Preosteoclast plays a pathogenic role in syndesmophyte formation of ankylosing spondylitis through the secreted PDGFB - GRB2/ERK/RUNX2 pathway.
Preosteoclast plays a pathogenic role in syndesmophyte formation of ankylosing spondylitis through the secreted PDGFB - GRB2/ERK/RUNX2 pathway.
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DOI：
10.1186/s13075-023-03142-3
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发表时间：
2023-10-05
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
作者：
强直性脊柱炎是一种主要累及骶髂关节和脊柱的慢性炎症性疾病。然而，免疫细胞对AS中韧带联合形成的真实的机制还没有很好的确定。我们的目的是寻找AS相关的关键细胞因子，并评估其在AS中的致病作用。在5名首次诊断的AS患者和5名年龄和性别匹配的健康对照中进行了1000种细胞因子的蛋白质阵列，以发现差异表达的细胞因子。通过多重蛋白定量（3种AS相关细胞因子和3种PDGF途径细胞因子）和ELISA（PDGFB）在独立样本（总共140名AS患者vs 140名健康对照）中进一步定量候选差异表达的细胞因子。分别以脂肪干细胞（ADSCs）和人胎儿成骨细胞系（hFOB1.19）作为体外间充质细胞和前成骨细胞模型，观察PDGFB对成骨细胞增殖的影响。此外，通过使用细胞模型进行全转录组测序和磷酸化肽的富集，以探索PDGFB的潜在机制。应用xCELLigence系统来检查PDGFR刺激的或PDGFR未刺激的细胞的增殖、趋化性和迁移能力。蛋白质芯片显示PDGF通路有异常表达，进一步发现PDGFB在140例中国AS患者中表达上调。重要的是，PDGFB表达与BASFI（Pearson系数/p值= 0.62/6.70E − 8）和mSASSS评分的方差（mSASSS 2年-基线，Pearson系数/p值= 0.76/8.75E − 10）显著相关。在AS患者中，前破骨细胞比健康对照分泌更多的PDGFB（p值= 1.16E − 2），这可以促进ADSC成骨并增强成骨细胞的胶原合成（COLI和COLIII）（hFOB 1.19）。此外，PDGFB促进ADSCs的增殖、趋化和迁移。PDGFB通过上调GRB 2的表达，刺激ERK磷酸化，进而上调RUNX 2的表达，促进ADSCs的成骨细胞分化。PDGFB通过激活ADSCs中的GRB 2/ERK/RUNX 2通路，促进ADSCs的成骨细胞生成，增强成骨细胞的细胞外基质，可能参与AS病理性骨形成。在线版本包含补充材料，可通过10.1186/s13075-023-03142-3获得。
Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects the sacroiliac joint and spine. However, the real mechanisms of immune cells acting on syndesmophyte formation in AS are not well identified. We aimed to find the key AS-associated cytokine and assess its pathogenic role in AS. A protein array with 1000 cytokines was performed in five AS patients with the first diagnosis and five age- and gender-matched healthy controls to discover the differentially expressed cytokines. The candidate differentially expressed cytokines were further quantified by multiplex protein quantitation (3 AS-associated cytokines and 3 PDGF-pathway cytokines) and ELISA (PDGFB) in independent samples (a total of 140 AS patients vs 140 healthy controls). The effects of PDGFB, the candidate cytokine, were examined by using adipose-derived stem cells (ADSCs) and human fetal osteoblast cell line (hFOB1.19) as in vitro mesenchymal cell and preosteoblast models, respectively. Furthermore, whole-transcriptome sequencing and enrichment of phosphorylated peptides were performed by using cell models to explore the underlying mechanisms of PDGFB. The xCELLigence system was applied to examine the proliferation, chemotaxis, and migration abilities of PDGFB-stimulated or PDGFB-unstimulated cells. The PDGF pathway was observed to have abnormal expression in the protein array, and PDGFB expression was further found to be up-regulated in 140 Chinese AS patients. Importantly, PDGFB expression was significantly correlated with BASFI (Pearson coefficient/p value = 0.62/6.70E − 8) and with the variance of the mSASSS score (mSASSS 2 years − baseline, Pearson coefficient/p value = 0.76/8.75E − 10). In AS patients, preosteoclasts secreted more PDGFB than the healthy controls (p value = 1.16E − 2), which could promote ADSCs osteogenesis and enhance collagen synthesis (COLI and COLIII) of osteoblasts (hFOB 1.19). In addition, PDGFB promoted the proliferation, chemotaxis, and migration of ADSCs. Mechanismly, in ADSCs, PDGFB stimulated ERK phosphorylation by upregulating GRB2 expression and then increased the expression of RUNX2 to promote osteoblastogenesis of ADSCs. PDGFB stimulates the GRB2/ERK/RUNX2 pathway in ADSCs, promotes osteoblastogenesis of ADSCs, and enhances the extracellular matrix of osteoblasts, which may contribute to pathological bone formation in AS. The online version contains supplementary material available at 10.1186/s13075-023-03142-3.
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影响因子：
3.7
作者：
Limame R;Wouters A;Pauwels B;Fransen E;Peeters M;Lardon F;De Wever O;Pauwels P
通讯作者：
Pauwels P
DOI：
10.3390/bioengineering8110165
发表时间：
2021-10-29
期刊：
Bioengineering (Basel, Switzerland)
影响因子：
--
作者：
Tsubosaka M;Maruyama M;Huang EE;Zhang N;Utsunomiya T;Gao Q;Shen H;Li X;Kushioka J;Hirata H;Yao Z;Yang YP;Goodman SB
通讯作者：
Goodman SB
影响因子：
2.5
作者：
Kong, Weiping;Tang, Yulong;Yan, Xiaoping
通讯作者：
Yan, Xiaoping
影响因子：
14.9
作者：
D'Andrea D;Grassi L;Mazzapioda M;Tramontano A
通讯作者：
Tramontano A
DOI：
10.1002/stem.2060
发表时间：
2015-09
期刊：
Stem cells (Dayton, Ohio)
影响因子：
--
作者：
Hung BP;Hutton DL;Kozielski KL;Bishop CJ;Naved B;Green JJ;Caplan AI;Gimble JM;Dorafshar AH;Grayson WL
通讯作者：
Grayson WL