PKCθ Regulates Pituitary Adenoma Bone Invasion by Activating Osteoclast in NF-κB/IL-1β-Dependent Manner

SIMPLE SUMMARY: Pituitary adenoma (PA) bone invasion seriously affects patient prognosis, and its mechanism needs more investigation. Through exploring the interaction between PA tumor cells and osteoclasts, we have revealed an essential theory of the progression of PA bone invasion. Localized inflammatory environment in PAs was identified as a feature of bone invasion. In this study, we identified PKCθ as a key signal for PA bone invasion, and PAs release IL-1β via the PKCθ/NF-κB/IL-1β pathway to induce monocyte–osteoclast differentiation in a paracrine manner. Meanwhile, we also found that celastrol, as a natural product, can obviously reduce the secretion of IL-1β as well as alleviate the progression of bone invasion, which is promising for clinical application. ABSTRACT: Background: Pituitary adenoma (PA) bone invasion results in adverse outcomes, such as reduced rates of complete surgical resection and biochemical remission as well as increased recurrence rates, though few studies have been conducted. Methods: We collected clinical specimens of PAs for staining and statistical analysis. Evaluation of the ability of PA cells to induce monocyte–osteoclast differentiation by coculturing PA cells with RAW264.7 in vitro. An in vivo model of bone invasion was used to simulate the process of bone erosion and evaluate the effect of different interventions in alleviating bone invasion. Results: We found an overactivation of osteoclasts in bone-invasive PAs and concomitant aggregation of inflammatory factors. Furthermore, activation of PKCθ in PAs was established as a central signaling promoting PA bone invasion through the PKCθ/NF-κB/IL-1β pathway. By inhibiting PKCθ and blocking IL1β, we were able to significantly reverse bone invasion in an in vivo study. Meanwhile, we also found that celastrol, as a natural product, can obviously reduce the secretion of IL-1β as well as alleviate the progression of bone invasion. Conclusions: By activating the PKCθ/NF-κB/IL-1β pathway, pituitary tumors are able to induce monocyte–osteoclast differentiation in a paracrine manner and promote bone invasion, which can be alleviated by celastrol.