2019,40(4):454-464.DOI:10.1055/a-0924-5491.
[3] Xu N,Xia B,Tao HW,et al.Epidemiological investigation and ultrasonic diagnosis of developmental dysplasia of the hip in Chinese infants:a large multi-center cohort study[J].Medicine (Baltimore),2022,101(2):e28320.DOI:10.1097/MD.0000000000028320.
[4] Li C,Peng Z,Zhou Y,et al.Comprehensive analysis of pathological changes in hip joint capsule of patients with developmental dysplasia of the hip[J].Bone Joint Res,2021,10(9):558-570.DOI:10.1302/2046-3758.109.BJR-2020-0421.R2.
[5] Chen J,Zhang WB,He JZ,et al.Developmental dysplasia of the hip:a special pathology[J].Chin J Traumatol,2018,21(4):238-242.DOI:10.1016/j.cjtee.2018.02.001.
[6] 苟永贵,黄晋,裴生太.发育性髋关节发育不良发病危险因素的研究进展[J].临床小儿外科杂志,2021,20(1):86-92.DOI:10.12260/lcxewkzz.2021.01.017. Gou YG,Huang J,Pei ST.Research advances for risk factors of developmental dysplasia of the hip[J].J Clin Ped Sur,2021,20(1):86-92.DOI:10.12260/lcxewkzz.2021.01.017.
[7] Storer SK,Skaggs DL.Developmental dysplasia of the hip[J].Am Fam Physician,2006,74(8):1310-1316.DOI:10.12968/hmed.2020.0223.
[8] Li LY,Sun KM,Zhang LJ,et al.Heritability and sibling recurrent risk of developmental dysplasia of the hip in Chinese population[J].Eur J Clin Invest,2013,43(6):589-594.DOI:10.1111/eci.12084.
[9] Stevenson DA,Mineau G,Kerber RA,et al.Familial predisposition to developmental dysplasia of the hip[J].J Pediatr Orthop,2009,29(5):463-466.DOI:10.1097/BPO.0b013e3181aa586b.
[10] Watson CM,Crinnion LA,Gleghorn L,et al.Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene,UFSP2,in an extended South African family with Beukes hip dysplasia[J].S Afr Med J,2015,105(7):558-563.DOI:10.7196/SAMJnew.7917.
[11] Basit S,Albalawi AM,Alharby E,et al.Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip[J].BMC Med Genet,2017,18(1):34.DOI:10.1186/s12881-017-0393-8.
[12] Kenanidis E,Gkekas NK,Karasmani A,et al.Genetic predisposition to developmental dysplasia of the hip[J].J Arthroplasty,2020,35(1):291-300.e1.DOI:10.1016/j.arth.2019.08.031.
[13] Le Maitre CL,Freemont AJ,Hoyland JA.Expression of cartilage-derived morphogenetic protein in human intervertebral discs and its effect on matrix synthesis in degenerate human nucleus pulposus cells[J].Arthritis Res Ther,2009,11(5):R137.DOI:10.1186/ar2808.
[14] Rouault K,Scotet V,Autret S,et al.Evidence of association between GDF5 polymorphisms and congenital dislocation of the hip in a Caucasian population[J].Osteoarthritis Cartilage,2010,18(9):1144-1149.DOI:10.1016/j.joca.2010.05.018.
[15] Harada M,Takahara M,Zhe P,et al.Developmental failure of the intra-articular ligaments in mice with absence of growth differentiation factor 5[J].Osteoarthritis Cartilage,2007,15(4):468-474.DOI:10.1016/j.joca.2006.09.003.
[16] Savarirayan R,White SM,Goodman FR,et al.Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families[J].Am J Med Genet A,2003,117A(2):136-142.DOI:10.1002/ajmg.a.10924.
[17] Hatzikotoulas K,Roposch A,Shah KM,et al.Genome-wide association study of developmental dysplasia of the hip identifies an association with GDF5[J].Commun Biol,2018,1:56.DOI:10.1038/s42003-018-0052-4.
[18] Sadat-Ali M,Al-Habdan IM,Bubshait DA.Genetic influence in developmental dysplasia of the hip in Saudi Arabian children due to GDF5 polymorphism[J].Biochem Genet,2018,56(6):618-626.DOI:10.1007/s10528-018-9864-7.
[19] Harsanyi S,Zamborsky R,Krajciova L,et al.Genetic study of IL6,GDF5 and PAPPA2 in association with developmental dysplasia of the hip[J].Genes (Basel),2021,12(7):986.DOI:10.3390/genes12070986.
[20] Harsanyi S,Zamborsky R,Krajciova L,et al.Association analysis of GDF5 and contributing factors in developmental dysplasia of the hip in infants[J].Ortop Traumatol Rehabil,2021,23(5):335-339.DOI:10.5604/01.3001.0015.4348.
[21] Baghdadi T,Nejadhosseinian M,Shirkoohi R,et al.DNA hypermethylation of GDF5 in developmental dysplasia of the hip (DDH)[J].Mol Genet Genomic Med,2019,7(9):e887.DOI:10.1002/mgg3.887.
[22] Feldman GJ,Parvizi J,Levenstien M,et al.Developmental dysplasia of the hip:linkage mapping and whole exome sequencing identify a shared variant in CX3CR1 in all affected members of a large multigeneration family[J].J Bone Miner Res,2013,28(12):2540-2549.DOI:10.1002/jbmr.1999.
[23] Harsanyi S,Zamborsky R,Kokavec M,et al.Genetics of developmental dysplasia of the hip[J].Eur J Med Genet,2020,63(9):103990.DOI:10.1016/j.ejmg.2020.103990.
[24] Li LY,Xi W,Zhao Q,et al.CX3CR1 polymorphisms associated with an increased risk of developmental dysplasia of the hip in human[J].J Orthop Res,2017,35(2):377-380.DOI:10.1002/jor.23294.
[25] Feldman G,Offemaria A,Sawan H,et al.A murine model for developmental dysplasia of the hip:ablation of CX3CR1 affects acetabular morphology and gait[J].J Transl Med,2017,15(1):233.DOI:10.1186/s12967-017-1335-0.
[26] Gumus E,Temiz E,Sarikaya B,et al.The association between BMP-2,UQCC1 and CX3CR1 polymorphisms and the risk of developmental dysplasia of the hip[J].Indian J Orthop,2021,55(1):169-175.DOI:10.1007/s43465-020-00235-y.
[27] Lorenzo P,Aspberg A,Onnerfjord P,et al.Identification and characterization of asporin.a novel member of the leucine-rich repeat protein family closely related to decorin and biglycan[J].J Biol Chem,2001,276(15):12201-12211.DOI:10.1074/jbc.M010932200.
[28] Nakajima M,Kizawa H,Saitoh M,et al.Mechanisms for asporin function and regulation in articular cartilage[J].J Biol Chem,2007,282(44):32185-32192.DOI:10.1074/jbc.M700522200.
[29] Shi DQ,Dai J,Zhu PS,et al.Association of the D repeat polymorphism in the ASPN gene with developmental dysplasia of the hip:a case-control study in Han Chinese[J].Arthritis Res Ther,2011,13(1):R27.DOI:10.1186/ar3252.
[30] Sekimoto T,Ishii M,Emi M,et al.Copy number loss in the region of the ASPN gene in patients with acetabular dysplasia:ASPN CNV in acetabular dysplasia[J].Bone Joint Res,2017,6(7):439-445.DOI:10.1302/2046-3758.67.BJR-2016-0094.R1.
[31] Kolund?i? R,Trkulja V,Mikolau?i? M,et al.Association of interleukin-6 and transforming growth factor-β1 gene polymorphisms with developmental hip dysplasia and severe adult hip osteoarthritis:a preliminary study[J].Cytokine,2011,54(2):125-128.DOI:10.1016/j.cyto.2011.02.004.
[32] ?engi? T,Trkulja V,Paveli? SK,et al.Association of TGFB129C/T and IL6-572G/C polymorphisms with developmental hip dysplasia:a case-control study in adults with severe osteoarthritis[J].Int Orthop,2015,39(4):793-798.DOI:10.1007/s00264-015-2675-0.
[33] Ma WL,Zha ZQ,Chen K,et al.Genetic association study of common variants in TGFB1 and IL-6 with developmental dysplasia of the hip in Han Chinese population[J].Sci Rep,2017,7(1):10287.DOI:10.1038/s41598-017-11185-1.
[34] Zhao LX,Tian W,Pan H,et al.Variations of the COL1A1 gene promoter and the relation to developmental dysplasia of the hip[J].Genet Test Mol Biomarkers,2013,17(11):840-843.DOI:10.1089/gtmb.2013.0179.
[35] 李连永,赵群,王莉莉,等.发育性髋关节发育不良患儿COL1A1基因启动子区突变筛查[J].中华小儿外科杂志,2010,31(6):440-443.DOI:10.3760/cma.j.issn.0253-3006.2010.06.010. Li LY,Zhao Q,Wang LL,et al.COL1A1 gene promoter mutations screening in children with developmental dysplasia of the hip[J].Chin J Pediatr Surg,2010,31(6):440-443.DOI:10.3760/cma.j.issn.0253-3006.2010.06.010.
[36] Zhang SC,Song J,Wu QJ,et al.Collagen I in the hip capsule plays a role in postoperative clinical function in patients with developmental dysplasia of the hip[J].Front Pediatr,2022,10:918660.DOI:10.3389/fped.2022.918660.
[37] 王恩波,赵群.发育性髋脱位髋关节囊中Ⅰ、Ⅲ型胶原的免疫组化研究[J].中华小儿外科杂志,2007,28(5):250-253.DOI:10.3760/cma.j.issn.0253-3006.2007.05.008. Wang EB,Zhao Q.Histoimmune expressions of collagen Ⅰ/Ⅲ in capsules of developmentally dislocated hip[J].Chin J Pediatr Surg,2007,28(5):250-253.DOI:10.3760/cma.j.issn.0253-3006.2007.05.008.
[38] Rouault K,Scotet V,Autret S,et al.Do HOXB9 and COL1A1 genes play a role in congenital dislocation of the hip? Study in a Caucasian population[J].Osteoarthritis Cartilage,2009,17(8):1099-1105.DOI:10.1016/j.joca.2008.12.012.
[39] Wynne-Davies R.Acetabular dysplasia and familial joint laxity:two etiological factors in congenital dislocation of the hip:a review of 589 patients and their families[J].J Bone Joint Surg Br,1970,52(4):704-716.
[40] 王炳海,韦宜山,丁良甲,等.发育性髋关节脱位早期髋臼软骨细胞凋亡的实验研究[J].中国矫形外科杂志,2013,21(17):1755-1760.DOI:10.3977/j.issn.1005-8478.2013.17.13. Wang BH,Wei YS,Ding LJ,et al.Experimental study on acetabular cartilage cell apoptosis of early developmental dislocation of the hip[J].Orthop J China,2013,21(17):1755-1760.DOI:10.3977/j.issn.1005-8478.2013.17.13.
[41] Wang EB,Liu TJ,Li JJ,et al.Does swaddling influence developmental dysplasia of the hip?:An experimental study of the traditional straight-leg swaddling model in neonatal rats[J].J Bone Joint Surg Am,2012,94(12):1071-1077.DOI:10.2106/JBJS.K.00720.
[42] Wei YS,Li DH,Liu WL,et al.Altered chondrocyte apoptosis status in developmental hip dysplasia in rabbits[J].Balkan Med J,2016,33(6):639-644.DOI:10.5152/balkanmedj.2016.150557.
[43] Schroeppel JP,Crist JD,Anderson HC,et al.Molecular regulation of articular chondrocyte function and its significance in osteoarthritis[J].Histol Histopathol,2011,26(3):377-394.DOI:10.14670/HH-26.377.
[44] Ning B,Wang P,Pei XH,et al.Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development[J].Int Orthop,2012,36(3):655-664.DOI:10.1007/s00264-011-1315-6.
[45] Yan WJ,Zheng LM,Xu XQ,et al.Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy[J].Proc Natl Acad Sci USA,2022,119(37):e2203557119.DOI:10.1073/pnas.2203557119.
[46] Yang T,Williams BO.Low-density lipoprotein receptor-related proteins in skeletal development and disease[J].Physiol Rev,2017,97(3):1211-1228.DOI:10.1152/physrev.00013.2016.
[47] Au DT,Migliorini M,Strickland DK,et al.Macrophage LRP1 promotes diet-induced hepatic inflammation and metabolic dysfunction by modulating Wnt signaling[J].Mediators Inflamm,2018,2018:7902841.DOI:10.1155/2018/7902841.
[48] Ji XL,Liu TJ,Zhao SY,et al.WISP-2,an upregulated gene in hip cartilage from the DDH model rats,induces chondrocyte apoptosis through PPARγ in vitro[J].FASEB J,2020,34(4):4904-4917.DOI:10.1096/fj.201901915R.
[49] Nakamura Y,Saitou M,Komura S,et al.Reduced dynamic loads due to hip dislocation induce acetabular cartilage degeneration by IL-6 and MMP3 via the STAT3/periostin/NF-κB axis[J].Sci Rep,2022,12(1):12207.DOI:10.1038/s41598-022-16585-6.
[50] Chen YF,Lv HX,Li LY,et al.Expression of PAPP-A2 and IGF pathway-related proteins in the hip joint of normal rat and those with developmental dysplasia of the hip[J].Int J Endocrinol,2019,2019:7691531.DOI:10.1155/2019/7691531.
[51] Jia JY,Li LY,Zhao Q,et al.Association of a single nucleotide polymorphism in pregnancy-associated plasma protein-A2 with developmental dysplasia of the hip:a case-control study[J].Osteoarthritis Cartilage,2012,20(1):60-63.DOI:10.1016/j.joca.2011.10.004.
[52] Chen YF,Li LY,Wang EB,et al.Abnormal expression of Pappa2 gene May indirectly affect mouse hip development through the IGF signaling pathway[J].Endocrine,2019,65(2):440-450.DOI:10.1007/s12020-019-01975-0.
[53] Yang D,Wang SQ,Ke CH,et al.Establishment of pediatric developmental dysplasia of the hip biobank:Shanghai children’s hospital experience[J].Cell Tissue Bank,2022,23(3):581-590.DOI:10.1007/s10561-022-09995-3.
相似文献/References:
[1]姜海,苗武胜,吴革,等. 发育性髋关节发育不良儿童髋臼形态学病理分型的探讨[J].临床小儿外科杂志,2016,15(02):179.
[2]李大进,张彬,高强,等.股骨截骨联合Salter骨盆截骨治疗残余髋臼发育不良的疗效分析[J].临床小儿外科杂志,2022,21(12):1159.[doi:10.3760/cma.j.cn101785-202112051-011]
Li Dajin,Zhang Bin,Gao Qiang,et al.Efficacy of femoral osteotomy for residual acetabular dysplasia with Salter pelvic osteotomy[J].Journal of Clinical Pediatric Surgery,2022,21(11):1159.[doi:10.3760/cma.j.cn101785-202112051-011]
[3]刘万林,孙亮,赵振群,等.骨化核与发育性髋关节发育不良闭合复位后股骨头缺血坏死相关性的研究进展[J].临床小儿外科杂志,2023,22(06):584.[doi:10.3760/cma.j.cn101785-202010041-017]
Liu Wanlin,Sun Liang,Zhao Zhenqun,et al.Research advances on the relationship of ossification nucleus with avascular necrosis of developmental hip dysplasia after closed reduction[J].Journal of Clinical Pediatric Surgery,2023,22(11):584.[doi:10.3760/cma.j.cn101785-202010041-017]
[4]李杰,龙江涛,王倩倩,等.发育性髋关节脱位患儿不同股骨颈前倾角对股骨生物力学的影响研究[J].临床小儿外科杂志,2023,22(08):757.[doi:10.3760/cma.j.cn101785-202205019-011]
Li Jie,Long Jiangtao,Wang Qianqian,et al.Effect of different femoral neck anteversion angles on femoral biomechanics in children with developmental dislocation of the hip[J].Journal of Clinical Pediatric Surgery,2023,22(11):757.[doi:10.3760/cma.j.cn101785-202205019-011]
[5]孙强,叶家军,周英.川藏藏族儿童发育性髋关节脱位的影响因素分析[J].临床小儿外科杂志,2023,22(11):1050.[doi:10.3760/cma.j.cn101785-202204079-009]
Sun Qiang,Ye Jiajun,Zhou Ying.Epidemiological survey and influencing factors of developmental dysplasia of the hip in Tibetan children of Sichuan and Tibet[J].Journal of Clinical Pediatric Surgery,2023,22(11):1050.[doi:10.3760/cma.j.cn101785-202204079-009]
备注/Memo
收稿日期:2022-10-14。
基金项目:广东省高水平医院建设专项经费资助(ynkt2022-zz09)
通讯作者:熊竹,Email:bamboobear@163.com