Ortiz Georgina, Ledesma-Colunga Maria G, Wu Zhijian, García-Rodrigo Jose F, Adan Norma, Martinez-Diaz Oscar F, De Los Ríos Ericka A, López-Barrera Fernando, Martínez de la Escalera Gonzalo, Clapp Carmen
Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Qro., 76230, México.
Ocular Gene Therapy Laboratory, Neurobiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Endocrinology. 2022 May 1;163(5). doi: 10.1210/endocr/bqac036.
Inflammatory arthritis defines a family of diseases influenced by reproductive hormones. Vasoinhibin, a fragment of the hormone prolactin (PRL), has antiangiogenic and proinflammatory properties. We recently showed that vasoinhibin reduces joint inflammation and bone loss in severe antigen-induced arthritis (AIA) by an indirect mechanism involving the inhibition of pannus vascularization. This unexpected finding led us to hypothesize that a severe level of inflammation in AIA obscured the direct proinflammatory action of vasoinhibin while allowing the indirect anti-inflammatory effect via its antiangiogenic properties. In agreement with this hypothesis, here we show that the intra-articular injection of an adeno-associated virus type-2 vector encoding vasoinhibin reduced joint inflammation in a severe AIA condition, but elevated joint inflammation in a mild AIA model. The proinflammatory effect, unmasked in mild AIA, resulted in joint swelling, enhanced leukocyte infiltration, and upregulation of expression of genes encoding proinflammatory mediators (Il1b, Il6, Inos, Mmp3), adhesion molecule (Icam1), and chemokines (Cxcl1, Cxcl2, Cxcl3, Ccl2). Furthermore, vasoinhibin induced the expression of proinflammatory mediators and chemokines in cultured synovial fibroblasts through nuclear factor-κB. Finally, matrix metalloproteases and cathepsin D, upregulated in the arthritic joint, cleaved PRL to vasoinhibin, and vasoinhibin levels increased in the circulation of mice subjected to AIA. We suggest that vasoinhibin is generated during inflammatory arthritis and acts on synovial fibroblasts and endothelial cells to initially promote and later inhibit inflammation, respectively. These opposite effects may work together to help keep joint inflammation under balance.
炎症性关节炎是一类受生殖激素影响的疾病。血管抑制素是催乳素（PRL）的一个片段，具有抗血管生成和促炎特性。我们最近发现，血管抑制素通过一种间接机制减轻严重抗原诱导性关节炎（AIA）中的关节炎症和骨质流失，该机制涉及抑制血管翳血管生成。这一意外发现使我们推测，AIA中严重程度的炎症掩盖了血管抑制素的直接促炎作用，同时通过其抗血管生成特性发挥间接抗炎作用。与这一假设一致，我们在此表明，在严重AIA条件下，关节内注射编码血管抑制素的2型腺相关病毒载体可减轻关节炎症，但在轻度AIA模型中会加剧关节炎症。在轻度AIA中显现出的促炎作用导致关节肿胀、白细胞浸润增强以及编码促炎介质（Il1b、Il6、Inos、Mmp3）、黏附分子（Icam1）和趋化因子（Cxcl1、Cxcl2、Cxcl3、Ccl2）的基因表达上调。此外，血管抑制素通过核因子-κB诱导培养的滑膜成纤维细胞中促炎介质和趋化因子的表达。最后，在关节炎关节中上调的基质金属蛋白酶和组织蛋白酶D将PRL切割成血管抑制素，并且在AIA小鼠的循环中血管抑制素水平升高。我们认为，血管抑制素在炎症性关节炎期间产生，并分别作用于滑膜成纤维细胞和内皮细胞，最初促进炎症，随后抑制炎症。这些相反的作用可能共同协作以帮助维持关节炎症的平衡。
