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

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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.