Bone matrix-embedded osteocytes and their regulatory function in bone remodelling during rheumatoid arthritis

骨细胞是终末分化的成骨细胞，包裹在钙化骨基质深处的空腔中。这些细胞通过树突高度连接，在骨内形成密集的网络。成骨细胞到骨细胞的转变是一个巨大的表型变化，从一个立方体到一个小的，静止的细胞，有许多长的树突延伸。据报道，在新嵌入的骨细胞中表达的跨膜糖蛋白podoplanin （PDPN，也称为gp38和E11）在树突延伸中起着至关重要的作用，因此似乎对功能性骨细胞网络的形成至关重要。类风湿性关节炎（RA）导致骨重塑不平衡，导致骨丢失，关节功能丧失和永久性残疾。然而，炎性关节炎期间骨细胞及其网络对骨重塑的影响通常是未知的。根据我的初步研究，在RA小鼠模型中，PDPN在骨细胞和受损骨区域的树突中高度表达，我将验证成骨细胞通过形态学和转录变化向骨细胞分化并改变其腔隙网络以适应环境变化的假设。鉴于骨细胞特异性PDPN缺失导致K/BxN血清转移小鼠RA模型中骨侵蚀增强，我假设PDPN对于成骨细胞向骨细胞分化、骨细胞腔隙-小管网络的组织以及炎症条件下骨重塑的调节至关重要。在这项研究中，我将探讨成骨细胞向骨细胞分化的分子机制以及网络变化如何影响RA期间的骨重塑。此外，我将研究炎症性关节炎期间皮质骨中的骨细胞群的功能。这项资助的结果将导致对骨细胞及其对类风湿性关节炎骨重塑的影响的进一步了解，这对未来骨修复治疗策略的发展至关重要。

Osteocytes are terminally differentiated osteoblasts, encysted in cavities deep inside the calcified bone matrix. These cells are highly connected via dendrites to develop a dense network inside the bone. Osteoblast-to-osteocyte transition is a dramatic phenotypic change from a cuboidal to a small, quiescent cell with numerous long dendritic extensions. The transmembrane glycoprotein podoplanin (PDPN, also known as gp38 and E11), expressed in newly embedded osteocytes, has been reported to play a crucial role in dendrite elongation and therefore appears to be essential for a functional osteocyte network formation. Rheumatoid arthritis (RA) leads to imbalanced bone remodelling and results in loss of bone, loss of joint function and permanent disability. However, the impact of osteocytes and their network on bone remodelling during inflammatory arthritis is generally unknown.Based on my preliminary studies that PDPN is highly expressed in osteocytes and dendrites in regions of damaged bone in mouse models of RA I will test the hypothesis that osteoblasts undergo morphological and transcriptional changes to differentiate towards osteocytes and change their lacunar-canalicular network to adapt to environmental changes. Given that osteocyte-specific PDPN deletion leads to enhanced bone erosion in the K/BxN serum transfer mouse model of RA, I hypothesise that PDPN is essential for osteoblast-to-osteocyte differentiation, for the organisation of the osteocyte lacunae-canalicular network and for regulation of bone-remodelling under inflammatory conditions. In this study I will investigate molecular mechanisms how osteoblasts differentiate to osteocytes and how network changes influence bone remodelling during RA. Moreover, I will examine the function of osteocyte populations in cortical bone during inflammatory arthritis. The results of this grant will lead to an increased understanding of osteocytes and their influence on bone remodelling in RA that is critical to enable the development of future therapeutic strategies for bone repair.