Molecular functions of Shank2 and Shank3 in bone integrity and osteoporosis

Shank2和Shank3在骨完整性和骨质疏松症中的分子功能

基本信息

项目摘要

Osteoporosis is a degenerative disease of the aging society, which is a significant burden for the health system. To increase bone quality novel drug targets favoring bone forming osteoblasts and their derived osteocytes are required. We identified novel regulators of osteoblast differentiation and function that could also lead to novel targets in osteoporosis treatment with a siRNA screen in primary osteoblasts. We found Shank family proteins (in particular Shank3) and many of their interacting factors required for osteoblast differentiation. Shank proteins localize to postsynaptic densities of excitatory synapses and are major scaffolding molecules. Shank mutations are known to be causative for neuropsychiatric disorders of the autism spectrum but in several cases also lead to short stature and facial dysmorphias indicating a Shank related misregulation of bone homeostasis in humans. Accordingly, we found that knockout mice for Shank2/3 have a dramatic osteopenia. We further detected that in undifferentiated osteoblasts Shank3 is nuclear localized and is found subsequently in cytoplasm and subcortical regions of the cell during osteoblast differentiation. We hypothesize that scaffolding proteins known from synapses have an essential role for bone formation and that during ageing their function decreases. We further hypothesize that distinct subcellular localizations of these proteins are regulating the differentiation process. We address this by the analysis of compound knockout mice, their primary cells and human osteoblasts derived from iPS cells of Phelan McDermid syndrome patients carrying mutations within Shank3 gene. Finally, we will test the hypothesis that treatment regimens used to treat Phelan McDermid patients might lead to improved bone formation. The expected results will give insights into molecular mechanisms of the bone abnormalities of Phelan McDermid syndrome patients as well as for bone disorders, such as osteoporosis in general.
骨质疏松症是老龄化社会的一种退行性疾病,是卫生系统的重大负担。为了提高骨质量,需要有利于成骨细胞及其衍生骨细胞的新型药物靶点。我们确定了成骨细胞分化和功能的新调节因子,这些调节因子也可能导致在原发性成骨细胞中进行siRNA筛选以治疗骨质疏松症的新靶点。我们发现了Shank家族蛋白(特别是Shank 3)和许多成骨细胞分化所需的相互作用因子。柄蛋白定位于兴奋性突触的突触后密度,是主要的支架分子。已知Shank突变是自闭症谱系神经精神障碍的病因,但在一些情况下也导致身材矮小和面部畸形,表明人类中与Shank相关的骨稳态失调。因此,我们发现Shank 2/3基因敲除小鼠具有显著的骨质减少。我们进一步检测到,在未分化的成骨细胞中,Shank 3是核定位的,并且在成骨细胞分化过程中随后在细胞的细胞质和皮质下区域被发现。我们假设,从突触中已知的支架蛋白对骨形成具有重要作用,并且在衰老过程中其功能下降。我们进一步假设,这些蛋白质的不同亚细胞定位调节分化过程。我们通过分析化合物敲除小鼠、其原代细胞和来源于携带Shank 3基因突变的McDermid综合征患者iPS细胞的人成骨细胞来解决这一问题。最后,我们将测试用于治疗McDermid患者的治疗方案可能导致骨形成改善的假设。预期的结果将使我们深入了解McDermid综合征患者骨异常的分子机制,以及骨疾病,如骨质疏松症。

项目成果

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Professor Dr. Tobias Böckers其他文献

Professor Dr. Tobias Böckers的其他文献

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{{ truncateString('Professor Dr. Tobias Böckers', 18)}}的其他基金

Generation, differentiation and analysis of human iPS cells with respect to defined synaptopathies
人类 iPS 细胞的生成、分化和分析(关于确定的突触病)
  • 批准号:
    187990092
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Die Rolle des ProSAP2/Shank3 interagierenden Proteins Abi-1 in postsynaptischen Dichten (PSDs) und im Zellkern
ProSAP2/Shank3 相互作用蛋白 Abi-1 在突触后密度 (PSD) 和细胞核中的作用
  • 批准号:
    47776129
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
    Research Grants
mRNA-Transport bei Proteinen der postsynaptischen Dichte
突触后密度蛋白中的 mRNA 转运
  • 批准号:
    5235112
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Untersuchungen zur Lokalisation und Funktion der synaptischen Proteine ProSAP1 und ProSAP2
突触蛋白ProSAP1和ProSAP2的定位和功能研究
  • 批准号:
    5326440
  • 财政年份:
    2001
  • 资助金额:
    --
  • 项目类别:
    Research Grants
mRNA-Transport bei Proteinen der postsynaptischen Dichte
突触后密度蛋白中的 mRNA 转运
  • 批准号:
    5235118
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:
    Research Units
Post-synaptic disruption drives motoneuron vulnerability and disease progression in ALS
突触后驱动破坏运动神经元脆弱性和 ALS 疾病进展
  • 批准号:
    431995586
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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