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，包囊在钙化骨基质深处的空腔中。这些细胞通过树突高度连接，在骨内形成致密的网络。成骨细胞向成骨细胞的转化是一个戏剧性的表型变化，从一个立方体到一个小的，静止的细胞与许多长的树突状延伸。跨膜糖蛋白podoplanin（PDPN，也称为gp 38和E11），在新嵌入的骨细胞中表达，已被报道在树突伸长中发挥关键作用，因此似乎是功能性骨细胞网络形成所必需的。风湿性关节炎（RA）导致骨重建失衡，导致骨丢失、关节功能丧失和永久性残疾。然而，骨细胞及其网络在炎症性关节炎骨重建中的作用尚不清楚，基于我的初步研究，PDPN在RA小鼠模型中受损骨的骨细胞和树突中高度表达，我将检验成骨细胞经历形态和转录变化以向骨细胞分化并改变其腔隙-小管网络以适应环境变化的假设。鉴于骨细胞特异性PDPN缺失导致增强骨侵蚀的K/BxN血清转移小鼠模型的RA，我假设PDPN是必不可少的成骨细胞分化，骨细胞的腔隙-小管网络的组织和炎症条件下的骨重塑的调节。在本研究中，我将探讨成骨细胞如何分化为骨细胞的分子机制，以及网络变化如何影响RA期间的骨重建。此外，我将检查炎症性关节炎时皮质骨中骨细胞群的功能。这项资助的结果将导致对骨细胞及其对RA骨重塑的影响的更多了解，这对于开发未来的骨修复治疗策略至关重要。

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.