Heritable Disorders Of Connective Tissue

结缔组织遗传性疾病

• 批准号: 7333691
• 负责人: Joan C Marini
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7333691
• 关键词: Heritable; Disorders; Connective; Tissue

The Bone and Extracellular Matrix Branch conducts research on the extracellular matrix of bone and on diseases resulting from defective matrix. The Section on Heritable Bone Disorders, led by Joan C. Marini, conducts an integrated program of laboratory and clinical research, focusing on osteogenesis imperfecta (OI) as a model disorder of extracellular matrix resulting in severe osteoporosis. They have shown that biochemical screening of type I collagen in osteogenesis imperfecta does not detect excess modification resulting from glycine substitutions at the amino ends of the alpha chains. Complete detection of substitutions in the amino third of the a1(I) and amino half of the a2(I) chain requires supplementation by sequencing (Cabral et al (2006) J Med Genet 43:685). Mutations at both the amino and carboxyl ends of the collagen molecule have been a primary research focus. At the amino end of the alpha1(I) helical region, they delineated distinct combined phenotype of OI and Ehlers Danlos Syndrome and showed that it was caused by mutations in a distinct 90-residue folding region. These mutations unfold the adjacent N-proteinase cleavage site and interfere with procollagen processing. Incorporation of pN-collageninto matrix results in fibrils with strikingly decreased diameter. Thus, the defects in OI/EDS collagen have a dual role - they cause osteoporosis directly by altering bone matrix structure and EDS indirectly by interfering with procollagen processing. (Cabral et al (2005) JBC 280:19259; Makareeva et al (2006) JBC 281:6463) The Section has also been investigating the carboxyl end of the procollagen chains, where they have identified 5 novel mutations in patients with types II (lethal), III (severe) and IV (moderate) OI. These mutations all delay incorporation of the mutant chains into the procollagen helix. Interestingly, the portion of the procollagen molecule containing these mutations is cleaved from the helix before fibril assembly. Therefore, the mutations per se are not expected to be present in tissue matrix. This implies that the mechanism of these mutations must differ from those in the collagen helix. Pericellular processing as well as collaborative in vitro digestion with C-proteinase (David Hulmes, Lyon, France) indicates delay in processing of the propeptide. The Section played an important role in OI treatment by conducting controlled trials of bisphosphonate drugs in both the Brtl mouse model for OI generated by this Section, and in the pediatric OI population. These investigations distinguished the beneficial and detrimental aspects of these compounds on OI bone. In the mouse, increased femoral bone volume and load at fracture came at the expense of decreased material strength and increased brittleness. Fracture risk was increased by persistence of mineralized cartilage rests and a toxic effect on the morphology of Brtl osteoblasts was noted. In the randomized controlled trial of pamidronate in children with types III and IV OI (Letocha et al (2005) JBMR 20:977), treated patients experienced a significant increase in vertebral BMD z-scores, increased L1-L4 mid-vertebral height and total vertebral area, compared to controls. However, the increases in BMD tapered after 1-2 years of treatment. Furthermore, treated patients did not experience positive functional effects in ambulation level, lower extremity strength or amelioration of pain. The changes previously reported in these parameters appear to have been placebo effects in uncontrolled trials. The Section is currently engaged in a dose comparison trial of pamidronate, to determine whether a lower dose of pamidronate in pediatric OI can deliver the beneficial effects with reduced side effects.

骨与细胞外基质分支对骨细胞外基质以及基质缺陷引起的疾病进行研究。由 Joan C. Marini 领导的遗传性骨疾病科开展了实验室和临床研究的综合项目，重点关注成骨不全症 (OI) 作为导致严重骨质疏松症的细胞外基质疾病模型。他们表明，对成骨不全症中的 I 型胶原蛋白进行生化筛查并不能检测到由于 α 链氨基末端的甘氨酸取代而导致的过度修饰。完整检测a1(I)链的氨基三分之一和a2(I)链的氨基一半中的取代需要通过测序进行补充(Cabral等人(2006) J Med Genet 43:685)。胶原蛋白分子氨基和羧基末端的突变一直是主要的研究焦点。在 α1(I) 螺旋区域的氨基末端，他们描绘了 OI 和埃勒斯丹洛斯综合征的独特组合表型，并表明它是由独特的 90 个残基折叠区域的突变引起的。这些突变会展开邻近的 N-蛋白酶切割位点并干扰前胶原加工。将 pN-胶原蛋白掺入基质中会导致原纤维直径显着减小。因此，OI/EDS 胶原蛋白的缺陷具有双重作用——它们通过改变骨基质结构直接导致骨质疏松，而 EDS 通过干扰前胶原加工间接导致骨质疏松。 （Cabral 等人 (2005) JBC 280:19259；Makareeva 等人 (2006) JBC 281:6463）该科还研究了原胶原链的羧基末端，他们在 II 型（致死）、III（严重）和 IV（中度）OI 患者中发现了 5 个新突变。这些突变都延迟了突变链并入前胶原螺旋。有趣的是，含有这些突变的原胶原分子部分在原纤维组装之前从螺旋上裂解下来。因此，预计突变本身不会存在于组织基质中。这意味着这些突变的机制一定与胶原蛋白螺旋中的突变机制不同。细胞周加工以及与 C-蛋白酶（David Hulmes，里昂，法国）的协同体外消化表明前肽加工的延迟。 该科通过在该科生成的 Brtl 成骨不全小鼠模型和儿科成骨不全人群中进行双膦酸盐药物对照试验，在成骨不全治疗中发挥了重要作用。这些研究区分了这些化合物对 OI 骨的有益和有害方面。在小鼠中，股骨体积和骨折负荷的增加是以材料强度下降和脆性增加为代价的。矿化软骨残留的持续存在会增加骨折风险，并且注意到对 Brtl 成骨细胞形态的毒性作用。在 III 型和 IV 型 OI 儿童中进行的帕米膦酸随机对照试验中（Letocha 等人 (2005) JBMR 20:977），与对照组相比，治疗患者的椎骨 BMD z 分数显着增加，L1-L4 椎体中部高度和总椎体面积增加。然而，BMD 的增加在治疗 1-2 年后逐渐减少。此外，接受治疗的患者在行走水平、下肢力量或疼痛改善方面没有出现积极的功能效果。先前报道的这些参数的变化似乎是非对照试验中的安慰剂效应。该科目前正在进行帕米膦酸的剂量比较试验，以确定较低剂量的帕米膦酸治疗儿童成骨不全症是否可以产生有益效果并减少副作用。