Pre-osteoclast调控的血管-骨形成偶联在骨性关节炎发病进展中的机制研究

Osteoarthritis (OA) is not just the disease of articular cartilage, but involving the function unit of cartilage and subchondral bone. During OA development, osteoclastic bone resorption in subchondral bone enhances, which leads to excessive activation and liberation of TGF-β and interrupts its original natural concentration gradient, finally, causing MSCs being recruited to bone marrow to form “osteoid islets”. However, the origin of MSCs for the formation of osteoid islets is still unclear until now. Recently, a new type of H-type vessels, also called CD31hiEmcnhi vessels, has been found with a function of coupling bone formation. We also found during the development of cortical bone, Pre-osteoclast induced the formation of H-type vessels to couple bone formation. However, during the onset of OA, it’s still unknown whether the subchondral bone sclerosis is accompanied with H-type vessels formation, and whether this type of vessels is induced by pre-osteoclast? Based on the theoretic basis above, we plan to introduce pre-osteoclast-regulated bone-vascular coupling mechanism into the OA development, to provide a new viewpoint for OA prevention and clinical treatment.

骨性关节炎（OA）不仅仅是关节软骨的疾患，是软骨和软骨下骨功能体整体的疾患。OA发病过程中，伴随软骨下骨破骨细胞（Osteoclast）表达增加，破坏了原有TGF-β溶度梯度，从而最终导致骨髓间充质干细胞（MSCs）被诱导至骨髓腔形成异位“骨岛”而诱发OA。但是MSCs的来源仍不清楚。近期学者提出一种新型的可以偶联骨形成的H-type血管，即CD31hiEmcnhi血管。我们也在试验中进一步证实在骨皮质生长发育过程中破骨前体细胞（Pre-osteoclast）诱导了H-type 血管形成。但是在OA发病过程中，软骨下骨硬化是否伴有H-type 血管形成，以及该血管是否由软骨下骨Pre-osteoclast诱导产生目前仍不清楚。基于以上理论基础，我们将Pre-osteoclast诱导的血管-骨形成偶联机制引入到OA发病机制的探讨中，旨在为骨性关节炎的预防和临床治疗提供一个新的视点和理论基础。

骨关节炎（OA）不仅仅是关节软骨的疾患，其是关节软骨和软骨下骨功能体整体的疾患。目前我国骨关节炎患者已经过亿，60岁以上老人中，有一半以上饱受OA困扰；同时由于年轻人运动不当外伤导致的骨关节炎也越来越常见，骨关节炎已经出现了低龄化的趋势。目前针对骨关节炎的治疗没有特别有效的疗法，其深在原因在于针对骨关节炎发生的细胞和分子生物学机制仍不完全清楚。本项目发现在骨关节炎发病过程中，软骨下骨破骨细胞（Osteoclasts）通过溶骨释放骨质中的分子蛋白进而介导H-type血管的形成；H-type血管与MSCs形成正反馈环介导软骨下骨异位成骨：即H-type血管为异位成骨提供了MSCs;同时MSCs自身p-FAK表达的增加，能够反过来通过FAK-Grb2-MAPK通路促进VEGF的分泌，进而反向促进H-type血管的形成，形成正反馈环。更为重要的是，软骨下骨局部给药FAK抑制剂，能够抑制软骨下骨H-type血管的形成，进而抑制软骨下骨异位成骨并最终抑制或延缓骨关节炎的发生。不仅如此，我们进一步发现软骨下骨H-type血管介导的异位成骨，能够偶联关节软骨的退行性变。首先软骨下骨H-type血管介导异位成骨，改变了软骨下骨及软骨下骨板（SBP）的骨显微结构，改变了SBP孔径大小，促进软骨下骨SDF-1由软骨下骨渗透至关节软骨；渗透至关节软骨的SDF-1进一步与软骨细胞表面的CXCR4结合，改变了关节软骨的代谢稳态：ALK1/ALK5比例升高，即由ALK5介导的合成代谢转变为由ALK1介导分解代谢，进而导致软骨细胞MMP13及ColX表达增加，裂解关节软骨的细胞外基质致使关节软骨退行性变及骨关节炎的发生。本项目从细胞和整体动物水平，阐明H-type血管-骨形成偶联在软骨下骨异位成骨的作用及机制；证实了调控软骨下骨H-type血管的形成如调控MSCs细胞的FAK通路可能作为一个理想的药物靶点来抑制骨关节炎的发生进展。