Integrative spatially resolved proteomic and metabolomic imaging reveals synovitis endotypes implicated in osteoarthritis progression.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-30 eCollection Date: 2025-01-01 DOI:10.7150/thno.117788
Lin Zhu, Xin Diao, Chenrui Yuan, Chun Man Lawrence Lau, Jianing Wang, Wenlong Wu, Ali Mobasheri, Xavier Houard, Chunyi Wen, Zongwei Cai
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引用次数: 0

Abstract

Rationale: Synovial fibrosis, driven by myofibroblast activation and extracellular matrix remodelling, is fundamental in osteoarthritis (OA) pathogenesis but remains poorly understood due to the spatial heterogeneity of synovial inflammation (synovitis). Accurate molecular endotyping of synovial inflammation is essential for effective treatment of OA given its multifactorial nature, yet it requires integrating multiple layers of information with spatial context due to the significant heterogeneity of the tissue. Methods: In this proof-of-concept study, we leveraged MALDI mass spectrometry imaging to achieve spatial metabolomic maps that complement high-content proteomic profiles. Microflow liquid chromatography was employed to improve the robustness and throughput of spatial proteomics. By coupling these spatially resolved datasets, we establish a pseudo time trajectory of heterogeneous synovitis in human knee OA using an integrative framework of spatially resolved proteomics and matrix-assisted laser desorption/ionization mass spectrometry imaging. Results: Clustering 3534 proteins and 79 energy metabolites from spatial proteomic and metabolomic image datasets reveals four distinct functional stages of OA synovitis, i.e., quiescent, microvasculopathic, pre-fibrotic, and post-fibrotic stages, which enables construction of a corresponding pseudo time. Network analyses elucidate the functional links among these stages, highlighting an immune-metabolic axis from endothelial injury and microvascular thrombosis toward myofibroblast activation. Conclusions: This integrative multi-omics imaging approach informs the inflammatory endotype of OA, supporting a vascular aetiology of synovial fibrosis and offering mechanistic insights that could inform more targeted therapeutic strategies. Validation in larger, stratified patient cohorts will be critical to refine our findings and accelerate their clinical usages.

综合空间分辨蛋白质组学和代谢组学成像揭示滑膜炎内型与骨关节炎进展有关。
理论基础:由肌成纤维细胞活化和细胞外基质重塑驱动的滑膜纤维化是骨关节炎(OA)发病机制的基础,但由于滑膜炎症(滑膜炎)的空间异质性,人们对其知之甚少。鉴于骨性关节炎的多因素性质,准确的滑膜炎症分子内分型对于有效治疗骨性关节炎至关重要,但由于组织的显著异质性,它需要将多层信息与空间背景整合起来。方法:在这项概念验证研究中,我们利用MALDI质谱成像来获得空间代谢组学图,以补充高含量的蛋白质组学图谱。采用微流液相色谱法提高空间蛋白质组学的鲁棒性和通量。通过耦合这些空间分辨数据集,我们利用空间分辨蛋白质组学和基质辅助激光解吸/电离质谱成像的综合框架,建立了人类膝关节OA患者异质性滑膜炎的伪时间轨迹。结果:从空间蛋白质组学和代谢组学图像数据集中聚类3534个蛋白质和79个能量代谢物,揭示了OA滑膜炎的四个不同功能阶段,即静止期、微血管病变期、纤维化前期和纤维化后期,从而可以构建相应的伪时间。网络分析阐明了这些阶段之间的功能联系,强调了从内皮损伤和微血管血栓形成到肌成纤维细胞激活的免疫代谢轴。结论:这种综合的多组学成像方法可以揭示OA的炎症性内型,支持滑膜纤维化的血管病因学,并提供机制见解,可以为更有针对性的治疗策略提供信息。在更大的、分层的患者队列中进行验证对于完善我们的发现和加速其临床应用至关重要。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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