骨稳态是一个复杂的过程,其中一些Eph激酶受体及其ephrin配体似乎参与其中。在本研究中,我们通过研究来解决这个问题,在体外和体内,EphB2和EphB3在MSC向骨组织分化中的作用。首先通过RT-qPCR和在特定培养基中培养的MSCs的组织学染色进行评估,而EphB2-/-MSCs主要表达促脂肪转录因子,EphB3-/-MSCs显示丰富的成骨转录本,例如Runx2、Msx2和Sp7。为了阐明潜在的分子机制,我们发现EphB3信号的缺乏改变了分化MSCs的遗传概况,减少BMP信号通路的许多抑制分子和拮抗剂的表达,增加Bmp7表达,一个强大的骨感应器。然后,为了证实EphB3在体内的成骨作用,我们研究了两种诱导骨丢失(卵巢切除术或长期糖皮质激素治疗)小鼠模型的情况。有趣的是,在这两种模型中,WT和EphB2-/-小鼠同样发展疾病,但EphB3-/-小鼠没有表现出典型的骨丢失,也不增加尿Ca2+或血清CTX-1。EphB3-KO小鼠的这种表型可能是由于其骨祖细胞和前成骨细胞的比例明显更高,破骨细胞数量较少,与WT和EphB2-KO小鼠相比。因此,我们得出结论,EphB3作为成骨分化的负调节因子,和它的缺乏防止骨丢失的小鼠接受卵巢切除术或地塞米松治疗。
骨质疏松影响超过2亿人,主要是女人。我们的工作表明EphB3受体限制骨形成,它的缺失可以防止骨质疏松小鼠的骨质流失。在EphB3缺陷小鼠中观察到的骨保护是由于存在更多的骨形成细胞和更少的骨降解细胞。分子上,我们发现当间充质干细胞中没有EphB3时,一些骨促进基因增加,而许多抑制剂减少。因此,这种受体可能成为新疗法的关键靶标,这将有助于改善患有骨骼疾病的人的生活质量。我们很高兴能与广大观众分享我们的发现,包括患者,医疗保健专业人员,研究人员,和生命科学产业。
Bone homeostasis is a complex process in which some Eph kinase receptors and their
ephrin ligands appear to be involved. In the present study, we address this issue by examining, both in vitro and in vivo, the role of EphB2 and EphB3 in mesenchymal stromal/stem cell (MSC) differentiation into bone tissue. This was first evaluated by quantitative reverse transcription PCR (RT-qPCR) and histological staining in MSCs cultured in specific mediums revealing that although EphB2-/- MSCs mainly expressed pro-adipogenic transcription factors, EphB3-/- MSCs showed abundant osteogenic transcripts, such as Runx2, Msx2, and Sp7. To clarify the underlying molecular mechanisms, we found that the lack of EphB3 signaling alters the genetic profile of differentiating MSCs, reducing the expression of many inhibitory molecules and antagonists of the BMP signaling pathway, and increasing Bmp7 expression, a robust bone inductor. Then, to confirm the osteogenic role of EphB3 in vivo, we studied the condition of 2 mouse models of induced bone loss (ovariectomy or long-term glucocorticoid treatment). Interestingly, in both models, both WT and EphB2-/- mice equally developed the disease but EphB3-/- mice did not exhibit the typical bone loss, nor an increase in urine Ca2+ or blood serum CTX-1. This phenotype in EphB3-KO mice could be due to their significantly higher proportions of osteoprogenitor cells and preosteoblasts, and their lower number of osteoclasts, as compared with WT and EphB2-KO mice. Thus, we conclude that EphB3 acts as a negative regulator of the osteogenic differentiation, and its absence prevents bone loss in mice subjected to ovariectomy or dexamethasone treatment.
Osteoporosis affects more than 200 million people, mostly women. Our work shows that the EphB3 receptor restricts bone formation, and its absence prevents bone loss in osteoporotic mice. The bone protection observed in EphB3-deficient mice is due to the presence of more bone-forming cells and fewer bone-degrading cells. Molecularly, we found that when there’s no EphB3 in mesenchymal stem cells, some bone-promoting genes are increased while many inhibitors are reduced. Therefore, this receptor could become a key target for new therapies that would help to improve the quality of life for those suffering from bone diseases. We’re really excited to share our findings with a broad audience, including patients, healthcare professionals, researchers, and the life sciences industry.