Jo S, Lee J S, Nam B, Lee Y L, Kim H, Lee E Y, Park Y-S, Kim T-H
Hanyang University Institute for Rheumatology Research, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Republic of Korea.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; GENOME INSIGHT Inc., Daejeon 34141, Republic of Korea.
Osteoarthritis Cartilage. 2022 Feb;30(2):280-290. doi: 10.1016/j.joca.2021.11.013. Epub 2021 Nov 23.
Although cartilage degeneration and invasion of the subchondral bone plate in entheseal lesion has been considered to consequently lead bony ankylosis in ankylosing spondylitis (AS), no evident mechanisms are known.
To identify histopathological and physiological changes in enthesitis-related ankylosis in AS, we performed molecular characterization of transcription factors and surface markers, and transcriptome analysis with human tissues. Entheseal tissue containing subchondral bone was obtained from the facet joints of 9 patients with AS and 10 disease controls, and assessed by using differential staining techniques. Enthesis cells were isolated, characterized, stimulated with TNF and/or IL-17A, and analysed by cell-based experimental tools.
We found diffusely distributed granular tissue and cartilage in the subchondral bone in AS. Co-expression of SOX9, a specific transcription factor in cartilage, and matrix metalloproteinase 13 (MMP13) was found in the granular tissues within the subchondral bone from AS patients. Intriguingly, SOX9 expression was significantly higher in AS enthesis cells than controls and correlated with TNFR1 and IL-17RA expressions, which is important for high reactivity to TNF and IL-17A cytokines. Co-stimulation by TNF and IL-17A resulted in accelerated mineralization/calcification features, and increased OCN expression in AS enthesis cells. Furthermore, SOX9 overexpression in enthesis leads to promoting mineralization feature by TNF and IL-17A stimuli. Finally, OCN expression is elevated in the destructive enthesis of advanced AS.
These findings provide insight into the links between inflammation and the mineralization of entheseal tissue as the initiation of spinal ankylosis, emphasizing the importance of SOX9 enthesis cells.
尽管在附着点病损中软骨退变和软骨下骨板侵蚀被认为会导致强直性脊柱炎（AS）的骨融合，但目前尚不清楚其具体机制。
为了确定AS中附着点炎相关骨融合的组织病理学和生理学变化，我们对转录因子和表面标志物进行了分子特征分析，并对人体组织进行了转录组分析。从9例AS患者和10例疾病对照的小关节获取含有软骨下骨的附着点组织，采用差异染色技术进行评估。分离、鉴定附着点细胞，用肿瘤坏死因子（TNF）和/或白细胞介素-17A（IL-17A）刺激，并通过基于细胞的实验工具进行分析。
我们发现AS患者软骨下骨中有弥漫分布的颗粒组织和软骨。在AS患者软骨下骨内的颗粒组织中发现了软骨特异性转录因子SOX9和基质金属蛋白酶13（MMP13）的共表达。有趣的是，AS附着点细胞中SOX9的表达明显高于对照组，且与TNFR1和IL-17RA的表达相关，这对于对TNF和IL-17A细胞因子的高反应性很重要。TNF和IL-17A的共同刺激导致AS附着点细胞矿化/钙化特征加速，骨钙素（OCN）表达增加。此外，附着点中SOX9的过表达导致TNF和IL-17A刺激促进矿化特征。最后，在晚期AS的破坏性附着点中OCN表达升高。
这些发现为炎症与附着点组织矿化之间的联系提供了见解，而这种联系是脊柱融合的起始，强调了SOX9在附着点细胞中的重要性。
