Osteocyte necroptosis drives osteoclastogenesis and alveolar bone resorption during orthodontic tooth movement

Orthodontic tooth movement (OTM) has been described as a bone remodeling process mediated by the expression of various inflammatory cytokines, including tumor necrosis factor-α (TNF-α). Necroptosis is a form of regulated cell death that is mainly induced by TNF-α, leading to the release of damage-associated molecular patterns (DAMPs) that cause inflammation. However, the role of osteocyte necroptosis in regulating osteoclastogenesis during OTM remains unclear. Here, we investigated the effects of osteocyte necroptosis on osteoclastogenesis in a mouse model of OTM. In wild-type mice, osteocyte death was remarkably increased on day 6 after OTM. Transmission electron microscopy identified apoptotic osteocytes, necrotic osteocytes, and empty lacunae based on morphological characteristics. TNF receptor type 1- and 2-deficient (TNFRsKO) mice showed a reduction in osteocyte death on day 6 after OTM. Immunofluorescence staining detected necroptosis markers in osteocytes on the compression side in wild-type OTM mice, whereas such osteocytes were almost undetectable in TNFRsKO OTM mice. Furthermore, the conditioned medium from primary osteocytes undergoing necroptosis significantly enhanced osteoclastogenesis. These findings suggest that TNF-α-induced osteocyte necroptosis enhances osteoclastogenesis and alveolar bone resorption on the compression side during OTM, involving the release of inflammatory factors including DAMPs.