Role of the sensory nervous system in subchondral bone remodeling and synovial inflammation in OA pathology

感觉神经系统在 OA 病理学中软骨下骨重塑和滑膜炎症中的作用

基本信息

项目摘要

The joints are innervated by calcitonin gene-related peptide (alpha-CGRP)- and substance P (SP) positive sensory nerve fibers and there is evidence that sensory neurotransmitters have crucial trophic effects which are essential for proper bone metabolism and bone remodeling. Alteration of sensory joint innervation might be partly responsible for degenerative changes, which contribute to development of osteoarthritis (OA). Underlying molecular mechanisms which add to abnormal subchondral bone remodeling during the pathogenesis of OA due to changes in sensory joint innervation and their respective neurotransmitter milieu are mostly unknown. In the first funding period we observed that cartilage matrix degradation was accelerated in both neuropeptide-deficient mouse strains) which was accompanied by altered biomechanical properties (increased stiffness) of the AC assessed by indentation-type AFM (IT-AFM) compared to WT mice. Applying µCT and high-resolution nanoCT, we found clear evidence that both neuropeptides protect from DMM-induced subchondral bone degeneration/sclerosis and ectopic bone formation in the meniscus affecting bone microarchitecture already in an early OA stage. Both sensory neuropeptides and their receptors are involved in murine macrophage mechanotransduction affecting neuropeptide impact on adhesion and ROS activity. Taken together, our results imply that both SP and αCGRP have preserving functions for bone and cartilage in the context of structural and mechanical properties.We hypothesize that sensory neuropeptides are modulators of osteocyte metabolism and phenotype in response to aberrant mechanical loading during OA pathogenesis and that they are involved in modulating inflammatory processes in the joint during OA. For that we want to characterize the contribution of sensory neuropeptides to cellular changes in osteocytes during pathogenesis of DMM induced OA plus forced exercise (mice) and during spontaneous OA (WP1). Secondly, we want to characterize the influence of sensory neuropeptides on infiltration, activity and maturation of mononuclear cells, i.e. macrophages, and pro-inflammatory mediators into synovial tissue after DMM induced OA plus forced exercise and spontaneous OA (WP2). Finally, we will test if intra-articular application of rAAV5 virus expressing alpha-CGRP and SP impacts on joint tissues pathophysiological changes after OA induction.
关节由降钙素基因相关肽(alpha-CGRP)和P物质(SP)阳性感觉神经纤维支配,并且有证据表明感觉神经递质具有对于适当的骨代谢和骨重塑至关重要的关键营养作用。感觉关节神经支配的改变可能是导致骨关节炎(OA)发生的退行性改变的部分原因。在OA发病过程中,由于感觉关节神经支配及其各自的神经递质环境的变化,导致软骨下骨重塑异常的潜在分子机制大多未知。在第一个资助期内,我们观察到两种神经肽缺陷小鼠品系的软骨基质降解加速,与WT小鼠相比,这伴随着通过压痕型AFM(IT-AFM)评估的AC的生物力学特性(刚度增加)的改变。应用µCT和高分辨率nanoCT,我们发现明确的证据表明,两种神经肽都可以防止DMM诱导的软骨下骨变性/硬化和半月板异位骨形成,从而影响早期OA阶段的骨微结构。感觉神经肽及其受体均参与小鼠巨噬细胞的机械转导,影响神经肽对粘附和ROS活性的影响。综上所述,我们的研究结果表明,SP和αCGRP在结构和力学性能方面对骨和软骨具有保护作用,我们假设感觉神经肽是骨细胞代谢和表型的调节剂,在OA发病过程中对异常的机械负荷作出反应,并且它们参与调节OA关节中的炎症过程。为此,我们想要表征在DMM诱导的OA加上强迫运动(小鼠)的发病机理期间和在自发性OA(WP 1)期间感觉神经肽对骨细胞中的细胞变化的贡献。其次,我们想表征感觉神经肽对DMM诱导的OA加上强迫运动和自发性OA(WP 2)后单核细胞(即巨噬细胞)和促炎介质向滑膜组织中的浸润、活性和成熟的影响。最后,我们将测试关节内应用表达α-CGRP和SP的rAAV 5病毒是否影响OA诱导后关节组织的病理生理学变化。

项目成果

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Professorin Dr. Susanne Grässel其他文献

Professorin Dr. Susanne Grässel的其他文献

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{{ truncateString('Professorin Dr. Susanne Grässel', 18)}}的其他基金

Role of the sensory nervous system in osteoarthritis pathology
感觉神经系统在骨关节炎病理学中的作用
  • 批准号:
    279910683
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Interaction between cartilage / subchondral interfaces and MSC in vitro and in vivo
软骨/软骨下界面与 MSC 体外和体内的相互作用
  • 批准号:
    225779175
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Chondroprotective role of the melanocortin system in osteoarthritis
黑皮质素系统在骨关节炎中的软骨保护作用
  • 批准号:
    163607946
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
    Research Units
The peripheral nervous system and focal bony erosions in arthritis
关节炎的周围神经系统和局灶性骨侵蚀
  • 批准号:
    168909685
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes
Microenviromental influence of cartilage and bone explants on chrondrogenic differentation of multipotent mesenchymal stem cells
软骨和骨外植体微环境对多能间充质干细胞慢性分化的影响
  • 批准号:
    71698147
  • 财政年份:
    2008
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Sox9 and adult bone marrow derived mesenchymal stem cells (MSC)
Sox9 和成人骨髓来源的间充质干细胞 (MSC)
  • 批准号:
    34609612
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Studien zur molekularen Interaktion von Kollagen XVI und Kollagen XVI-positiven Fibrillen
XVI 型胶原蛋白与 XVI 型胶原蛋白阳性原纤维分子相互作用的研究
  • 批准号:
    5436093
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Influence of neuropeptides and catecholamines on endochondral bone formation during fracture healing
神经肽和儿茶酚胺对骨折愈合过程中软骨内骨形成的影响
  • 批准号:
    5354709
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Studien zur Struktur und dem Bindungsverhalten von Kollagen XVI
XVI型胶原蛋白结构及结合行为的研究
  • 批准号:
    5176026
  • 财政年份:
    1999
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Coordination Funds
协调基金
  • 批准号:
    289307251
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Units

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Defining the Role of Enteric Nervous System Dysfunction in Gastrointestinal Motor and Sensory Abnormalities in Down Syndrome
确定肠神经系统功能障碍在唐氏综合症胃肠运动和感觉异常中的作用
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    2023
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The role of Tex15 in shaping stochastic olfactory receptor gene choice.
Tex15 在塑造随机嗅觉受体基因选择中的作用。
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    10826734
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    2023
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Role of oligodendrocyte-derived IL-33 in brain aging and Alzheimer's disease
少突胶质细胞来源的 IL-33 在大脑衰老和阿尔茨海默病中的作用
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    10736636
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    2023
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The role of mechanosensory activity in the transcriptional maturation of primary somatosensory neurons
机械感觉活动在初级体感神经元转录成熟中的作用
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    10567984
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Role of POU4F1 in a Novel Form of Ataxia
POU4F1 在新型共济失调中的作用
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    2023
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The role of the extracellular matrix in establishing Schwann cell polarity
细胞外基质在建立雪旺细胞极性中的作用
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    10666769
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阐明 NMDA 在雪貂视觉皮层水平连接的发育和功能中的作用的遗传方法
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Role of Primary Sensory Neuron CaMKII Signaling in Regulation of Pain
初级感觉神经元 CaMKII 信号传导在疼痛调节中的作用
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    10656886
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