Mechanisms of osteocyte induction and regulation of pathogen-induced osteolysis

近年来，人们发现骨细胞是一种多功能细胞，可以作为发育的靶点

Recently, it has been discovered that osteocytes are multifunctional cells that can serve as targets to develop new therapeutics. However, it is not known if osteocytes can be a therapeutic target for osteomyelitis and periodontitis, and if so, which molecular mechanism can be targeted. To our surprise, the magnitude of Pam3CSK4-induced calvarial osteolysis in “osteocyte MYD88-restoration mice” was similar to wild-type animals even though MYD88 was globally deleted in all other cells including immune cells. Subcutaneous inflammatory infiltrates expressed TNF-ɑ, IL-1β, and IL-6 and were rich in neutrophils and macrophages. These findings suggest that osteocyte-derived inflammatory factors are inducing bone resorption and inflammatory cell migration. In vitro, the multiplex analysis showed that Pam3CSK4 stimulates the secretion of CCL2, CCL3, CXCL1, and IL-6 from primary osteocytes. In addition, “osteocyte MYD88-restoration mice” exhibited bacterially-induced periodontitis with alveolar bone loss. Together, our data provide the novel observation suggesting that MYD88 pathway activation of osteocytes alone is sufficient to trigger and develop considerable inflammatory osteolysis. More importantly, these data offer the opportunity to target the activation of immune cells and osteoclast progenitors on the bone surface through the osteocyte and its molecular signaling mechanisms. However, it remains unknown how bacterially-induced osteolysis is controlled by the osteocyte MYD88 pathway when normal (MYD88-sufficient) immune and osteoclast progenitor cells are present. Furthermore, it remains untested if MYD88 is a convincing beneficial drug target for osteolysis due to bone infections in vivo. We hypothesize that A) MYD88-mediated osteocyte inflammation regulates osteolysis in cooperation with normal immune and osteoclast progenitor cells and B) blocking the osteocyte MYD88 pathway by MYD88 inhibitors suppresses osteocyte-derived inflammatory mediators, resulting in the protection against and treatment of osteolysis due to bone infections. To test the hypotheses, the following specific aims are proposed: Aim 1) Determine the impact of the deletion of osteocyte MYD88 function on calvarial osteolysis. Aim 2) Determine the impact of the deletion of osteocyte MYD88 function on P.gingivalis-induced periodontitis. Aim 3) Determine whether and how pharmacological inhibition of osteocyte MYD88 can be effective for treating osteolysis due to bacterial inflammation. We propose that the osteocytes play a role in bacterially-induced osteolysis conditions and understanding the important role could lead to new therapeutics. We will uncover a novel and essential role of osteocytes as inflammatory cells that regulate immune cell activation and osteoclast formation. The new aspect of osteocytes will provide new therapeutic strategies for osteomyelitis and periodontitis.