A novel mutation combining with rs66612022 in a Chinese pedigree suggests a new pathogenesis to osteogenesis imperfecta via whole genome sequencing

Osteogenesis imperfecta (OI) is a rare heritable disease with systemic connective tissue disorder. Most of the patients represent autosomal dominant form of OI, and are usually resulting from the mutations in type I collagen genes. However, the gene mutations reported previously only account for ∼70% of the OI cases. Here, in a Chinese OI family, we examined seven patients and nine normal individuals using the whole genome sequencing and molecular genetic analysis. The mutation of rs66612022 (COL1A2:p.Gly328Ser) related to glycine substitution was found in the seven patients. Moreover, we identified a novel missense mutation (HMMR:p.Glu2Gln). Interestingly, the individuals of this family with both the mutations were suffering from OI, while the others carried one or none of them are normal. The mutations of COL1A2 and HMMR and their combined effect on OI would further expand the genetic spectrum of OI.     

CRTAP mutations in lethal and severe osteogenesis imperfecta: the importance of combining biochemical and molecular genetic analysis

Autosomal recessive lethal and severe osteogenesis imperfecta (OI) is caused by the deficiency of cartilage-associated protein (CRTAP) and prolyl-3-hydroxylase 1 (P3H1) because of CRTAP and LEPRE1 mutations. We analyzed five families in which 10 individuals had a clinical diagnosis of lethal and severe OI with an overmodification of collagen type I on biochemical testing and without a mutation in the collagen type I genes. CRTAP mutations not described earlier were identified in the affected individuals. Although it seems that one important feature of autosomal recessive OI due to CRTAP mutations is the higher consistency of radiological features with OI type II-B/III, differentiation between autosomal dominant and autosomal recessive OI on the basis of clinical, radiological and biochemical investigations proves difficult in the affected individuals reported here. These observations confirm that once a clinical diagnosis of OI has been made in an affected individual, biochemical testing for overmodification of collagen type I should always be combined with molecular genetic analysis of the collagen type I genes. If no mutations in the collagen type I genes are found, additional molecular genetic analysis of the CRTAP and LEPRE1 genes should follow. This approach will allow proper identification of the genetic cause of lethal or severe OI, which is important in providing prenatal diagnosis, preimplantation genetic diagnosis and estimating recurrence risk.     

Deficient expression of the small proteoglycan decorin in a case of severe/lethal osteogenesis imperfecta

In osteogenesis imperfecta (OI) the effects of mutations in type I collagen genes generally reflect their nature and localization. Unrelated individuals sharing identical mutations present, in general, similar clinical phenotypes. However, in some such cases the clinical phenotype differs. This variable clinical expression could be the result of abnormalities in other connective tissue proteins. Since decorin is a component of connective tissue, binds to type I collagen fibrils and plays a role in matrix assembly, we studied decorin production in skin fibroblasts from OI patients. Cultured fibroblasts from one patient with extremely severe osteogenesis imperfecta (classified as type II/III) who has an α1(I)gly415ser mutation were found to secrete barely detectable amounts of decorin into culture medium. Western blotting using antibodies raised against decorin confirmed the reduction of the decorin core protein and Northern blot analysis showed decorin mRNA levels below the limit of detection. Cells from a patient, with a less severe phenotype, bearing a mutation in the same position of the triple helix (α1(I)gly415) expressed decorin normally. The different clinical phenotypes could be due to the differing genetic backgrounds of the patients so it is tempting to conclude that in our most severely affected patient the absence of decorin aggravates the clinical phenotype. © 1996 Wiley-Liss, Inc.     

The evolution of the nosology of osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a relatively common genetic skeletal disorder with an estimated frequency of 1 in 20 000 worldwide. The manifestations are diverse and although individually rare, the several different forms contribute to the production of a significant number of affected individuals with considerable morbidity and mortality. During the last decade, there have been extensive molecular investigations into the etiology of OI and these advances have direct relevance to the medical management of the disorder, and the purpose of this review is to document the history and evolution of the nosology of OI. The current nosology, based on molecular concepts, which are crucial in the identification of genotype‐phenotype correlations in persons with OI, is also outlined. The successive revisions of the nosology and classification of OI have highlighted the importance of the nomenclature of the condition in order for it to be recognized by clinicians, scientists and patient advocacy groups. In this way, improved counseling of patients and individualized, tailored therapeutic approaches based on the underlying pathophysiology of the individual's type of OI have been facilitated.     

巨噬细胞的骨免疫学效应

背景：巨噬细胞以其显著的骨免疫学效应得到学者们的广泛关注,其功能和应用已成为研究热点。目前研究主要涉及巨噬细胞的起源、极化、骨免疫学效应及其在骨修复中的应用。目的：综述巨噬细胞的骨免疫学效应及其在骨修复中应用的研究进展,证实巨噬细胞在骨组织工程中具有卓越的研究价值和应用前景。方法：利用PubMed、Web of Science和CNKI数据库检索2010-2022年发表的相关文献,检索词为“巨噬细胞极化、骨、成骨、骨免疫学、生物材料、组织工程”“macrophage polarization,bone,osteogenesis,osteoimmunology,biomaterials,tissue engineering”,并纳入少量年份久远的经典文献。通过阅读标题和摘要进行初筛,排除与文章主题不相关的文献,最终纳入120篇文献进行综述分析。结果与结论：(1)巨噬细胞包括单核细胞来源的炎性巨噬细胞和组织驻留巨噬细胞,其中不同组织的驻留巨噬细胞具有不同的发育起源组合,绝大多数组织驻留巨噬细胞起源于胚胎时期的卵黄囊;(2)巨噬细胞具有高度可塑性,在不同刺激下极化为M1/M2表型,分别释放促...     

骨髓基质干细胞复合煅烧骨的皮下成骨

背景：研究证明骨髓基质干细胞与煅烧骨支架材料结合后可形成组织工程化骨,但在动物体内的生物相容性及皮下诱导成骨的能力国内报道较少。 目的：观察骨髓基质细胞复合异种煅烧骨植入BALB/c裸鼠背部皮下的成骨性能及煅烧骨材料作为组织工程骨支架材料的可行性。 方法：选用经脱脂及脱蛋白处理后高温煅烧形成的骨支架材料与梯度密度离心法分离培养至第3代的羊骨髓基质干细胞构建细胞-煅烧骨复合物植入BALB/c裸鼠背部皮下,选同期对侧背部皮下植入单纯煅烧骨为对照组。 结果与结论：煅烧后的松质骨块为白垩色,表面呈蜂窝状多孔结构,保留了天然松质骨的多孔状空间结构。骨小梁结构完整,孔隙相互连通。骨髓基质干细胞接种到煅烧骨后24 h可见大量细胞黏附于支架上,7 d后细胞分泌大量细胞外基质,细胞与基质分界不清,细胞能在材料上良好地黏附、增殖与生长,细胞活性未受到支架材料的影响。植入4周后,两组均可见煅烧骨边缘出现少量残片,细胞-煅烧骨复合物组煅烧骨孔隙周边可发现骨细胞,对照组煅烧骨表面可见纤维结缔组织包绕。植入后8周,两组均可见到煅烧骨部分降解为片状类骨质,周围有成纤维细胞包绕,排列紧密,形态多样,细胞-煅烧骨复合物组煅烧骨孔隙内可见煅烧骨表面有排列成行的成骨细胞,孔隙间有散在淋巴细胞浸润。对照组标本可见孔隙内有大量结缔组织长入,未见明显成骨迹象。结果说明,经高温煅烧后的松质骨材料,具有良好的生物相容性和生物安全性,可作为骨髓基质干细胞的良好载体,复合后植入体内能够诱导新生骨组织形成,可作为骨缺损组织工程修复的支架材料。     

骨松安激活Runx 2/Osterix途径促进骨质疏松性骨折愈合的机制研究

目的 初步探索骨松安促进骨质疏松性骨折愈合的机制.方法 建立骨质疏松性骨折大鼠模型,采用骨松安进行治疗,分别于7、14、21 d取出骨折端骨痂,通过HE染色观察骨痂生长情况,采用免疫组化、RT-qPCR检测Runx 2、Osterix的表达.结果 HE染色结果显示,骨松安治疗可在早期促进骨质疏松性骨折大鼠骨折端软骨细胞...     

前颌中缝牵张修复牙槽裂的实验研究

目的　探索用缝牵张成骨技术以组织再生的原理修复牙槽裂。方法　采用犬牙槽裂模型 ,牙槽裂形成术后 2周 ,于前颌中缝处安置缝牵张器 ,外张力 2 0 0g。牵张 2～ 3周 ,裂隙侧的前颌骨向侧方移动贴紧远中裂缘 ,用局部黏骨膜瓣修复牙槽裂隙。保持 2周后去除缝牵张器。临床观察、连续X线、头颅干骨和组织学检查评价治疗结果。结果　所有对照动物形成规则的牙槽裂 ,无自发骨性愈合。前颌中缝牵张后 ,裂隙侧前颌缓慢向裂侧上颌靠拢 ,2～ 3周与远中裂缘密切贴合。X线片示前颌中缝呈现由窄渐宽的三角形 ,三角形的尖端指向后方 ,三角区域的骨密度逐渐增加。骨膜成形术后 3个月 ,原牙槽嵴缺损处骨质连续性完全恢复 ,且牙槽骨段在三维方向上均与对侧相同。前颌中缝恢复正常直线形态。结论　该牙槽裂模型稳定性和重复性好 ;前颌中缝牵张诱导缝区新骨形成 ,一侧前颌向裂隙移位和局部骨膜成形可达到完善的牙槽裂修复。     

颧骨三维牵张器的初步研制

目的：探讨颧骨外固定三维牵张器的设计和制作。方法：根据机械移动原理，设计两块可相对移动的支撑板，一定范围内在两个垂直方向任意移动，带动牵张杆改变牵张方向，进行三维牵张成骨，在离体羊颅骨模型上进行模拟牵张成骨。结果：研制的三维缝牵张器重量30g，牵张杆前后向移动2cm左右、上下方向移动3．5cm左右，向外移动3cm左右，牵张控制准确，三维变向简便易行。结论：设计的外固定三维牵张器可以三维牵张，操作简便易行，控制准确。