Abstract
The transmembrane glycoprotein E11/Podoplanin (Pdpn) has been implicated in the initial stages of osteocyte differentiation. However, its precise function and regulatory mechanisms are still unknown. Due to the known embryonic lethality induced by global Pdpn deletion, we have herein explored the effect of bone‐specific Pdpn knockdown on osteocyte form and function in the post‐natal mouse. Extensive skeletal phenotyping of male and female 6‐week‐old Oc‐cre;Pdpn flox/flox (cKO) mice and their Pdpn flox/flox controls (fl/fl) has revealed that Pdpn deletion significantly compromises tibial cortical bone microarchitecture in both sexes, albeit to different extents (p < 0.05). Consistent with this, we observed an increase in stiffness in female cKO mice in comparison to fl/fl mice (p < 0.01). Moreover, analysis of the osteocyte phenotype by phalloidin staining revealed a significant decrease in the dendrite volume (p < 0.001) and length (p < 0.001) in cKO mice in which deletion of Pdpn also modifies the bone anabolic loading response (p < 0.05) in comparison to age‐matched fl/fl mice. Together, these data confirm a regulatory role for Pdpn in osteocyte dendrite formation and as such, in the control of osteocyte function. As the osteocyte dendritic network is known to play vital roles in regulating bone modeling/remodeling, this highlights an essential role for Pdpn in bone homeostasis.
Highlights
Osteocytes are the most numerous of all the cells within bone and are critical regulators of bone structure and function
Osteocytes play an integral role in maintaining bone homeostasis by regulating bone modeling and remodeling through their production of the Wnt
We have previously shown that Pdpn is expressed by early embedding osteocytes, identifying it as a factor which likely contributes to the vital, early stages of osteocyte differentiation (Staines, Prideaux, et al, 2016)
Summary
Osteocytes are the most numerous of all the cells within bone and are critical regulators of bone structure and function. It is known that Pdpn expression in osteocytes is up-regulated in response to mechanical strain in vivo (Zhang et al, 2006) and that increased Pdpn expression, through overexpression in ROS 17/2.6 cells and through stabilization by proteasome inhibitors in MLO-A5 cells, leads to the formation of long dendritic processes (Sprague, Wetterwald, Heinzman, & Atkinson, 1996; Staines, Prideaux, et al, 2016). The formation of these cytoplasmic processes is abrogated in cells pre-treated with siRNA targeted against Pdpn (Zhang et al, 2006). We show that a significant reduction in the expression of Pdpn in mice affects tibial microarchitecture, compromises osteocyte dendrite elongation, and thereby implicating Pdpn as a regulator of both osteocyte form and function
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