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Endothelial cells are spatially close to osteoblasts and regulate osteogenesis. Moreover, they are sensitive to mechanical stimuli, therefore we hypothesized that they are implicated in the regulation of bone metabolism during unloading. Conditioned media from endothelial cells (EC-CM) subjected to simulated microgravity (0.08 g  and 0.008 g ) increased osteoblast proliferation and decreased their differentiation compared to unit gravity (1 g ) EC-CM. Microgravity-EC-CM increased the expression of osteoblast  Rankl  and subsequent osteoclastogenesis, and induced the osteoblast de-differentiating factor, Lipocalin 2 (Lcn2), whose downregulation recovered osteoblast activity, decreased  Rankl  expression and reduced osteoclastogenesis. Microgravity - EC-CM enhanced osteoblast  NO-Synthase2 (NOS2 ) and  CycloOXygenase2 (COX2 ) expression. Inhibition of NOS2 or NO signaling reduced osteoblast proliferation and rescued their differentiation. Nuclear translocation of the Lcn2/NOS2 transcription factor, NF-κB, occurred in microgravity-EC-CM-treated osteoblasts and in microgravity-treated endothelial cells, alongside high expression of the NF-κB activator, IL-1β. IL-1β depletion and NF-κB inhibition reduced osteoblast proliferation and rescued differentiation.  Lcn2  and  NOS2  were incremented in  ex vivo  calvarias cultured in microgravity - EC-CM, and  in vivo  tibias and calvarias injected with microgravity-EC-CM. Furthermore, tibias of botulin A toxin-treated and tail-suspended mice, which featured unloading and decreased bone mass, showed higher expression of  IL-1β, Lcn2  and  Nos2 , suggesting their pathophysiologic involvement in endothelial cell-osteoblast crosstalk.

Interleukin-1β, lipocalin 2 and nitric oxide synthase 2 are mechano-responsive mediators of mouse and human endothelial cell-osteoblast crosstalk