BackgroundInterleukin-6 (IL-6) with IL-6 receptor (IL-6R) play an important role in the tissue regeneration in vivo, especially bone metabolism. Bone marrow -derived mesenchymal stem cells (BM-MSCs) are multipotent stromal cells, which are main origin of osteoblasts. However, the roles of IL-6 and IL-6R in the osteogenic differentiation of BM-MSCs are still unclear.MethodsThe expression of IL-6 and IL-6R was detected in BM-MSCs during osteogenic differentiation. The activation of the STAT3 pathway was assessed and its role in the osteogenic differentiation of BM-MSCs was determined using the specific inhibitor AG490. Exogenous IL-6/soluble IL-6R or antibodies against IL-6/IL-6R were used to confirm the mechanism by which the IL-6/IL-6R complex promotes the osteogenic differentiation.ResultsThe levels of IL-6 and IL-6R, especially the level of membranous IL-6R but not that of soluble IL-6R, increased during osteogenic differentiation in BM-MSCs. The levels of IL-6 and IL-6R were positively correlated with the osteogenic potential of BM-MSCs. The STAT3 signaling pathway was activated during the osteogenic differentiation of BM-MSCs. AG490 markedly inhibited the activation of the STAT3 pathway and, subsequently, the osteogenic differentiation potential of BM-MSCs. Additionally, exogenous IL-6 and soluble IL-6R accelerated the osteogenic differentiation of BM-MSCs. In contrast, antibodies against IL-6 or IL-6R suppressed the osteogenic differentiation of BM-MSCs. Moreover, IL-6 and IL-6R were found to stimulate each other’s expression in BM-MSCs.ConclusionsIL-6 and IL-6R levels increase during the osteogenic differentiation of BM-MSCs. These two molecules form a complex to activate the downstream STAT3 signaling pathway, which promotes osteogenic differentiation in BM-MSCs via an autocrine/paracrine feedback loop.Electronic supplementary materialThe online version of this article (10.1186/s13287-017-0766-0) contains supplementary material, which is available to authorized users.

Bone marrow‐derived mesenchymal stem cells (BM‐MSCs) are the main source of osteoblasts in vivo and are widely used in stem cell therapy. Previously, we analyzed long noncoding RNA (lncRNA) expression profiles during BM‐MSC osteogenesis, and further investigation is needed to elucidate how lncRNAs regulate BM‐MSC osteogenesis. Herein, we used customized microarrays to determine lncRNA expression profiles in BM‐MSCs on days 0 and 10 of osteogenic differentiation. In addition, we identified a novel osteogenesis‐associated lncRNA (lncRNA‐OG) that is upregulated during this process. Functional assays showed that lncRNA‐OG significantly promotes BM‐MSC osteogenesis. Mechanistically, lncRNA‐OG interacts with heterogeneous nuclear ribonucleoprotein K (hnRNPK) protein to regulate bone morphogenetic protein signaling pathway activation. Surprisingly, hnRNPK positively regulates lncRNA‐OG transcriptional activity by promoting H3K27 acetylation of the lncRNA‐OG promoter. Therefore, our study revealed a novel lncRNA with a positive function on BM‐MSC osteogenic differentiation and proposed a new interaction between hnRNPK and lncRNA. Stem Cells 2018 Stem Cells 2019;37:270–283

Ankylosing spondylitis (AS) is a chronic inflammatory disease possessing a morbid serum microenvironment with enhanced oxidative stress. Long-term exposure to an oxidative environment usually results in cellular senescence alone with cellular dysfunction. Mesenchymal stem cells (MSCs) are a kind of stem cell possessing strong capabilities for immunoregulation, and senescent MSCs may increase inflammation and participate in AS pathogenesis. The objective of this study was to explore whether and how the oxidative serum environment of AS induces MSC senescence. Here, we found that AS serum facilitated senescence of MSCs in vitro, and articular tissues from AS patients exhibited higher expression levels of the cell cycle arrest-related proteins p53, p21 and p16. Importantly, the levels of advanced oxidative protein products (AOPPs), markers of oxidative stress, were increased in AS serum and positively correlated with the extent of MSC senescence induced by AS serum. Furthermore, MSCs cultured with AS serum showed decreased mitochondrial membrane potential and ATP production together with a reduced oxygen consumption rate. Finally, we discovered that AS serum-induced mitochondrial dysfunction resulted in elevated reactive oxygen species (ROS) in MSCs, and ROS inhibition successfully rescued MSCs from senescence. In conclusion, our data demonstrated that the oxidative serum environment of AS facilitated MSC senescence through inducing mitochondrial dysfunction and excessive ROS production. These results may help elucidate the pathogenesis of AS and provide potential targets for AS treatment.