Mechanisms of altered extracellular matrix signaling in Osteogenesis Imperfecta

成骨不全中细胞外基质信号传导改变的机制

• 批准号: 8782805
• 负责人: STEFANIE L ALEXANDER
• 金额: $ 4.01万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2017-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8782805
• 关键词: Affect; Binding; Biochemical; Biological Availability; Biology; Biomechanics; Bone Development; Bone Marrow; Bone Tissue; Calorimetry; Cell Culture System; Cell Transplants; Collagen; Collagen Type I; Craniofacial Abnormalities; Data; Deformity; Dentin Dysplasia; Disease; Extracellular Matrix; Fracture; Genetic; Goals; Health; Homeostasis; Human; Immature Bone; Knock-out; Knockout Mice; Lead; Leucine; Link; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Osteoblasts; Osteogenesis Imperfecta; Osteoporosis; Paper; Pathogenesis; Patients; Phenotype; Post-Translational Protein Processing; Property; Proteoglycan; Reporting; Research; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Stromal Cells; Structural Protein; Structure; Surface Plasmon Resonance; Testing; Tissues; Titrations; Transforming Growth Factor beta; asporin; base; biglycan; bone; bone mass; cell behavior; decorin; evaluation/testing; fetal; mouse model; new therapeutic target; novel; overexpression; protein complex; therapeutic target; tomography

DESCRIPTION (provided by applicant): Osteogenesis imperfecta (OI) is a debilitating genetic osteodysplasia that results in low bone mass, bone deformity, and bone fractures. Despite extensive research, the molecular pathogenesis behind OI is still poorly understood. Most cases of OI are caused by mutations in the structural protein type I collagen (dominant OI) or in protein complexes that post-translationally modify type I collagen (recessive OI); both types of mutations often lead to biochemical overmodification. Type I collagen, while important for structural integrity of bone is also essential for extracellular matrix (ECM) cell signaling. It extensively interacts with ECM components that regulate bioavailability of signaling molecules, thereby affecting tissue-specific cell behavior. We have demonstrated that excessive activation of the transforming growth factor-beta (TGFβ) signaling pathway is pathogenic in mouse models of dominant (Col1α2tm1.1Mcbr) and recessive (Crtap-/-) OI. However, the mechanism by which altered collagen structure or post-translational modification leads to altered signaling in OI is unclear. Small leucine-rich proteoglycans (SLRPs) are important regulators of matrix signaling that also bind type I collagen and could establish a link between structural proteins and signaling. Currently, the SLRPs decorin (Dcn), biglycan (Bgn), and asporin (Aspn) are the only matrix components known to bind both type I collagen and TGFβ. Their importance in bone is demonstrated by the phenotype in their absence. The Bgn- knockout mouse has an osteoporosis phenotype with altered sequestration and signaling of TGFβ in bone. Only one paper has studied the bone from Dcn-/- mice, but Dcn-knockdown osteoblast cells transplanted into mice generate immature, highly mineralized bone reminiscent of bone from OI patients. Decorin and biglycan from human OI bone samples are produced and secreted in a fetal-like form suggesting a connection between OI and changes in SLRPs. We hypothesize that changes in type I collagen in OI disturb binding to the SLRPs decorin, biglycan, and asporin, which in turn alters TGFβ availability in the matrix. We aim to test this hypothesis by comparing the biochemical interaction of SLRPs with type I collagen from wildtype, dominant OI, or recessive OI mice and determining the effects of SLRPs on TGFβ bioavailability and signaling in OI. Our preliminary data implies that decorin binds less to type I collagen from Crtap-/- mutant mice than wildtype mice. Based on this data and the phenotype of Dcn-knockout osteoblasts, the third aim of this project is to characterize the bone phenotype of the Dcn-/- mouse to assess the phenotypic overlap with OI bone. This research is important for establishing common mechanisms of disease, which may provide potential therapeutic targets for patients with dominant or recessive OI.

描述（由申请人提供）：成骨不全症（Osteogenesis imperfecta， OI）是一种使人衰弱的遗传性骨发育不良，导致骨量低、骨畸形和骨折。尽管进行了广泛的研究，但对成骨不全的分子发病机制仍知之甚少。大多数成骨不全病例是由结构蛋白I型胶原（显性成骨不全）或蛋白质突变引起的