Tenascin-C-mediated suppression of extracellular matrix adhesion force promotes entheseal new bone formation through activation of Hippo signalling in ankylosing spondylitis.
Tenascin-C-mediated suppression of extracellular matrix adhesion force promotes entheseal new bone formation through activation of Hippo signalling in ankylosing spondylitis.
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Tenascin-C 介导的细胞外基质粘附力抑制通过激活强直性脊柱炎中的 Hippo 信号促进附着点新骨形成
DOI：
10.1136/annrheumdis-2021-220002
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发表时间：
2021-07
影响因子：
27.4
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Li Z;Chen S;Cui H;Li X;Chen D;Hao W;Wang J;Li Z;Zheng Z;Zhang Z;Liu H
本研究的目的是确定tenascin-C（TNC）在附着点新骨形成中的作用，并探讨其分子机制。韧带组织样本在手术过程中从强直性脊柱炎（AS）患者中获得。建立胶原抗体诱导的关节炎模型和DBA/1模型，观察附着点新骨形成情况。免疫组化染色检测TNC表达。在动物模型中进行TNC的全身抑制或遗传消融。用原子力显微镜测定细胞外基质的力学性能。通过RNA测序分析TNC的下游途径，并通过体外和体内药理学调节证实。通过单细胞RNA测序（scRNA-seq）分析TNC的细胞来源，并通过免疫荧光染色确认。TNC在AS患者和动物模型的韧带和附着点组织中异常上调。TNC抑制显著抑制附着点新骨形成。功能测定显示，TNC通过增强软骨内骨化过程中的软骨分化促进新骨形成。从机制上讲，TNC抑制ECM的粘附力，导致下游Hippo/yes相关蛋白信号转导的激活，这反过来又增加了软骨形成基因的表达。scRNA-seq和免疫荧光染色进一步揭示了TNC主要由附着点炎症微环境中的成纤维细胞特异性蛋白-1（FSP 1）+成纤维细胞分泌。炎症诱导的FSP 1+成纤维细胞TNC异常表达通过抑制ECM粘附力和激活Hippo信号传导促进附着点新骨形成
The aim of this study was to identify the role of tenascin-C (TNC) in entheseal new bone formation and to explore the underlying molecular mechanism. Ligament tissue samples were obtained from patients with ankylosing spondylitis (AS) during surgery. Collagen antibody-induced arthritis and DBA/1 models were established to observe entheseal new bone formation. TNC expression was determined by immunohistochemistry staining. Systemic inhibition or genetic ablation of TNC was performed in animal models. Mechanical properties of extracellular matrix (ECM) were measured by atomic force microscopy. Downstream pathway of TNC was analysed by RNA sequencing and confirmed with pharmacological modulation both in vitro and in vivo. Cellular source of TNC was analysed by single-cell RNA sequencing (scRNA-seq) and confirmed by immunofluorescence staining. TNC was aberrantly upregulated in ligament and entheseal tissues from patients with AS and animal models. TNC inhibition significantly suppressed entheseal new bone formation. Functional assays revealed that TNC promoted new bone formation by enhancing chondrogenic differentiation during endochondral ossification. Mechanistically, TNC suppressed the adhesion force of ECM, resulting in the activation of downstream Hippo/yes-associated protein signalling, which in turn increased the expression of chondrogenic genes. scRNA-seq and immunofluorescence staining further revealed that TNC was majorly secreted by fibroblast-specific protein-1 (FSP1)+fibroblasts in the entheseal inflammatory microenvironment. Inflammation-induced aberrant expression of TNC by FSP1+fibroblasts promotes entheseal new bone formation by suppressing ECM adhesion forces and activating Hippo signalling.
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影响因子：
27.4
作者：
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通讯作者：
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作者：
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