Osteocyte death promotes bone loss
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Excessive osteocyte death can occur in several skeletal diseases, including bone fracture, osteonecrosis and inflammatory bone diseases, and is thought to stimulate osteoclast-mediated bone resorption. However, the molecular mechanisms linking osteocyte death and bone loss have been unclear. New findings suggest that damage-associated molecular patterns (DAMPs) released from dying osteocytes promote osteoclast formation and activity, as well as bone loss, providing a new potential therapeutic avenue for these diseases.

In an inducible osteocyte ablation model diphtheria toxin-mediated osteocyte death resulted in an osteoporotic bone phenotype, reaffirming the link between osteocyte death and bone loss. In terms of cell death, because of their inaccessibility to phagocytic cells, apoptotic osteocytes undergo secondary necrosis, leading to loss of membrane integrity and the release of DAMPs. In the new study, necrotic but not apoptotic splenocytes could induce osteoclast activation in vitro. Furthermore, the supernatant from cultured necrotic osteocytes, had pro-osteoclastogenic effects.

Further analysis showed that osteoclasts can detect and respond to osteocyte necrosis via macrophage-inducible C-type lectin (MINCLE). The bindings of this receptor to DAMPs released by necrotic osteocytes modulates the gene expression network of osteoclasts, skewing their metabolism towards oxidative phosphorylation and promoting osteoclast activation.

Notably, the mRNA expression of CLEC4E (encoding MINCLE) was upregulated in human osteoclasts during osteoclastogenesis in vitro. Further, the bone lesions of patients with osteonecrosis contained an enrichment of MINCLE-positive osteoclasts compared with corresponding healthy bone sections, and in the osteonecrotic lesions, the mRNA expression of CLEC4E positively correlated with the expression of various osteoclast activity markers.

source: https://www.nature.com/articles/s41584-020-0498-x